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e208f8da207bd1e7e86660d90f5c9df2b1d36962 | wikidoc | Cri du chat | Cri du chat
# Overview
Cri du chat syndrome (French for Cry or call of the cat refering to the specific cry of the child), also called deletion 5p syndrome,5p minus or Le Jeune’s syndrome, is a rare genetic disorder due to a missing portion of chromosome 5. It was first described by Jérôme Lejeune in 1963. The condition affects an estimated 1 in 20,000 to 50,000 live births. The disorder is found in people of all ethnic backgrounds and is slightly more common in females.
# Genetics
Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5. Approximately 80% of cases results from a sporadic de novo deletion, while about 10-15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome. The phenotypes in these individuals may be more severe than in those with isolated monosomy of 5p because of this additional trisomic portion of the genome.
Most cases involve terminal deletions with 30-60% loss of 5p material. Fewer than 10% of cases have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations).The deleted chromosome 5 is paternal in origin in about 80% of the cases.
Loss of a small region in band 5p15.2 (cri-du-chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's etiology. Two genes, Semaphorine F (SEMAF) and delta-catenine (CTNND2), which have been mapped to the critical regions are potentially involved in cerebral development and its deletion may be associated in CdCS patients. Also the deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 should contribute to the phenotypic changes in CdCS.
Although the size of the deletion varies, a deletion at region 5p15.3 is responsible for the unique cry and deletion at the critical region of 5p15.2 for the other features. The deletion is of paternal origin in about 80% of cases in which the syndrome is de novo.
# Signs and symptoms
The syndrome gets its name from the characteristic cry of infants born with the disorder. The infant sounds just like a meowing kitten, due to problems with the larynx and nervous system. This cry identifies the syndrome. About 1/3 of children lose the cry by age 2. Other symptoms of cri-du-chat syndrome may include:
- feeding problems because of difficulty swallowing and sucking,
- low birth weight and poor growth,
- severe cognitive, speech, and motor delays,
- behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements,
- unusual facial features which may change over time.
In addition, common findings include low birth weight, hypotonia, microcephaly, growth retardation, a round face with full cheeks, hypertelorism, epicanthal folds, down-slanting palpebral fissures, strabismus, flat nasal bridge, down-turned mouth, micrognathia, low-set ears, short fingers, single palmar creases, and cardiac defects (eg, ventricular septal defect , atrial septal defect , patent ductus arteriosus , tetralogy of Fallot).
Less frequently encountered findings include cleft lip and palate, preauricular tags and fistulas, thymic dysplasia, gut malrotation, megacolon, inguinal hernia, dislocated hips, cryptorchidism, hypospadias, rare renal malformations (eg, horseshoe kidneys, renal ectopia or agenesis, hydronephrosis), clinodactyly of the fifth fingers, talipes equinovarus, pes planus, syndactyly of the second and third fingers and toes, oligosyndactyly, and hyperextensible joints.
Late childhood and adolescence findings include severe mental retardation, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion, and scoliosis.
Affected females reach puberty, develop secondary sex characteristics, and menstruate at the usual time. The genital tract is usually normal in females except for a report of a bicornuate uterus.
In males, testes are often small, but spermatogenesis is thought to be normal.
Dermatoglyphics: Transverse flexion creases, distal axial triradius, increased whorls and arches on digits, single line on the palm of the hand (simian crease).
# Diagnosis
Diagnosis is based on the distinctive cry and accompanying physical problems.
Genetic testing can confirm the diagnosis. Molecular cytogenetic studies using fluorescent in situ hybridization (FISH) allow the diagnosis to be made in patients with very small deletions. FISH uses genetic markers that have been precisely localized to the area of interest. The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions is indicative of monosomy for that chromosomal region.
Genetic counseling and genetic testing may be offered to families with cri du chat syndrome. | Cri du chat
For patient information click here
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cri du chat syndrome (French for Cry or call of the cat refering to the specific cry of the child), also called deletion 5p syndrome,5p minus or Le Jeune’s syndrome, is a rare genetic disorder due to a missing portion of chromosome 5. It was first described by Jérôme Lejeune in 1963.[1] The condition affects an estimated 1 in 20,000 to 50,000 live births. The disorder is found in people of all ethnic backgrounds and is slightly more common in females.
# Genetics
Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5. Approximately 80% of cases results from a sporadic de novo deletion, while about 10-15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome. The phenotypes in these individuals may be more severe than in those with isolated monosomy of 5p because of this additional trisomic portion of the genome.
Most cases involve terminal deletions with 30-60% loss of 5p material. Fewer than 10% of cases have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations).The deleted chromosome 5 is paternal in origin in about 80% of the cases.
Loss of a small region in band 5p15.2 (cri-du-chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's etiology. Two genes, Semaphorine F (SEMAF) and delta-catenine (CTNND2), which have been mapped to the critical regions are potentially involved in cerebral development and its deletion may be associated in CdCS patients. Also the deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 should contribute to the phenotypic changes in CdCS.
Although the size of the deletion varies, a deletion at region 5p15.3 is responsible for the unique cry and deletion at the critical region of 5p15.2 for the other features. The deletion is of paternal origin in about 80% of cases in which the syndrome is de novo.
# Signs and symptoms
The syndrome gets its name from the characteristic cry of infants born with the disorder. The infant sounds just like a meowing kitten, due to problems with the larynx and nervous system. This cry identifies the syndrome. About 1/3 of children lose the cry by age 2. Other symptoms of cri-du-chat syndrome may include:
- feeding problems because of difficulty swallowing and sucking,
- low birth weight and poor growth,
- severe cognitive, speech, and motor delays,
- behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements,
- unusual facial features which may change over time.
In addition, common findings include low birth weight, hypotonia, microcephaly, growth retardation, a round face with full cheeks, hypertelorism, epicanthal folds, down-slanting palpebral fissures, strabismus, flat nasal bridge, down-turned mouth, micrognathia, low-set ears, short fingers, single palmar creases, and cardiac defects (eg, ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot).
Less frequently encountered findings include cleft lip and palate, preauricular tags and fistulas, thymic dysplasia, gut malrotation, megacolon, inguinal hernia, dislocated hips, cryptorchidism, hypospadias, rare renal malformations (eg, horseshoe kidneys, renal ectopia or agenesis, hydronephrosis), clinodactyly of the fifth fingers, talipes equinovarus, pes planus, syndactyly of the second and third fingers and toes, oligosyndactyly, and hyperextensible joints.
Late childhood and adolescence findings include severe mental retardation, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion, and scoliosis.
Affected females reach puberty, develop secondary sex characteristics, and menstruate at the usual time. The genital tract is usually normal in females except for a report of a bicornuate uterus.
In males, testes are often small, but spermatogenesis is thought to be normal.
Dermatoglyphics: Transverse flexion creases, distal axial triradius, increased whorls and arches on digits, single line on the palm of the hand (simian crease).
# Diagnosis
Diagnosis is based on the distinctive cry and accompanying physical problems.
Genetic testing can confirm the diagnosis. Molecular cytogenetic studies using fluorescent in situ hybridization (FISH) allow the diagnosis to be made in patients with very small deletions. FISH uses genetic markers that have been precisely localized to the area of interest. The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions is indicative of monosomy for that chromosomal region.
Genetic counseling and genetic testing may be offered to families with cri du chat syndrome. | https://www.wikidoc.org/index.php/5p-_Syndrome | |
6efd063dbd9adeb97b1958d4bf4b2315b677574d | wikidoc | 7+3 regimen | 7+3 regimen
# Overview
"7+3" in the context of chemotherapy is an acronym for a chemotherapy regimen that is most often used today (as of 2014) as first-line induction therapy (to induce remission) in acute myelogenous leukemia, excluding the acute promyelocytic leukemia form, which is better treated with ATRA and/or arsenic trioxide and requires less chemotherapy (if requires it at all, which is not always the case).
The name "7+3" comes from the duration of chemotherapy course, which consists of 7 days of standard-dose cytarabine, and 3 days of an anthracycline antibiotic or an anthracenedione, most often daunorubicin (can be substituted for doxorubicin or idarubicin or mitoxantrone).
# Regimen
## Standard-dose cytarabine plus daunorubicin
77 days of Cytarabine
33 days of Daunorubicin
## Standard-dose cytarabine plus idarubicin
77 days of Cytarabine
33 days of Idarubicin
## Standard-dose cytarabine plus mitoxantrone
77 days of Cytarabine
33 days of Mitoxantrone
## Intensified versions
There were attempts to intensify the "7+3" regimen in order to try to improve its efficacy. Attempts were made to prolong the course (cytarabine for 10 days instead of 7, or daunorubicin/idarubicin for 4–5 days instead of 3).
On the other hand, there were attempts to minimize the toxicity of the regimen by reducing the dose or the duration of the course. But this proved to compromise the efficacy of the regimen.
The addition of vinca alkaloids (vincristine or vinblastine) to the "7+3" regimen, which addition was quite popular in AML in old times (when the biology of AML and the differences between AML and ALL was poorly understood) proved to be harmful in AML, lowering the chance of the patient to get remission. This is because vinca alkaloids are rapidly deactivated in myeloid cells by their enzyme myeloperoxidase. So the vinca alkaloids do much more damage to the lymphoid cell lines (including the T-cell lines responsible for antileukemic immunity) than to the myeloid cell lines. Moreover, vinca alkaloids in the context of AML cause AML cells to undergo a cell cycle arrest in the phase that renders those cells less sensitive to cytarabine and anthracyclines.
Addition of glucocorticoids (like prednisolone) or methotrexate or alkylating drugs (like cyclophosphamide or melphalan) to the "7+3" regimen is also of no benefit in AML.
The addition of etoposide to the standard "7+3" regimen is sometimes of benefit in poor-risk patients (many of which are primary refractory to standard "7+3" induction regimens). It gave rise to the so-called ADE (or DAE = DA + etoposide) induction regimen in AML. The ADE induction (unlike, say, combinations of 7+3 with vinca alkaloids or prednisolone) is still sometimes used, especially in poor-risk AML patients.
The addition of thioguanine gave rise to the DAT regimen, and the addition of 6-mercaptopurine gave rise to the DAM regimen.
# Indications
- Acute myelogenous leukemia, excluding the acute promyelocytic leukemia | 7+3 regimen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Overview
"7+3" in the context of chemotherapy is an acronym for a chemotherapy regimen that is most often used today (as of 2014) as first-line induction therapy (to induce remission) in acute myelogenous leukemia,[1][2] excluding the acute promyelocytic leukemia form, which is better treated with ATRA and/or arsenic trioxide and requires less chemotherapy (if requires it at all, which is not always the case).
The name "7+3" comes from the duration of chemotherapy course, which consists of 7 days of standard-dose cytarabine, and 3 days of an anthracycline antibiotic or an anthracenedione, most often daunorubicin (can be substituted for doxorubicin or idarubicin or mitoxantrone).
# Regimen
## Standard-dose cytarabine plus daunorubicin
77 days of Cytarabine
33 days of Daunorubicin
## Standard-dose cytarabine plus idarubicin
77 days of Cytarabine
33 days of Idarubicin
## Standard-dose cytarabine plus mitoxantrone
77 days of Cytarabine
33 days of Mitoxantrone
## Intensified versions
There were attempts to intensify the "7+3" regimen in order to try to improve its efficacy. Attempts were made to prolong the course (cytarabine for 10 days instead of 7, or daunorubicin/idarubicin for 4–5 days instead of 3).
On the other hand, there were attempts to minimize the toxicity of the regimen by reducing the dose or the duration of the course. But this proved to compromise the efficacy of the regimen.
The addition of vinca alkaloids (vincristine or vinblastine) to the "7+3" regimen, which addition was quite popular in AML in old times (when the biology of AML and the differences between AML and ALL was poorly understood) proved to be harmful in AML, lowering the chance of the patient to get remission. This is because vinca alkaloids are rapidly deactivated in myeloid cells by their enzyme myeloperoxidase. So the vinca alkaloids do much more damage to the lymphoid cell lines (including the T-cell lines responsible for antileukemic immunity) than to the myeloid cell lines. Moreover, vinca alkaloids in the context of AML cause AML cells to undergo a cell cycle arrest in the phase that renders those cells less sensitive to cytarabine and anthracyclines.
Addition of glucocorticoids (like prednisolone) or methotrexate or alkylating drugs (like cyclophosphamide or melphalan) to the "7+3" regimen is also of no benefit in AML.
The addition of etoposide to the standard "7+3" regimen is sometimes of benefit in poor-risk patients (many of which are primary refractory to standard "7+3" induction regimens). It gave rise to the so-called ADE (or DAE = DA + etoposide) induction regimen in AML. The ADE induction (unlike, say, combinations of 7+3 with vinca alkaloids or prednisolone) is still sometimes used, especially in poor-risk AML patients.
The addition of thioguanine gave rise to the DAT regimen, and the addition of 6-mercaptopurine gave rise to the DAM regimen.
# Indications
- Acute myelogenous leukemia, excluding the acute promyelocytic leukemia[3][4] | https://www.wikidoc.org/index.php/7%2B3 | |
67d51099f46bd331fc75dee65990c53c008f9b91 | wikidoc | 80 Lead EKG | 80 Lead EKG
# Overview
ST elevation myocardial infarction (STEMI) is the most serious form of heart attack. The ST segments elevate because the full thickness of heart muscle is injured (transmural injury). This full thickness injury and ST elevation is the result of a total occlusion of a coronary artery. Some STEMIs, particularly those involving the posterior or back surface of the heart, may be missed by the present traditional system of placing a limited number of leads on the front of the chest.
In contrast to the 12 leads of data and the limited anterior or front view of the heart from a traditional EKG, an 80 lead EKG (such as the PRIME ECG®) utilizes 80 leads placed on both the front and back of the patient to analyze a 360-degree spatial view of the heart. This new technology may allow the more rapid and accurate detection of STEMI and thereby potentially speed the delivery of care.
# Display of 80 Lead EKG Data
Analysis is performed on a computer selected representative beat. ST-segment elevation and depression are translated into colors (red = elevation, blue = depression) and displayed against a 3 dimensional torso image for physician review. These images allow for rapid pattern recognition that identifies problem areas that correlate with regions of ischemia or infarction. This use of graphic imaging allows the physician to quickly focus on specific ECG morphology that contains the most valuable diagnostic information without having to expend time exploring data from all 80 leads.
System software facilitates examination of the actual ECG trace for each of the 80 recordings. The user places a cursor over the suspect area and a pop-up window reveals the underlying electrode tracing and provides the value of elevation or depression at that lead.
# Sensitivity and Specificity of 80 Lead EKGs
Ten years of clinical data and in-hospital experience have demonstrated an increase in sensitivity over the 12 lead EKG in the range of 18% with no loss in specificity. As a result, there is the potential to detect up to 40% more ST Elevation MIs (serious heart attacks) than the traditional 12-lead EKG.
# Delays in Diagnosing ST Elevation MI with Traditional 12 Lead Systems
Registry data from the National Registry of Myocardial Infarction (NRMI), CRUSADE and GRACE have demonstrated that there are significant opportunities for improvement in door-to-balloon time and door-to-needle time in the management of serious heart attacks (STEMI). The 80 lead ECG may provide a technological advance that would speed the correct diagnosis of ST elevation MI. A substantial number of patients have a non-diagnostic 12-lead and these patients may wait for extended periods in the emergency room pending the results of tests that measure enzymes released into the bloodstream (biomarkers) to diagnose a heart attack.
# The Potential to Miss the Diagnosis of STEMI Using the Traditional 12 Lead EKG
Heart attacks involving the back side of the heart may cause ST depression rather than ST elevation (STEMI) becuase the pattern of electrical injury is reversed on the traditional 12 lead EKG. One of These patients may currently be receiving less aggressive care because of a diagnosis of non-ST-elevation MI (NSTEMI) based on ST-depression, which may in fact be ST-elevation in a portion of the heart not visible with the 12 lead. Assuming approximately 20-30% of diagnosed MI patients are now diagnosed as STEMI patients and 70-80% are diagnosed as NSTEMI, the PRIME data would indicate that approximately 1 in every 3 patients may in fact be at a higher risk which would make them suitable for more aggressive care.
# Example of a STEMI Missed on 12 Lead EKG Detected on 80 Lead EKG
Be sure to click on the images below to enlarge them
Shown below is the 12 lead EKG in a patient that presented with substernal chest pain. Note that there are non diagnostic changes. There is no evidence of ST segment elevation.
- 80 lead EKG.
An 80 lead EKG vest was then placed. Shown to the right are the 80 EKG lead tracings displayed individually. The anterior leads are displayed on the left hand side. The posterior or back of the heart leads are displayed on the right hand side of the figure. For instance lead 68 shows ST elevation. Posterior and right-sided leads reveal ST-elevation, where the 12-lead was silent.
In order to display the data in a more clinically relevant and intuitive fashion, the area of injury is shown in red on the patient's back, corresponding to the inferior-posterior location of the MI.
# Clinical Application of the 80 Lead EKG
One 80 lead system, the PRIME ECG ® system, is currently approved for use in the US under a 510k. | 80 Lead EKG
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
ST elevation myocardial infarction (STEMI) is the most serious form of heart attack. The ST segments elevate because the full thickness of heart muscle is injured (transmural injury). This full thickness injury and ST elevation is the result of a total occlusion of a coronary artery. Some STEMIs, particularly those involving the posterior or back surface of the heart, may be missed by the present traditional system of placing a limited number of leads on the front of the chest.
In contrast to the 12 leads of data and the limited anterior or front view of the heart from a traditional EKG, an 80 lead EKG (such as the PRIME ECG®) utilizes 80 leads placed on both the front and back of the patient to analyze a 360-degree spatial view of the heart. This new technology may allow the more rapid and accurate detection of STEMI and thereby potentially speed the delivery of care.
# Display of 80 Lead EKG Data
Analysis is performed on a computer selected representative beat. ST-segment elevation and depression are translated into colors (red = elevation, blue = depression) and displayed against a 3 dimensional torso image for physician review. These images allow for rapid pattern recognition that identifies problem areas that correlate with regions of ischemia or infarction. This use of graphic imaging allows the physician to quickly focus on specific ECG morphology that contains the most valuable diagnostic information without having to expend time exploring data from all 80 leads.
System software facilitates examination of the actual ECG trace for each of the 80 recordings. The user places a cursor over the suspect area and a pop-up window reveals the underlying electrode tracing and provides the value of elevation or depression at that lead.
# Sensitivity and Specificity of 80 Lead EKGs
Ten years of clinical data and in-hospital experience have demonstrated an increase in sensitivity over the 12 lead EKG in the range of 18% with no loss in specificity. As a result, there is the potential to detect up to 40% more ST Elevation MIs (serious heart attacks) than the traditional 12-lead EKG.
# Delays in Diagnosing ST Elevation MI with Traditional 12 Lead Systems
Registry data from the National Registry of Myocardial Infarction (NRMI), CRUSADE and GRACE have demonstrated that there are significant opportunities for improvement in door-to-balloon time and door-to-needle time in the management of serious heart attacks (STEMI). The 80 lead ECG may provide a technological advance that would speed the correct diagnosis of ST elevation MI. A substantial number of patients have a non-diagnostic 12-lead and these patients may wait for extended periods in the emergency room pending the results of tests that measure enzymes released into the bloodstream (biomarkers) to diagnose a heart attack.
# The Potential to Miss the Diagnosis of STEMI Using the Traditional 12 Lead EKG
Heart attacks involving the back side of the heart may cause ST depression rather than ST elevation (STEMI) becuase the pattern of electrical injury is reversed on the traditional 12 lead EKG. One of These patients may currently be receiving less aggressive care because of a diagnosis of non-ST-elevation MI (NSTEMI) based on ST-depression, which may in fact be ST-elevation in a portion of the heart not visible with the 12 lead. Assuming approximately 20-30% of diagnosed MI patients are now diagnosed as STEMI patients and 70-80% are diagnosed as NSTEMI, the PRIME data would indicate that approximately 1 in every 3 patients may in fact be at a higher risk which would make them suitable for more aggressive care.
# Example of a STEMI Missed on 12 Lead EKG Detected on 80 Lead EKG
Be sure to click on the images below to enlarge them
Shown below is the 12 lead EKG in a patient that presented with substernal chest pain. Note that there are non diagnostic changes. There is no evidence of ST segment elevation.
- 80 lead EKG.
An 80 lead EKG vest was then placed. Shown to the right are the 80 EKG lead tracings displayed individually. The anterior leads are displayed on the left hand side. The posterior or back of the heart leads are displayed on the right hand side of the figure. For instance lead 68 shows ST elevation. Posterior and right-sided leads reveal ST-elevation, where the 12-lead was silent.
In order to display the data in a more clinically relevant and intuitive fashion, the area of injury is shown in red on the patient's back, corresponding to the inferior-posterior location of the MI.
# Clinical Application of the 80 Lead EKG
One 80 lead system, the PRIME ECG ® system, is currently approved for use in the US under a 510k. | https://www.wikidoc.org/index.php/80_Lead_ECG | |
24d80f3fcbbd914eb25c0de3764181814627281e | wikidoc | AAMP (gene) | AAMP (gene)
Angio-associated, migratory cell protein, also known as AAMP, is a protein which in humans is encoded by the AAMP gene. This protein has been conserved in evolution and is so common to many mammals. and it also has a yeast homolog which is the protein YCR072c.
# Localisation
The gene is located on the second human chromosome, near the end of the chromosome's arm (2q35), between the codons 85-87 and 1387-1389. It contains 6042 bp and 11 exons When transcribed, it gives a 1859 bp mRNA.
. The vascular endothelial growth factor is a promoting factor of the protein synthesis and localisation in the different parts of the cells.
The protein's expression is higher in the intracellular than in the extracellular space.
# Function
The gene product is an immunoglobulin-type protein of 434 amino acids and 49 kDa. It is found to be expressed strongly in the cytosol of endothelial cells, cytotrophoblasts, and poorly differentiated colon adenocarcinoma cells found in lymphatics and has been observed at the luminal edges of endometrial cells and in the extracellular environment of vascular-associated mesenchymal cells.
The protein contains a WD40 domain which permits multi-proteins complexes formation and a heparin-binding domain which mediates heparin-sensitive cell adhesion.
AAMP helps to regulate vascular endothelial cell migration regulation and angiogenesis, with other signaling pathway like RhoA/Rho-kinase signaling.
A malfunction can therefore lead to different diseases (see Associated diseases). For example, in the smooth muscle cells, if AAMP is overexpressed, it activates RhoA, which activates Rho-kinase (this one generates GTP) and it finally leads to increased smooth muscle cell migration and division, causing atherosclerosis and restenosis.
# Associated diseases
Note : In all these diseases we can observe the expression of the AAMP gene. This one can either remain stable, increase or decrease depending on the disease.
List of the diseases : gastrointestinal stromal tumor (GIST) (for this disease and the ductal carcinomas, the expression levels are to correlate with necrosis in situ), myeloid leukemia (chronic (CML) and acute (AML) forms), lymphoma, breast cancer, glial brain tumors, colon neoplasia, epidermoid carcinoma, cervical cancer, ovarian cancer, papillary thyroid cancer, pulmonary cancer, atherosclerosis, restenosis. | AAMP (gene)
Angio-associated, migratory cell protein, also known as AAMP, is a protein which in humans is encoded by the AAMP gene.[1] This protein has been conserved in evolution and is so common to many mammals. [2] and it also has a yeast homolog which is the protein YCR072c.[3][4]
# Localisation
The gene is located on the second human chromosome, near the end of the chromosome's arm (2q35), between the codons 85-87 and 1387-1389. It contains 6042 bp and 11 exons[2] When transcribed, it gives a 1859 bp mRNA.
.[2] The vascular endothelial growth factor is a promoting factor of the protein synthesis and localisation in the different parts of the cells.[5]
The protein's expression is higher in the intracellular than in the extracellular space.[3]
# Function
The gene product is an immunoglobulin-type protein of 434 amino acids and 49 kDa.[2] It is found to be expressed strongly in the cytosol of endothelial cells, cytotrophoblasts, and poorly differentiated colon adenocarcinoma cells found in lymphatics and has been observed at the luminal edges of endometrial cells and in the extracellular environment of vascular-associated mesenchymal cells.[2]
The protein contains a WD40 domain which permits multi-proteins complexes formation [2] and a heparin-binding domain which mediates heparin-sensitive cell adhesion.[1]
AAMP helps to regulate vascular endothelial cell migration regulation and angiogenesis, with other signaling pathway like RhoA/Rho-kinase signaling.[5]
A malfunction can therefore lead to different diseases (see Associated diseases). For example, in the smooth muscle cells, if AAMP is overexpressed, it activates RhoA, which activates Rho-kinase (this one generates GTP) and it finally leads to increased smooth muscle cell migration and division, causing atherosclerosis and restenosis.[6]
# Associated diseases
Note : In all these diseases[2] we can observe the expression of the AAMP gene. This one can either remain stable, increase or decrease depending on the disease.
List of the diseases : gastrointestinal stromal tumor (GIST) (for this disease and the ductal carcinomas, the expression levels are to correlate with necrosis in situ[7]), myeloid leukemia (chronic (CML) and acute (AML) forms), lymphoma, breast cancer, glial brain tumors, colon neoplasia, epidermoid carcinoma, cervical cancer, ovarian cancer, papillary thyroid cancer, pulmonary cancer, atherosclerosis, restenosis. | https://www.wikidoc.org/index.php/AAMP_(gene) | |
3a19a8d2584c7b628fda2904024ada8c5c1bccc8 | wikidoc | ABCD rating | ABCD rating
Steven C. Campbell, M.D., Ph.D.
# Overview
ABCD rating, also called the Jewett staging system or the Whitmore-Jewett staging system, is a staging system for prostate cancer that uses the letters A, B, C, and D.
- “A” and “B” refer to cancer that is confined to the prostate.
- “C” refers to cancer that has grown out of the prostate but has not spread to lymph nodes or other places in the body.
- “D” refers to cancer that has spread to lymph nodes or to other places in the body.
ABCD rating can also refer to a test for the warning signs of melanoma, usually found in moles.
- "A" Asymmetry
- "B" Border Irregularity
- "C" Color. If the patch is multi-colored, it may be melanoma.
- "D" Diameter. If the patch is wider than 6 millimeters, it may be melanoma. | ABCD rating
Steven C. Campbell, M.D., Ph.D.
# Overview
ABCD rating, also called the Jewett staging system or the Whitmore-Jewett staging system, is a staging system for prostate cancer that uses the letters A, B, C, and D.
- “A” and “B” refer to cancer that is confined to the prostate.
- “C” refers to cancer that has grown out of the prostate but has not spread to lymph nodes or other places in the body.
- “D” refers to cancer that has spread to lymph nodes or to other places in the body.
ABCD rating can also refer to a test for the warning signs of melanoma, usually found in moles.
- "A" Asymmetry
- "B" Border Irregularity
- "C" Color. If the patch is multi-colored, it may be melanoma.
- "D" Diameter. If the patch is wider than 6 millimeters, it may be melanoma. | https://www.wikidoc.org/index.php/ABCD_rating | |
e2f90ecd7619847a057618f45770dff3adb02672 | wikidoc | ADNP (gene) | ADNP (gene)
Activity-dependent neuroprotector homeobox is a protein that in humans is encoded by the ADNP gene.
# Function
Vasoactive intestinal peptide is a neuroprotective factor that has a stimulatory effect on the growth of some tumor cells and an inhibitory effect on others. This gene encodes a protein that is upregulated by vasoactive intestinal peptide and may be involved in its stimulatory effect on certain tumor cells. The encoded protein contains one homeobox and nine zinc finger domains, suggesting that it functions as a transcription factor. This gene is also upregulated in normal proliferative tissues. Finally, the encoded protein may increase the viability of certain cell types through modulation of p53 activity. Alternatively spliced transcript variants encoding the same protein have been described.
# Clinical aspects
Mutations in ADNP cause autism . | ADNP (gene)
Activity-dependent neuroprotector homeobox is a protein that in humans is encoded by the ADNP gene.[1]
# Function
Vasoactive intestinal peptide is a neuroprotective factor that has a stimulatory effect on the growth of some tumor cells and an inhibitory effect on others. This gene encodes a protein that is upregulated by vasoactive intestinal peptide and may be involved in its stimulatory effect on certain tumor cells. The encoded protein contains one homeobox and nine zinc finger domains, suggesting that it functions as a transcription factor. This gene is also upregulated in normal proliferative tissues. Finally, the encoded protein may increase the viability of certain cell types through modulation of p53 activity. Alternatively spliced transcript variants encoding the same protein have been described.[1]
# Clinical aspects
Mutations in ADNP cause autism .[2] | https://www.wikidoc.org/index.php/ADNP_(gene) | |
e7b724aada81ab345a0faa55a8b3060bfa1d309b | wikidoc | Coombs test | Coombs test
For the WikiPatient page for this topic, click here
# Overview
Coombs test (also known as Coombs' test, antiglobulin test or AGT) refers to two clinical blood tests used in immunohematology and immunology.
The two Coombs tests are:
- Direct Coombs test (also known as direct antiglobulin test or DAT).
- Indirect Coombs test (also known as indirect antiglobulin test or IAT).
The direct Coombs test is used to detect red blood cells sensitized with igG alloantibody, IgG autoantibody, and complement proteins. It detects antibodies bound to the surface of red blood cells in vivo. The red blood cells (RBCs) are washed (removing the patient's own plasma) and then incubated with antihuman globulin (also known as "Coombs reagent"). If this produces agglutination of the RBCs, the direct Coombs test is positive.
The indirect Coombs test is used in prenatal testing of pregnant women, and in testing blood prior to a blood transfusion. It detects antibodies against RBCs that are present unbound in the patient's serum. In this case, serum is extracted from the blood, and the serum is incubated with RBCs of known antigenicity. If agglutination occurs, the indirect Coombs test is positive.
# Mechanism
The two Coombs tests are based on the fact that anti-human antibodies, which are produced by immunizing non-human species with human serum, will bind to human antibodies, commonly IgG or IgM. Animal anti-human antibodies will also bind to human antibodies that may be fixed onto antigens on the surface of red blood cells (also referred to as RBCs), and in the appropriate test tube conditions this can lead to agglutination of RBCs. The phenomenon of agglutination of RBCs is important here, because the resulting clumping of RBCs can be visualised; when clumping is seen the test is positive and when clumping is not seen the test is negative.
Common clinical uses of the Coombs test include the preparation of blood for transfusion in cross-matching, screening for atypical antibodies in the blood plasma of pregnant women as part of antenatal care, and detection of antibodies for the diagnosis of immune-mediated haemolytic anaemias.
Coombs tests are done on serum from venous blood samples which are taken from patients by venipuncture. The venous blood is taken to a laboratory (or blood bank), where trained scientific technical staff do the Coombs tests. The clinical significance of the result is assessed by the physician who requested the Coombs test, perhaps with assistance from a laboratory-based hematologist.
# Direct Coombs Test
The direct Coombs test (also known as the direct antiglobulin test or DAT) is used to detect if antibodies or complement system factors have bound to RBC surface antigens in vivo. The DAT is not currently required for pre-transfusion testing but may be included by some laboratories.
## Examples of diseases that give a positive direct Coombs test
The direct Coombs test is used clinically when immune-mediated hemolytic anemia (antibody-mediated destruction of RBCs) is suspected. A positive Coombs test indicates that an immune mechanism is attacking the patient's own RBC's. This mechanism could be autoimmunity, alloimmunity or a drug-induced immune-mediated mechanism.
### Examples of alloimmune hemolysis
- Hemolytic disease of the newborn (also known as HDN or erythroblastosis fetalis)
Rhesus D hemolytic disease of the newborn (also known as Rh disease)
ABO hemolytic disease of the newborn (the indirect Coombs test may only be weakly positive)
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Rhesus D hemolytic disease of the newborn (also known as Rh disease)
- ABO hemolytic disease of the newborn (the indirect Coombs test may only be weakly positive)
- Anti-Kell hemolytic disease of the newborn
- Rhesus c hemolytic disease of the newborn
- Rhesus E hemolytic disease of the newborn
- Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Alloimmune hemolytic transfusion reactions
### Examples of autoimmune hemolysis
- Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus
Evans' syndrome (antiplatelet antibodies and hemolytic antibodies)
- Idiopathic
- Systemic lupus erythematosus
- Evans' syndrome (antiplatelet antibodies and hemolytic antibodies)
- Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
- Idiopathic cold hemagglutinin syndrome
- Infectious mononucleosis
- Paroxysmal cold hemoglobinuria (rare)
### Drug-induced immune-mediated haemolysis
- Cefepime
- Ceftazidime
- Methyldopa (IgG mediated type II hypersensitivity)
- Penicillin (high dose)
- Quinidine (IgM mediated activation of classical complement pathway and Membrane attack complex, MAC)
(A memory device to remember that the DAT tests the RBCs and is used to test infants for haemolytic disease of the newborn is:
Rh Disease; R = RBCs, D = DAT.)
## Laboratory method
The patient's red blood cells (RBCs) are washed (removing the patient's own serum) and then incubated with antihuman globulin (also known as Coombs reagent). If immunoglobulin or complement factors have been fixed on to the RBC surface in-vivo, the antihuman globulin will agglutinate the RBCs and the direct Coombs test will be positive. (A visual representation of a positive direct Coombs test is shown in the upper half of the schematic).
# Indirect Coombs test
The indirect Coombs test (also known as the indirect antiglobulin test or IAT) is used to detect in-vitro antibody-antigen reactions. It is used to detect very low concentrations of antibodies present in a patient's plasma/serum prior to a blood transfusion. In antenatal care, the IAT is used to screen pregnant women for antibodies that may cause hemolytic disease of the newborn. The IAT can also be used for compatibility testing, antibody identification, RBC phenotyping, and titration studies.
## Examples of clinical uses of the indirect Coombs test
### Blood transfusion preparation
The indirect Coombs test is used to screen for antibodies in the preparation of blood for blood transfusion. The donor's and recipient's blood must be ABO and Rhesus D compatible. Donor blood for transfusion is also screened for infections in separate processes.
- Antibody screening
A blood sample from the recipient and a blood sample from every unit of donor blood are screened for antibodies with the indirect Coombs test. Each sample is incubated against a wide range of RBCs that together exhibit a full range of surface antigens (ie blood types).
- Cross matching
The indirect Coombs test is used to test a sample of the recipient's serum against a sample of the blood donor's RBCs. This is sometimes called cross-matching blood.
### Antenatal antibody screening
The indirect Coombs test is used to screen pregnant women for IgG antibodies that are likely to pass through the placenta into the foetal blood and cause haemolytic disease of the newborn.
## Laboratory method
The IAT is a two-stage test. (A cross match is shown visually in the lower half of the schematic as an example of an indirect Coombs test).
### First stage
Washed test red blood cells (RBCs) are incubated with a test serum. If the serum contains antibodies to antigens on the RBC surface, the antibodies will bind onto the surface of the RBCs.
### Second stage
The RBCs are washed three or four times with isotonic saline and then incubated with antihuman globulin. If antibodies have bound to RBC surface antigens in the first stage, RBCs will agglutinate when incubated with the antihuman globulin (also known Coombs reagent) in this stage, and the indirect Coombs test will be positive.
### Titrations
By diluting a serum containing antibodies the quantity of the antibody in the serum can be gauged. This is done by using doubling dilutions of the serum and finding the maximum dilution of test serum that is able to produce agglutination of relevant RBCs.
# Coombs reagent
Coombs reagent (also known as Coombs antiglobulin or antihuman globulin) is used in both the direct Coombs test and the indirect Coombs test. Coombs reagent is antihuman globulin. It is made by injecting human globulin into animals. Coombs reagent contains animal antibodies specific for human immunoglobulins and human complement system factors. More specific Coombs reagents or monoclonal antibodies can be used.
# Enhancement Media
Both IgM and IgG antibodies react strongly with their antigens. IgG antibodies are most reactive at 37°C. IgM antibodies are easily detected in saline at room temperature as IgM antibodies are able to bridge between RBC’s owing to their large size, efficiently creating what is seen as agglutination. IgG antibodies are smaller and require assistance to bridge well enough to form a visual agglutination reaction. Reagents used to enhance IgG detection are referred to as potentiators. RBCs have a net negative charge called zeta potential which causes them to have a natural repulsion for one another. Potentiators reduce the zeta potential of RBC membranes. Common potentiators include low ionic strength solution (LISS), albumin, polyethylene glycol (PEG), and proteolytic enzymes.
# History of the Coombs test
The Coombs test was first described in 1945 by Cambridge immunologists Robin Coombs (after whom it is named), Arthur Mourant and Rob Race. Historically, it was done in test tubes. Today, it is commonly done using microarray and gel technology. | Coombs test
For the WikiPatient page for this topic, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Coombs test (also known as Coombs' test, antiglobulin test or AGT) refers to two clinical blood tests used in immunohematology and immunology.
The two Coombs tests are:
- Direct Coombs test (also known as direct antiglobulin test or DAT).
- Indirect Coombs test (also known as indirect antiglobulin test or IAT).
The direct Coombs test is used to detect red blood cells sensitized with igG alloantibody, IgG autoantibody, and complement proteins. It detects antibodies bound to the surface of red blood cells in vivo. The red blood cells (RBCs) are washed (removing the patient's own plasma) and then incubated with antihuman globulin (also known as "Coombs reagent"). If this produces agglutination of the RBCs, the direct Coombs test is positive.
The indirect Coombs test is used in prenatal testing of pregnant women, and in testing blood prior to a blood transfusion. It detects antibodies against RBCs that are present unbound in the patient's serum. In this case, serum is extracted from the blood, and the serum is incubated with RBCs of known antigenicity. If agglutination occurs, the indirect Coombs test is positive.[1]
# Mechanism
The two Coombs tests are based on the fact that anti-human antibodies, which are produced by immunizing non-human species with human serum, will bind to human antibodies, commonly IgG or IgM. Animal anti-human antibodies will also bind to human antibodies that may be fixed onto antigens on the surface of red blood cells (also referred to as RBCs), and in the appropriate test tube conditions this can lead to agglutination of RBCs. The phenomenon of agglutination of RBCs is important here, because the resulting clumping of RBCs can be visualised; when clumping is seen the test is positive and when clumping is not seen the test is negative.
Common clinical uses of the Coombs test include the preparation of blood for transfusion in cross-matching, screening for atypical antibodies in the blood plasma of pregnant women as part of antenatal care, and detection of antibodies for the diagnosis of immune-mediated haemolytic anaemias.
Coombs tests are done on serum from venous blood samples which are taken from patients by venipuncture. The venous blood is taken to a laboratory (or blood bank), where trained scientific technical staff do the Coombs tests. The clinical significance of the result is assessed by the physician who requested the Coombs test, perhaps with assistance from a laboratory-based hematologist.
# Direct Coombs Test
The direct Coombs test (also known as the direct antiglobulin test or DAT) is used to detect if antibodies or complement system factors have bound to RBC surface antigens in vivo. The DAT is not currently required for pre-transfusion testing but may be included by some laboratories.
## Examples of diseases that give a positive direct Coombs test
The direct Coombs test is used clinically when immune-mediated hemolytic anemia (antibody-mediated destruction of RBCs) is suspected. A positive Coombs test indicates that an immune mechanism is attacking the patient's own RBC's. This mechanism could be autoimmunity, alloimmunity or a drug-induced immune-mediated mechanism.
### Examples of alloimmune hemolysis
- Hemolytic disease of the newborn (also known as HDN or erythroblastosis fetalis)
Rhesus D hemolytic disease of the newborn (also known as Rh disease)
ABO hemolytic disease of the newborn (the indirect Coombs test may only be weakly positive)
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Rhesus D hemolytic disease of the newborn (also known as Rh disease)
- ABO hemolytic disease of the newborn (the indirect Coombs test may only be weakly positive)
- Anti-Kell hemolytic disease of the newborn
- Rhesus c hemolytic disease of the newborn
- Rhesus E hemolytic disease of the newborn
- Other blood group incompatibility (RhC, Rhe, Kid, Duffy, MN, P and others)
- Alloimmune hemolytic transfusion reactions
### Examples of autoimmune hemolysis
- Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus
Evans' syndrome (antiplatelet antibodies and hemolytic antibodies)
- Idiopathic
- Systemic lupus erythematosus
- Evans' syndrome (antiplatelet antibodies and hemolytic antibodies)
- Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis
Paroxysmal cold hemoglobinuria (rare)
- Idiopathic cold hemagglutinin syndrome
- Infectious mononucleosis
- Paroxysmal cold hemoglobinuria (rare)
### Drug-induced immune-mediated haemolysis
- Cefepime
- Ceftazidime
- Methyldopa (IgG mediated type II hypersensitivity)
- Penicillin (high dose)
- Quinidine (IgM mediated activation of classical complement pathway and Membrane attack complex, MAC)
(A memory device to remember that the DAT tests the RBCs and is used to test infants for haemolytic disease of the newborn is:
Rh Disease; R = RBCs, D = DAT.)
## Laboratory method
The patient's red blood cells (RBCs) are washed (removing the patient's own serum) and then incubated with antihuman globulin (also known as Coombs reagent). If immunoglobulin or complement factors have been fixed on to the RBC surface in-vivo, the antihuman globulin will agglutinate the RBCs and the direct Coombs test will be positive. (A visual representation of a positive direct Coombs test is shown in the upper half of the schematic).
# Indirect Coombs test
The indirect Coombs test (also known as the indirect antiglobulin test or IAT) is used to detect in-vitro antibody-antigen reactions. It is used to detect very low concentrations of antibodies present in a patient's plasma/serum prior to a blood transfusion. In antenatal care, the IAT is used to screen pregnant women for antibodies that may cause hemolytic disease of the newborn. The IAT can also be used for compatibility testing, antibody identification, RBC phenotyping, and titration studies.
## Examples of clinical uses of the indirect Coombs test
### Blood transfusion preparation
The indirect Coombs test is used to screen for antibodies in the preparation of blood for blood transfusion. The donor's and recipient's blood must be ABO and Rhesus D compatible. Donor blood for transfusion is also screened for infections in separate processes.
- Antibody screening
A blood sample from the recipient and a blood sample from every unit of donor blood are screened for antibodies with the indirect Coombs test. Each sample is incubated against a wide range of RBCs that together exhibit a full range of surface antigens (ie blood types).
- Cross matching
The indirect Coombs test is used to test a sample of the recipient's serum against a sample of the blood donor's RBCs. This is sometimes called cross-matching blood.
### Antenatal antibody screening
The indirect Coombs test is used to screen pregnant women for IgG antibodies that are likely to pass through the placenta into the foetal blood and cause haemolytic disease of the newborn.
## Laboratory method
The IAT is a two-stage test. (A cross match is shown visually in the lower half of the schematic as an example of an indirect Coombs test).
### First stage
Washed test red blood cells (RBCs) are incubated with a test serum. If the serum contains antibodies to antigens on the RBC surface, the antibodies will bind onto the surface of the RBCs.
### Second stage
The RBCs are washed three or four times with isotonic saline and then incubated with antihuman globulin. If antibodies have bound to RBC surface antigens in the first stage, RBCs will agglutinate when incubated with the antihuman globulin (also known Coombs reagent) in this stage, and the indirect Coombs test will be positive.
### Titrations
By diluting a serum containing antibodies the quantity of the antibody in the serum can be gauged. This is done by using doubling dilutions of the serum and finding the maximum dilution of test serum that is able to produce agglutination of relevant RBCs.
# Coombs reagent
Coombs reagent (also known as Coombs antiglobulin or antihuman globulin) is used in both the direct Coombs test and the indirect Coombs test. Coombs reagent is antihuman globulin. It is made by injecting human globulin into animals. Coombs reagent contains animal antibodies specific for human immunoglobulins and human complement system factors. More specific Coombs reagents or monoclonal antibodies can be used.
# Enhancement Media
Both IgM and IgG antibodies react strongly with their antigens. IgG antibodies are most reactive at 37°C. IgM antibodies are easily detected in saline at room temperature as IgM antibodies are able to bridge between RBC’s owing to their large size, efficiently creating what is seen as agglutination. IgG antibodies are smaller and require assistance to bridge well enough to form a visual agglutination reaction. Reagents used to enhance IgG detection are referred to as potentiators. RBCs have a net negative charge called zeta potential which causes them to have a natural repulsion for one another. Potentiators reduce the zeta potential of RBC membranes. Common potentiators include low ionic strength solution (LISS), albumin, polyethylene glycol (PEG), and proteolytic enzymes.
# History of the Coombs test
The Coombs test was first described in 1945 by Cambridge immunologists Robin Coombs (after whom it is named), Arthur Mourant and Rob Race.[2] Historically, it was done in test tubes. Today, it is commonly done using microarray and gel technology. | https://www.wikidoc.org/index.php/AGT | |
63a304133e0cbe2301e9b7f547a7cfecb8fad2b0 | wikidoc | Amoxicillin | Amoxicillin
# Disclaimer
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# Overview
Amoxicillin is an antibiotic that is FDA approved for the treatment of infections of the ear, nose, throat, genitourinary tract and lower respiratory tract. Also for Gonorrhea and Helicobacter infections. Common adverse reactions include rash, diarrhea, nausea, headache and vulvovaginitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Triple Therapy:
Amoxicillin
Clarithromycin
Lansoprazole
- Amoxicillin
- Clarithromycin
- Lansoprazole
The recommended adult oral dose is 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (q12h) for 14 days.
### Community Acquired Pneumonia
- In patients wit comorbidities or use of antimicrobials within the previous 3 month
Dosage: 875mg PO q12h OR 500mg q8h
- Dosage: 875mg PO q12h OR 500mg q8h
### Acute Bacterial Rhinosinusitis
- Mild/Moderate: 500mg q12h or 250mg q8h
- Severe: 875mg q12h or 500mg q8h
### Gonorrhea, Acute uncomplicated Anogenital and Urethral Infections due to Neisseria Gonorrhoeae
- Dosage: 3g as single oral dose
### Helicobacter Pylori Infection
- Triple Therapy for 14 days
Amoxicillin: 1g q12h PO
Clarithromycin: 500mg q12h
Lansoprazole: 30mg q12h
- Amoxicillin: 1g q12h PO
- Clarithromycin: 500mg q12h
- Lansoprazole: 30mg q12h
- Dual Therapy
Amoxicillin: 1g q8h
Lansoprazole: 30mg q8h
- Amoxicillin: 1g q8h
- Lansoprazole: 30mg q8h
### Infection of Skin and/or Subcutaneous Tissue
- Mild/moderate: 500mg q12h or 250mg q8h
- Severe: 875mg q12h or 500mg q8h
### Infectious Disease of Genitourinary System
- Mild/Moderate: 500 mg q12h or 250mg q8h
- Severe: 875mg q8h or 500mg q8h
### Lower Respiratory Tract Infection
- Dosage: 875 mg q12h or 500 mg q8h
### Tonsillitis and/or Pharyngitis
- Dosage: 775mg once daily taken within 1 hour of finishing a meal, for 10 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Bacterial Endocarditis Prophylaxis
- Dosage: 2g PO q24h
### Chlamydial Infection
- Pregnant women: 500mg q8h PO for 7 days.
### Lyme's Disease
- Eritema migrans dosage: 500mg PO TID for 14-21 days
- Seventh-cranial nerve palsy: 500mg PO TID for 14-21 days
- Lyme's arthritis: 500mg PO TID for 14-21 days
### Non–Guideline-Supported Use
### Actinomycotic Infection
- Dosage: 500mg q8h PO (in combination with cotrimoxazole (80mg/400mg) 2 tablets q12h for 2-5 months for home regimen)
### Acute Infective Exacerbation of Chronic Obstructive Pulmonary Disease
- Dosage: 1g q12h PO.
### Cutaneous Anthrax
- When first-line drugs are contraindicated in the patient
Dosage: 1g q8h PO
- Dosage: 1g q8h PO
### Periodontal infection
- Dosage: 500mg Amoxicillin q8h in combination with metronidazole 250-400mg q8h
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Otitis Media with Effusion
- Mild/Moderate: 25 mg/kg/day in divided doses q12h or 20 mg/kg/day in divided doses q8h
- Severe: 45 mg/kg/day in divided doses q12h or 40 mg/kg/day in divided doses q8h
### Acute Bacterial Rhinosinusitis
- Mild/Moderate: 25 mg/kg/day in divided doses q12h or 20 mg/kg/day in divided doses q8h
- Severe: 45 mg/kg/day in divided doses q12h or 40 mg/kg/day in divided doses q8h
### Gonorrhea, Acute Uncomplicated Anogenital and Urethral Infections due to Neisseria Gonorrhoeae
- Dosage: 50 mg/kg Amoxicillin combined with 25 mg/kg Probenecid (Only in pediatric population >2 years old).
### Infection of skin and/or subcutaneous tissue
- Mild/Moderate: 25mg/kg/day in divided doses q12h or 20mg/kg/day in divided doses q8h
- Severe: 45mg/kg/day in divided doses q12h or 40mg/kg/day in divided doses q8h
### Infectious Disease of Genitourinary System
- Mild/Moderate: 25mg/kg/day in divided doses q12h or 20mg/kg/day in divided doses q8h
- Severe: 45mg/kg/day in divided doses q12h or 40 mg/kg/day in divided doses q8h
### Lower Respiratory Tract Infection
- Dosage: 45mg/kg/day in divided doses q12h or 40mg/kg/day in divided doses q8h
### Tonsillitis and/or Pharyngitis
- Dosage: (>12 year old) 775mg once daily taken within 1 hour of finishing a meal, for 10 days.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
### Lyme's Disease
- Eritema migrans dosage: 50mg/kg/day PO in 3 divided doses (Max: 1500mg)
- Lyme's arthritis: 50 mg/kg/day PO in 3 divided doses (Max: 1500mg)
- Seventh-cranial nerve palsy: 50 mg/kg/day PO in 3 divided doses (Max: 1500mg)
### Streptococcal pharyngitis
- Dosage: 50 mg/kg once daily (Max: 1 g/day)
### Non–Guideline-Supported Use
### Periodontal infection
- Dosage: 500mg Amoxicillin q8h in combination with metronidazole 250-400mg q8h
### Post Infective Arthritis
- Dosage: 40mg/kg/day (Max: 2g/day) for 10-14 days in combination with an antirheumathic drug.
### Preterm premature rupture of membranes
- Dosage: Ampicillin 2 g IV every 6 hours with erythromycin 250 mg every 6 hours, for 48 hours followed by amoxicillin 250 mg orally every 8 hours and erythromycin base 333 mg every 8 hours for 5 days.
# Contraindications
A history of allergic reaction to any of the penicillins is a contraindication.
# Warnings
### Hypersensitivity
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with amoxicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated.
### Clostridium Difficile Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
- Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
### Infections and Infestations
- Mucocutaneous candidiasis.
### Gastrointestinal
- Nausea
- Vomiting
- Diarrhea
- Black hairy tongue
- Hemorrhagic/pseudomembranous colitis
### Hypersensitivity Reactions
- Anaphylaxis
- Serum sickness-like reactions
- Erythematous maculopapular rashes
- Erythema multiforme
- Stevens-Johnson syndrome
- Exfoliative dermatitis
- Toxic epidermal necrolysis
- Acute generalized exanthematous pustulosis
- Hypersensitivity vasculitis
- Urticaria
NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.
### Liver
- Rise in AST (SGOT) and/or ALT (SGPT)
- Cholestatic jaundice
- Hepatic cholestasis
- Acute cytolytic hepatitis
### Renal
- Crystalluria
### Hemic and Lymphatic Systems
- Anemia, including hemolytic anemia
- Thrombocytopenia
- Thrombocytopenic purpura
- Eosinophilia
- Leukopenia
- Agranulocytosis
NOTE: These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.
### Central Nervous System
- Hyperactivity
- Agitation
- Anxiety
- Insomnia
- Confusion
- Convulsions
- Behavioral changes
- Dizziness
### Miscellaneous
- Tooth discoloration: brown, yellow, or gray staining.
### Combination Therapy with Clarithromycin and Lansoprazole
In clinical trials using combination therapy with amoxicillin plus clarithromycin and lansoprazole, and amoxicillin plus lansoprazole, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with amoxicillin, clarithromycin, or lansoprazole.
### Triple Therapy for H. pylori
Amoxicillin/Clarithromycin/Lansoprazole:The most frequently reported adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen.
### Dual Therapy for H. pylori with Amoxicillin/Lansoprazole
The most frequently reported adverse events for patients who received amoxicillin three times daily plus lansoprazole three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with amoxicillin three times daily plus lansoprazole three times daily dual therapy than with lansoprazole alone.
## Postmarketing Experience
There is limited information regarding Amoxicillin Postmarketing Experience in the drug label.
# Drug Interactions
- Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.
- Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice and rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to amoxicillin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): A
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amoxicillin in women who are pregnant.
### Labor and Delivery
- Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions but moderately increased the height and duration of contractions. However, it is not known whether use of amoxicillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.
### Nursing Mothers
- Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.
### Pediatric Use
- Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin should be modified in pediatric patients 12 weeks or younger (≤ 3 months)
### Geriatic Use
- An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1,811 subjects treated with capsules of amoxicillin, 85% were < 60 years old, 15% were ≥ 61 years old and 7% were ≥ 71 years old. This analysis and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Amoxicillin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amoxicillin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amoxicillin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Amoxicillin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Amoxicillin and potassium clavulanate was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 3 times the human dose in mg/m2).
### Immunocompromised Patients
There is no FDA guidance one the use of Amoxicillin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- oral
### Monitoring
As with any potent drug, periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with amoxicillin should have a follow-up serologic test for syphilis after 3 months.
# IV Compatibility
There is limited information regarding the compatibility of Amoxicillin and IV administrations.
# Overdosage
- In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.
- Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.
- Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.
Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin may be removed from circulation by hemodialysis.
# Pharmacology
## Mechanism of Action
- Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide.
## Structure
- Chemically it is (2S,5R,6R)-6--3,3-dimethyl-7-oxo-4-thia-1-azabicyclo heptane-2-carboxylic acid trihydrate. The amoxicillin molecular formula is C16H19N3O5S3H2O, and the molecular weight is 419.45.
## Pharmacodynamics
There is limited information regarding Amoxicillin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from amoxicillin tablets and amoxicillin suspension has been partially investigated. The 400 mg and 875 mg formulations have been studied only when administered at the start of a light meal. However, food effect studies have not been performed with the 200 mg and 500 mg formulations. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% protein-bound.
- Orally administered doses of 250 mg and 500 mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively.
- Mean amoxicillin pharmacokinetic parameters from an open, two-part, single-dose crossover bioequivalence study in 27 adults comparing 875 mg of amoxicillin with 875 mg of amoxicillin/ clavulanate potassium showed that the 875 g tablet of amoxicillin produces an AUC0-∞ of 35.4 ±8.1 mcghr/mL and a Cmax of 13.8 ±4.1 mcg/mL. Dosing was at the start of a light meal following an overnight fast.
- Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3 mcg/mL and 3.5 mcg/mL to 5 mcg/mL, respectively.
## Nonclinical Toxicology
There is limited information regarding Amoxicillin Nonclinical Toxicology in the drug label.
# Clinical Studies
### H. Pylori Eradication to Reduce the Risk of Duodenal UlcerRecurrence
- Randomized, double-blind clinical studies performed in the United States in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within 1 year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14 day therapy, or in combination with amoxicillin capsules as dual 14 day therapy, for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established:
- Triple Therapy: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily.
- Dual Therapy: Amoxicillin 1 gram three times daily/ lansoprazole 30 mg three times daily.
All treatments were for 14 days. H. pylori eradication was defined as 2 negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.
Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
H. pylori Eradication Rates – Triple Therapy (amoxicillin/clarithromycin/lansoprazole) Percent of Patients Cured (Number of Patients)
H. pylori Eradication Rates – Dual Therapy (amoxicillin/lansoprazole) Percent of Patients Cured (Number of Patients)
# How Supplied
### Amoxicillin Capsules, USP
- Each capsule contains 250 mg or 500 mg amoxicillin as the trihydrate.
- 250 mg yellow opaque cap and yellow opaque body, size 2, printed “RX654” on both cap and body.
NDC 63304-654-20 bottles of 20
NDC 63304-654-30 bottles of 30
NDC 63304-654-01 bottles of 100
NDC 63304-654-05 bottles of 500
NDC 63304-654-77 Unit-dose 100s
- NDC 63304-654-20 bottles of 20
- NDC 63304-654-30 bottles of 30
- NDC 63304-654-01 bottles of 100
- NDC 63304-654-05 bottles of 500
- NDC 63304-654-77 Unit-dose 100s
- 500 mg maroon opaque cap and yellow opaque body, size 0-el, printed “RX655” on both cap and body.
NDC 63304-762-82 bottles of 12
NDC 63304-762-20 bottles of 20
NDC 63304-762-01 bottles of 100
NDC 63304-762-13 bottles of 120
NDC 63304-762-05 bottles of 500
- NDC 63304-762-82 bottles of 12
- NDC 63304-762-20 bottles of 20
- NDC 63304-762-01 bottles of 100
- NDC 63304-762-13 bottles of 120
- NDC 63304-762-05 bottles of 500
### Amoxicillin Tablets, USP
Each tablet contains 500 mg or 875 mg amoxicillin as the trihydrate.
- 500 mg pink colored, film coated, capsule shaped tablets; debossed with “RX762” on one side and plain on the other side.
NDC 63304-762-82 bottles of 12
NDC 63304-762-20 bottles of 20
NDC 63304-762-01 bottles of 100
NDC 63304-762-13 bottles of 120
NDC 63304-762-05 bottles of 500
- NDC 63304-762-82 bottles of 12
- NDC 63304-762-20 bottles of 20
- NDC 63304-762-01 bottles of 100
- NDC 63304-762-13 bottles of 120
- NDC 63304-762-05 bottles of 500
- 875 mg pink colored, film coated, capsule shaped tablets; debossed with “RX763” on one side and scored on reverse side.
NDC 63304-763-82 bottles of 12
NDC 63304-763-20 bottles of 20
NDC 63304-763-01 bottles of 100
NDC 63304-763-13 bottles of 120
NDC 63304-763-05 bottles of 500
- NDC 63304-763-82 bottles of 12
- NDC 63304-763-20 bottles of 20
- NDC 63304-763-01 bottles of 100
- NDC 63304-763-13 bottles of 120
- NDC 63304-763-05 bottles of 500
### Amoxicillin Chewable Tablets, USP
Each chewable tablet contains 125 mg, 200 mg, 250 mg or 400 mg amoxicillin as the trihydrate.
- 125 mg pink colored, strawberry flavored, oval biconvex tablets, with mottled appearance; debossed with “RX514” on one side.
NDC 63304-514-01 bottles of 100
NDC 63304-514-05 bottles of 500
- NDC 63304-514-01 bottles of 100
- NDC 63304-514-05 bottles of 500
- 200 mg light pink colored, strawberry flavored, circular, flat faced, beveled edge tablets, with mottled appearance; debossed with “RX760” on one side.
NDC 63304-760-20 bottles of 20
NDC 63304-760-01 bottles of 100
NDC 63304-760-05 bottles of 500
- NDC 63304-760-20 bottles of 20
- NDC 63304-760-01 bottles of 100
- NDC 63304-760-05 bottles of 500
- 250 mg pink colored, strawberry flavored, circular, flat faced, beveled edge tablets, with mottled appearance; debossed with “RX515” on one side.
NDC 63304-515-30 bottles of 30
NDC 63304-515-01 bottles of 100
NDC 63304-515-04 bottles of 250
- NDC 63304-515-30 bottles of 30
- NDC 63304-515-01 bottles of 100
- NDC 63304-515-04 bottles of 250
- 400 mg light pink colored, strawberry flavored, circular, flat faced, beveled edge tablets, with mottled appearance; debossed with “RX716” on one side.
NDC 63304-761-20 bottles of 20
NDC 63304-761-01 bottles of 100
NDC 63304-761-05 bottles of 500
- NDC 63304-761-20 bottles of 20
- NDC 63304-761-01 bottles of 100
- NDC 63304-761-05 bottles of 500
### Amoxicillin For Oral Suspension USP is available in
- The 200 mg per 5 mL oral suspension is off white to light orange granular powder forming a light orange to orange suspension on constitution with water. The resulting suspension has a characteristic fruity flavor and is available as follows:
NDC 63304-969-03 50 mL bottles
NDC 63304-969-01 75 mL bottles
NDC 63304-969-04 100 mL bottles
- NDC 63304-969-03 50 mL bottles
- NDC 63304-969-01 75 mL bottles
- NDC 63304-969-04 100 mL bottles
The 400 mg per 5 mL oral suspension is off white to light orange granular powder forming a light orange to orange suspension- on constitution with water. The resulting suspension has a characteristic fruity flavor and is available as follows:
- NDC 63304-970-03 50 mL bottle
NDC 63304-970-01 75 mL bottle
NDC 63304-970-04 100 mL bottle
- NDC 63304-970-03 50 mL bottle
- NDC 63304-970-01 75 mL bottle
- NDC 63304-970-04 100 mL bottle
## Storage
- SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration preferable, but not required.
- Store amoxicillin capsules 250 mg and 500 mg, amoxicillin tablets 500 mg and 875 mg, amoxicillin chewable tablets 125 mg, 200 mg, 250 mg and 400 mg and amoxicillin unreconstituted powder 200 mg/5 mL and 400 mg/5 mL at controlled room temperature 15° – 30° C (59° – 86° F) (see USP).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Amoxicillin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Amoxicillin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Amoxil
- Trimox
- Wymox
- Moxatag
# Look-Alike Drug Names
There is limited information regarding Amoxicillin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Amoxicillin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Amoxicillin is an antibiotic that is FDA approved for the treatment of infections of the ear, nose, throat, genitourinary tract and lower respiratory tract. Also for Gonorrhea and Helicobacter infections. Common adverse reactions include rash, diarrhea, nausea, headache and vulvovaginitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Triple Therapy:
Amoxicillin
Clarithromycin
Lansoprazole
- Amoxicillin
- Clarithromycin
- Lansoprazole
The recommended adult oral dose is 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (q12h) for 14 days.
### Community Acquired Pneumonia
- In patients wit comorbidities or use of antimicrobials within the previous 3 month
Dosage: 875mg PO q12h OR 500mg q8h
- Dosage: 875mg PO q12h OR 500mg q8h
### Acute Bacterial Rhinosinusitis
- Mild/Moderate: 500mg q12h or 250mg q8h
- Severe: 875mg q12h or 500mg q8h
### Gonorrhea, Acute uncomplicated Anogenital and Urethral Infections due to Neisseria Gonorrhoeae
- Dosage: 3g as single oral dose
### Helicobacter Pylori Infection
- Triple Therapy for 14 days
Amoxicillin: 1g q12h PO
Clarithromycin: 500mg q12h
Lansoprazole: 30mg q12h
- Amoxicillin: 1g q12h PO
- Clarithromycin: 500mg q12h
- Lansoprazole: 30mg q12h
- Dual Therapy
Amoxicillin: 1g q8h
Lansoprazole: 30mg q8h
- Amoxicillin: 1g q8h
- Lansoprazole: 30mg q8h
### Infection of Skin and/or Subcutaneous Tissue
- Mild/moderate: 500mg q12h or 250mg q8h
- Severe: 875mg q12h or 500mg q8h
### Infectious Disease of Genitourinary System
- Mild/Moderate: 500 mg q12h or 250mg q8h
- Severe: 875mg q8h or 500mg q8h
### Lower Respiratory Tract Infection
- Dosage: 875 mg q12h or 500 mg q8h
### Tonsillitis and/or Pharyngitis
- Dosage: 775mg once daily taken within 1 hour of finishing a meal, for 10 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
### Bacterial Endocarditis Prophylaxis
- Dosage: 2g PO q24h [1]
### Chlamydial Infection
- Pregnant women: 500mg q8h PO for 7 days. [2]
### Lyme's Disease
- Eritema migrans dosage: 500mg PO TID for 14-21 days
- Seventh-cranial nerve palsy: 500mg PO TID for 14-21 days
- Lyme's arthritis: 500mg PO TID for 14-21 days[3]
### Non–Guideline-Supported Use
### Actinomycotic Infection
- Dosage: 500mg q8h PO (in combination with cotrimoxazole (80mg/400mg) 2 tablets q12h for 2-5 months for home regimen) [4]
### Acute Infective Exacerbation of Chronic Obstructive Pulmonary Disease
- Dosage: 1g q12h PO. [5]
### Cutaneous Anthrax
- When first-line drugs are contraindicated in the patient
Dosage: 1g q8h PO [6]
- Dosage: 1g q8h PO [6]
### Periodontal infection
- Dosage: 500mg Amoxicillin q8h in combination with metronidazole 250-400mg q8h[7]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Otitis Media with Effusion
- Mild/Moderate: 25 mg/kg/day in divided doses q12h or 20 mg/kg/day in divided doses q8h
- Severe: 45 mg/kg/day in divided doses q12h or 40 mg/kg/day in divided doses q8h
### Acute Bacterial Rhinosinusitis
- Mild/Moderate: 25 mg/kg/day in divided doses q12h or 20 mg/kg/day in divided doses q8h
- Severe: 45 mg/kg/day in divided doses q12h or 40 mg/kg/day in divided doses q8h
### Gonorrhea, Acute Uncomplicated Anogenital and Urethral Infections due to Neisseria Gonorrhoeae
- Dosage: 50 mg/kg Amoxicillin combined with 25 mg/kg Probenecid (Only in pediatric population >2 years old).
### Infection of skin and/or subcutaneous tissue
- Mild/Moderate: 25mg/kg/day in divided doses q12h or 20mg/kg/day in divided doses q8h
- Severe: 45mg/kg/day in divided doses q12h or 40mg/kg/day in divided doses q8h
### Infectious Disease of Genitourinary System
- Mild/Moderate: 25mg/kg/day in divided doses q12h or 20mg/kg/day in divided doses q8h
- Severe: 45mg/kg/day in divided doses q12h or 40 mg/kg/day in divided doses q8h
### Lower Respiratory Tract Infection
- Dosage: 45mg/kg/day in divided doses q12h or 40mg/kg/day in divided doses q8h
### Tonsillitis and/or Pharyngitis
- Dosage: (>12 year old) 775mg once daily taken within 1 hour of finishing a meal, for 10 days.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
### Lyme's Disease
- Eritema migrans dosage: 50mg/kg/day PO in 3 divided doses (Max: 1500mg)
- Lyme's arthritis: 50 mg/kg/day PO in 3 divided doses (Max: 1500mg)
- Seventh-cranial nerve palsy: 50 mg/kg/day PO in 3 divided doses (Max: 1500mg)[3]
### Streptococcal pharyngitis
- Dosage: 50 mg/kg once daily (Max: 1 g/day) [8]
### Non–Guideline-Supported Use
### Periodontal infection
- Dosage: 500mg Amoxicillin q8h in combination with metronidazole 250-400mg q8h[7]
### Post Infective Arthritis
- Dosage: 40mg/kg/day (Max: 2g/day) for 10-14 days in combination with an antirheumathic drug. [9]
### Preterm premature rupture of membranes
- Dosage: Ampicillin 2 g IV every 6 hours with erythromycin 250 mg every 6 hours, for 48 hours followed by amoxicillin 250 mg orally every 8 hours and erythromycin base 333 mg every 8 hours for 5 days. [10]
# Contraindications
A history of allergic reaction to any of the penicillins is a contraindication.
# Warnings
### Hypersensitivity
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with amoxicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated.
### Clostridium Difficile Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
- Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
### Infections and Infestations
- Mucocutaneous candidiasis.
### Gastrointestinal
- Nausea
- Vomiting
- Diarrhea
- Black hairy tongue
- Hemorrhagic/pseudomembranous colitis
### Hypersensitivity Reactions
- Anaphylaxis
- Serum sickness-like reactions
- Erythematous maculopapular rashes
- Erythema multiforme
- Stevens-Johnson syndrome
- Exfoliative dermatitis
- Toxic epidermal necrolysis
- Acute generalized exanthematous pustulosis
- Hypersensitivity vasculitis
- Urticaria
NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.
### Liver
- Rise in AST (SGOT) and/or ALT (SGPT)
- Cholestatic jaundice
- Hepatic cholestasis
- Acute cytolytic hepatitis
### Renal
- Crystalluria
### Hemic and Lymphatic Systems
- Anemia, including hemolytic anemia
- Thrombocytopenia
- Thrombocytopenic purpura
- Eosinophilia
- Leukopenia
- Agranulocytosis
NOTE: These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.
### Central Nervous System
- Hyperactivity
- Agitation
- Anxiety
- Insomnia
- Confusion
- Convulsions
- Behavioral changes
- Dizziness
### Miscellaneous
- Tooth discoloration: brown, yellow, or gray staining.
### Combination Therapy with Clarithromycin and Lansoprazole
In clinical trials using combination therapy with amoxicillin plus clarithromycin and lansoprazole, and amoxicillin plus lansoprazole, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with amoxicillin, clarithromycin, or lansoprazole.
### Triple Therapy for H. pylori
Amoxicillin/Clarithromycin/Lansoprazole:The most frequently reported adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen.
### Dual Therapy for H. pylori with Amoxicillin/Lansoprazole
The most frequently reported adverse events for patients who received amoxicillin three times daily plus lansoprazole three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with amoxicillin three times daily plus lansoprazole three times daily dual therapy than with lansoprazole alone.
## Postmarketing Experience
There is limited information regarding Amoxicillin Postmarketing Experience in the drug label.
# Drug Interactions
- Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.
- Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice and rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to amoxicillin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): A
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amoxicillin in women who are pregnant.
### Labor and Delivery
- Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions but moderately increased the height and duration of contractions. However, it is not known whether use of amoxicillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.
### Nursing Mothers
- Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.
### Pediatric Use
- Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin should be modified in pediatric patients 12 weeks or younger (≤ 3 months)
### Geriatic Use
- An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1,811 subjects treated with capsules of amoxicillin, 85% were < 60 years old, 15% were ≥ 61 years old and 7% were ≥ 71 years old. This analysis and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Amoxicillin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Amoxicillin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Amoxicillin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Amoxicillin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Amoxicillin and potassium clavulanate was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 3 times the human dose in mg/m2).
### Immunocompromised Patients
There is no FDA guidance one the use of Amoxicillin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- oral
### Monitoring
As with any potent drug, periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with amoxicillin should have a follow-up serologic test for syphilis after 3 months.
# IV Compatibility
There is limited information regarding the compatibility of Amoxicillin and IV administrations.
# Overdosage
- In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.
- Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.
- Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.
Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin may be removed from circulation by hemodialysis.
# Pharmacology
## Mechanism of Action
- Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide.
## Structure
- Chemically it is (2S,5R,6R)-6-[(R)-(-)-2- amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate. The amoxicillin molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45.
## Pharmacodynamics
There is limited information regarding Amoxicillin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from amoxicillin tablets and amoxicillin suspension has been partially investigated. The 400 mg and 875 mg formulations have been studied only when administered at the start of a light meal. However, food effect studies have not been performed with the 200 mg and 500 mg formulations. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% protein-bound.
- Orally administered doses of 250 mg and 500 mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively.
- Mean amoxicillin pharmacokinetic parameters from an open, two-part, single-dose crossover bioequivalence study in 27 adults comparing 875 mg of amoxicillin with 875 mg of amoxicillin/ clavulanate potassium showed that the 875 g tablet of amoxicillin produces an AUC0-∞ of 35.4 ±8.1 mcg•hr/mL and a Cmax of 13.8 ±4.1 mcg/mL. Dosing was at the start of a light meal following an overnight fast.
- Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3 mcg/mL and 3.5 mcg/mL to 5 mcg/mL, respectively.
## Nonclinical Toxicology
There is limited information regarding Amoxicillin Nonclinical Toxicology in the drug label.
# Clinical Studies
### H. Pylori Eradication to Reduce the Risk of Duodenal UlcerRecurrence
- Randomized, double-blind clinical studies performed in the United States in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within 1 year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14 day therapy, or in combination with amoxicillin capsules as dual 14 day therapy, for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established:
- Triple Therapy: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily.
- Dual Therapy: Amoxicillin 1 gram three times daily/ lansoprazole 30 mg three times daily.
All treatments were for 14 days. H. pylori eradication was defined as 2 negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.
Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
H. pylori Eradication Rates – Triple Therapy (amoxicillin/clarithromycin/lansoprazole) Percent of Patients Cured [95% Confidence Interval] (Number of Patients)
H. pylori Eradication Rates – Dual Therapy (amoxicillin/lansoprazole) Percent of Patients Cured [95% Confidence Interval] (Number of Patients)
# How Supplied
### Amoxicillin Capsules, USP
- Each capsule contains 250 mg or 500 mg amoxicillin as the trihydrate.
- 250 mg yellow opaque cap and yellow opaque body, size 2, printed “RX654” on both cap and body.
NDC 63304-654-20 bottles of 20
NDC 63304-654-30 bottles of 30
NDC 63304-654-01 bottles of 100
NDC 63304-654-05 bottles of 500
NDC 63304-654-77 Unit-dose 100s
- NDC 63304-654-20 bottles of 20
- NDC 63304-654-30 bottles of 30
- NDC 63304-654-01 bottles of 100
- NDC 63304-654-05 bottles of 500
- NDC 63304-654-77 Unit-dose 100s
- 500 mg maroon opaque cap and yellow opaque body, size 0-el, printed “RX655” on both cap and body.
NDC 63304-762-82 bottles of 12
NDC 63304-762-20 bottles of 20
NDC 63304-762-01 bottles of 100
NDC 63304-762-13 bottles of 120
NDC 63304-762-05 bottles of 500
- NDC 63304-762-82 bottles of 12
- NDC 63304-762-20 bottles of 20
- NDC 63304-762-01 bottles of 100
- NDC 63304-762-13 bottles of 120
- NDC 63304-762-05 bottles of 500
### Amoxicillin Tablets, USP
Each tablet contains 500 mg or 875 mg amoxicillin as the trihydrate.
- 500 mg pink colored, film coated, capsule shaped tablets; debossed with “RX762” on one side and plain on the other side.
NDC 63304-762-82 bottles of 12
NDC 63304-762-20 bottles of 20
NDC 63304-762-01 bottles of 100
NDC 63304-762-13 bottles of 120
NDC 63304-762-05 bottles of 500
- NDC 63304-762-82 bottles of 12
- NDC 63304-762-20 bottles of 20
- NDC 63304-762-01 bottles of 100
- NDC 63304-762-13 bottles of 120
- NDC 63304-762-05 bottles of 500
- 875 mg pink colored, film coated, capsule shaped tablets; debossed with “RX763” on one side and scored on reverse side.
NDC 63304-763-82 bottles of 12
NDC 63304-763-20 bottles of 20
NDC 63304-763-01 bottles of 100
NDC 63304-763-13 bottles of 120
NDC 63304-763-05 bottles of 500
- NDC 63304-763-82 bottles of 12
- NDC 63304-763-20 bottles of 20
- NDC 63304-763-01 bottles of 100
- NDC 63304-763-13 bottles of 120
- NDC 63304-763-05 bottles of 500
### Amoxicillin Chewable Tablets, USP
Each chewable tablet contains 125 mg, 200 mg, 250 mg or 400 mg amoxicillin as the trihydrate.
- 125 mg pink colored, strawberry flavored, oval biconvex tablets, with mottled appearance; debossed with “RX514” on one side.
NDC 63304-514-01 bottles of 100
NDC 63304-514-05 bottles of 500
- NDC 63304-514-01 bottles of 100
- NDC 63304-514-05 bottles of 500
- 200 mg light pink colored, strawberry flavored, circular, flat faced, beveled edge tablets, with mottled appearance; debossed with “RX760” on one side.
NDC 63304-760-20 bottles of 20
NDC 63304-760-01 bottles of 100
NDC 63304-760-05 bottles of 500
- NDC 63304-760-20 bottles of 20
- NDC 63304-760-01 bottles of 100
- NDC 63304-760-05 bottles of 500
- 250 mg pink colored, strawberry flavored, circular, flat faced, beveled edge tablets, with mottled appearance; debossed with “RX515” on one side.
NDC 63304-515-30 bottles of 30
NDC 63304-515-01 bottles of 100
NDC 63304-515-04 bottles of 250
- NDC 63304-515-30 bottles of 30
- NDC 63304-515-01 bottles of 100
- NDC 63304-515-04 bottles of 250
- 400 mg light pink colored, strawberry flavored, circular, flat faced, beveled edge tablets, with mottled appearance; debossed with “RX716” on one side.
NDC 63304-761-20 bottles of 20
NDC 63304-761-01 bottles of 100
NDC 63304-761-05 bottles of 500
- NDC 63304-761-20 bottles of 20
- NDC 63304-761-01 bottles of 100
- NDC 63304-761-05 bottles of 500
### Amoxicillin For Oral Suspension USP is available in
- The 200 mg per 5 mL oral suspension is off white to light orange granular powder forming a light orange to orange suspension on constitution with water. The resulting suspension has a characteristic fruity flavor and is available as follows:
NDC 63304-969-03 50 mL bottles
NDC 63304-969-01 75 mL bottles
NDC 63304-969-04 100 mL bottles
- NDC 63304-969-03 50 mL bottles
- NDC 63304-969-01 75 mL bottles
- NDC 63304-969-04 100 mL bottles
The 400 mg per 5 mL oral suspension is off white to light orange granular powder forming a light orange to orange suspension* on constitution with water. The resulting suspension has a characteristic fruity flavor and is available as follows:
- NDC 63304-970-03 50 mL bottle
NDC 63304-970-01 75 mL bottle
NDC 63304-970-04 100 mL bottle
- NDC 63304-970-03 50 mL bottle
- NDC 63304-970-01 75 mL bottle
- NDC 63304-970-04 100 mL bottle
## Storage
- SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration preferable, but not required.
- Store amoxicillin capsules 250 mg and 500 mg, amoxicillin tablets 500 mg and 875 mg, amoxicillin chewable tablets 125 mg, 200 mg, 250 mg and 400 mg and amoxicillin unreconstituted powder 200 mg/5 mL and 400 mg/5 mL at controlled room temperature 15° – 30° C (59° – 86° F) (see USP).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Amoxicillin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Amoxicillin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Amoxil
- Trimox
- Wymox
- Moxatag
# Look-Alike Drug Names
There is limited information regarding Amoxicillin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/AMC | |
9757e43d9897981cdbb7e1dcd975357b24a01dd9 | wikidoc | Amodiaquine | Amodiaquine
# Overview
Amodiaquine (trade names Camoquin, Flavoquine), a 4-aminoquinoline compound related to chloroquine, is used as an antimalarial and anti-inflammatory agent.
Amodiaquine has been shown to be more effective than chloroquine in treating chloroquine-resistant Plasmodium falciparum malaria infections and may afford more protection than chloroquine when used as weekly prophylaxis. Amodiaquine, like chloroquine, is generally well tolerated. Although licensed, this drug is not marketed in the United States, but is widely available in Africa. Its use, therefore, is probably more practicable in long-term visitors and persons who will reside in Africa.
Amodiaquine is a histamine N-methyltransferase inhibitor.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
# Medical uses
Amodiaquine has become an important drug in the combination therapy for malaria treatment in Africa.
# Pharmacogenetics
It is bioactivated hepatically to its primary metabolite, N-desethylamodiaquine, by the cytochrome p450 enzyme CYP2C8. Among amodiaquine users, several rare but serious side effects have been reported and linked to variants in the CYP2C8 alleles. CYP2C8*1 is characterized as the wild-type allele, which shows an acceptable safety profile, while CYP2C8*2, *3 and *4 all show a range of “poor metabolizer” phenotypes. People who are poor metabolizers of amodiaquine display lower treatment efficacy against malaria, as well as increased toxicity. Several studies have been conducted to determine the prevalence of CYP2C8 alleles amongst malaria patients in East Africa, and have tentatively shown the variant alleles have significant prevalence in that population. About 3.6% of the population studied showed high risk for a poor reaction to or reduced treatment outcomes when treated with amodiaquine. This information is useful in developing programs of pharmacovigilance in East Africa, and have important clinical considerations for prescribing antimalarial medications in regions with high CYP2C8 variant frequency.
## Cancer
Recent research suggests that amodiaquine targets malignant melanoma cells through induction of autophagic-lysosomal and proliferative blockade sensitizing cancer cells to starvation- and chemotherapy-induced cell death. | Amodiaquine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amodiaquine (trade names Camoquin, Flavoquine), a 4-aminoquinoline compound related to chloroquine, is used as an antimalarial and anti-inflammatory agent.
Amodiaquine has been shown to be more effective than chloroquine in treating chloroquine-resistant Plasmodium falciparum malaria infections and may afford more protection than chloroquine when used as weekly prophylaxis. Amodiaquine, like chloroquine, is generally well tolerated. Although licensed, this drug is not marketed in the United States, but is widely available in Africa. Its use, therefore, is probably more practicable in long-term visitors and persons who will reside in Africa.[1]
Amodiaquine is a histamine N-methyltransferase inhibitor.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[2]
# Medical uses
Amodiaquine has become an important drug in the combination therapy for malaria treatment in Africa.[3]
# Pharmacogenetics
It is bioactivated hepatically to its primary metabolite, N-desethylamodiaquine, by the cytochrome p450 enzyme CYP2C8. Among amodiaquine users, several rare but serious side effects have been reported and linked to variants in the CYP2C8 alleles. CYP2C8*1 is characterized as the wild-type allele, which shows an acceptable safety profile, while CYP2C8*2, *3 and *4 all show a range of “poor metabolizer” phenotypes. People who are poor metabolizers of amodiaquine display lower treatment efficacy against malaria, as well as increased toxicity.[4] Several studies have been conducted to determine the prevalence of CYP2C8 alleles amongst malaria patients in East Africa, and have tentatively shown the variant alleles have significant prevalence in that population.[5] About 3.6% of the population studied showed high risk for a poor reaction to or reduced treatment outcomes when treated with amodiaquine. This information is useful in developing programs of pharmacovigilance in East Africa, and have important clinical considerations for prescribing antimalarial medications in regions with high CYP2C8 variant frequency.
## Cancer
Recent research suggests that amodiaquine targets malignant melanoma cells through induction of autophagic-lysosomal and proliferative blockade sensitizing cancer cells to starvation- and chemotherapy-induced cell death.[6] | https://www.wikidoc.org/index.php/AMODIAQUINE | |
9bf5577ade94c520e3fd4a4099505e10556114f1 | wikidoc | AMUSE score | AMUSE score
# Overview
The AMUSE score includes clinical variables in addition to the results of a qualitative D-dimer test to evaluate the need to proceed with ultrasonography among patients with suspected DVT. The study of the AMUSE score was designed for the primary care setting.
# AMUSE Score
The AMUSE score includes clinical variables in addition to the results of a qualitative D-dimer test to evaluate the need to proceed with ultrasonography among patients with suspected DVT. The study of the AMUSE score was designed for the primary care setting.
# AMUSE Score Calculator
Shown below is the calculator for AMUSE score (check all the boxes that apply):
function calcScore(){
var score = 0;
if(document.forms.checked == 1){score += 6;}
if(document.forms.checked == 1){score += 2;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
if(document.forms.checked == 1){score += 1;}
document.forms.value = score;
if(score <= 3){document.forms.value = "Not high suspicion of DVT, should not proceed with ultrasonography";}
if(score >= 4){document.forms.value = "High suspicion of DVT, should proceed with ultrasonography";}
# Interpretation
The interpretation of the score is as follows:
- Score ≤3: Not high suspicion of DVT, should not proceed with ultrasonography
- Score ≥4: High suspicion of DVT, should proceed with ultrasonography
# Limitations of the AMUSE Score
- The study of the AMUSE score was not randomized.
- Follow up for the detection of missed thrombotic disease was based on clinical evaluation.
- Patient population is from the primary care setting. | AMUSE score
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]
# Overview
The AMUSE score includes clinical variables in addition to the results of a qualitative D-dimer test to evaluate the need to proceed with ultrasonography among patients with suspected DVT. The study of the AMUSE score was designed for the primary care setting.
# AMUSE Score
The AMUSE score includes clinical variables in addition to the results of a qualitative D-dimer test to evaluate the need to proceed with ultrasonography among patients with suspected DVT. The study of the AMUSE score was designed for the primary care setting.[1]
# AMUSE Score Calculator
Shown below is the calculator for AMUSE score (check all the boxes that apply):
function calcScore(){
var score = 0;
if(document.forms["AMUSE_Cal"]["input1"].checked == 1){score += 6;}
if(document.forms["AMUSE_Cal"]["input2"].checked == 1){score += 2;}
if(document.forms["AMUSE_Cal"]["input3"].checked == 1){score += 1;}
if(document.forms["AMUSE_Cal"]["input4"].checked == 1){score += 1;}
if(document.forms["AMUSE_Cal"]["input5"].checked == 1){score += 1;}
if(document.forms["AMUSE_Cal"]["input6"].checked == 1){score += 1;}
if(document.forms["AMUSE_Cal"]["input7"].checked == 1){score += 1;}
if(document.forms["AMUSE_Cal"]["input8"].checked == 1){score += 1;}
document.forms["AMUSE_Cal"]["result"].value = score;
if(score <= 3){document.forms["AMUSE_Cal"]["longanswer"].value = "Not high suspicion of DVT, should not proceed with ultrasonography";}
if(score >= 4){document.forms["AMUSE_Cal"]["longanswer"].value = "High suspicion of DVT, should proceed with ultrasonography";}
}
# Interpretation
The interpretation of the score is as follows:
- Score ≤3: Not high suspicion of DVT, should not proceed with ultrasonography
- Score ≥4: High suspicion of DVT, should proceed with ultrasonography
# Limitations of the AMUSE Score
- The study of the AMUSE score was not randomized.
- Follow up for the detection of missed thrombotic disease was based on clinical evaluation.
- Patient population is from the primary care setting. | https://www.wikidoc.org/index.php/AMUSE_score | |
6824b3b364e418ac0251b4f145cd8c856e2c987a | wikidoc | Apomorphine | Apomorphine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Apomorphine is a non-ergoline dopamine agonist that is FDA approved for the treatment of advanced Parkinson's disease. Common adverse reactions include yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Apomorphine should be initiated with the use of a concomitant antiemetic. Oral trimethobenzamide (300 mg three times a day) should be started 3 days prior to the initial dose of Apomorphine and continued at least during the first two months of therapy. Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated.
- The recommended starting dose of Apomorphine is 0.2 mL (2 mg). Titrate on the basis of effectiveness and tolerance, up to a maximum recommended dose of 0.6 mL (6 mg). There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average frequency of dosing in the development program was 3 times per day. There is limited experience with single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses greater than 2 mL (20 mg).
- Begin dosing when patients are in an "off" state. The initial dose should be a 0.2 mL (2 mg) test dose in a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who develop clinically significant orthostatic hypotension in response to this test dose of Apomorphine should not be considered candidates for treatment with Apomorphine.
- If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 0.2 mL (2 mg), used on an as needed basis to treat recurring "off" episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.
- The general principle guiding subsequent dosing (described in detail below) is to determine that the patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose.
- If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of 0.4 mL (4 mg) may be administered under medical supervision, at least 2-hours after the initial test dose, at the next observed "off" period. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring "off" episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.
- If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be administered during a separate "off" period under medical supervision, at least 2-hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing "off" episodes. If needed, and the 0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an out-patient basis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Apomorphine hydrochloride in adult patients.
### Non–Guideline-Supported Use
- Dosage
Subcutaneous injections: 0.25 to 1 milligram/day.
Sublingual: 2mg
- Subcutaneous injections: 0.25 to 1 milligram/day.
- Sublingual: 2mg
- Dosage: Subcutaneous injections of 12 to 18 milligrams/night.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Apomorphine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Apomorphine hydrochloride in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Apomorphine hydrochloride in pediatric patients.
# Contraindications
Apomorphine is contraindicated in patients:
- Using concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron. There have been reports of profound hypotension and loss of consciousness when Apomorphine was administered with ondansetron.
- With hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema to apomorphine or to any of the excipients including a sulfite (i.e., sodium metabisulfite). Patients with a sulfite sensitivity may experience various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. Patients who experience any hypersensitivity/allergic reaction to Apomorphine should avoid taking Apomorphine again.
# Warnings
- Following intravenous administration of Apomorphine, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, Apomorphine should not be administered intravenously.
- Apomorphine causes severe nausea and vomiting when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an antiemetic, for three days prior to study enrollment, and were then encouraged to continue trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical studies, 31% and 11% of the Apomorphine-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued Apomorphine due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing Apomorphine The average time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years).
- The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) to reduce the incidence of nausea and/or vomiting in Apomorphine-treated patients has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with Parkinson's disease and should be avoided.
- There have been reports in the literature of patients treated with Apomorphine subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with Apomorphine and it is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not give such a history. Somnolence was reported in 35% of patients treated with Apomorphine and in none of the patients in the placebo group. Prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Before initiating treatment with Apomorphine, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with Apomorphine, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation (e.g., conversations, eating, etc.), Apomorphine should ordinarily be discontinued. If a decision is made to continue Apomorphine patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- In clinical studies, approximately 2% of Apomorphine-treated patients experienced syncope.
- Dopamine agonists, including Apomorphine, may cause orthostatic hypotension at any time but especially during dose escalation. Patients with Parkinson's disease may also have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.
- Patients undergoing titration of Apomorphine showed an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (≥ 20 mmHg decrease) when evaluated at various times after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension (≥ 30 mmHg decrease and systolic BP ≤ 90 mmHg) after subcutaneous apomorphine injection. In clinical trials of Apomorphine in patients with advanced Parkinson's disease, 59 of 550 patients (11%) had orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 4 patients (< 1%) and resulted in withdrawal of Apomorphine in 10 patients (2%). These events occurred both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other significant adverse events seen (e.g., falls), is unknown. Apomorphine causes dose-related decreases in systolic blood pressure (SBP) and diastolic blood pressure (DBP).
- The hypotensive effects of Apomorphine may be increased by the concomitant use of alcohol, antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid alcohol when using Apomorphine. Check blood pressure for hypotension and orthostatic hypotension in patients Apomorphine with concomitant antihypertensive medications and/or vasodilators.
- Patients with Parkinson's disease (PD) are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat PD. Subcutaneous Apomorphine might increase the risk of falling by simultaneously lowering blood pressure and altering mobility. In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of patients had falls that were considered serious.
- In clinical studies, hallucinations were reported by 14% of the Apomorphine-treated patients. In one randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10% of patients treated with Apomorphine and 0% of patients treated with placebo. Hallucinations resulted in discontinuation of Apomorphine in 1% of patients.
- Post marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing the dose of Apomorphine. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium.
- Patients with a major psychotic disorder should ordinarily not be treated with Apomorphine because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Apomorphine.
- Apomorphine may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical studies, dyskinesia or worsening of dyskinesia was reported in 24% of patients. Overall, 2% of Apomorphine-treated patients withdrew from studies due to dyskinesias.
- Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges and the inability to control these urges while taking one or more of the medications, including Apomorphine, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Apomorphine Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Apomorphine.
- In clinical studies, 4% of patients treated with Apomorphine experienced angina, myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close proximity to Apomorphine dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. Apomorphine has been shown to reduce resting systolic and diastolic blood pressure and may have the potential to exacerbate coronary (and cerebral) ischemia in patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, prescribers should re-evaluate the continued use of Apomorphine.
- There is a small dose related prolongation of QTc interval with doses of Apomorphine greater than 6 mg. Doses greater than 6 mg do not provide additional clinical benefit and are not recommended. Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes has not been observed in association with the use of Apomorphine at recommended doses in clinical studies, experience is too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes. The risks and benefits of Apomorphine treatment should be considered prior to initiating treatment with Apomorphine in patients with risk factors for prolonged QTc.
- A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Apomorphine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, whether other, nonergot derived dopamine agonists, such as Apomorphine can cause these reactions is unknown.
- Apomorphine may cause prolonged painful erections in some patients. In clinical studies, painful erections were reported by 3 of 361 Apomorphine-treated men, and one patient withdrew from Apomorphine therapy because of priapism. Although no patients in the clinical studies required surgical intervention, severe priapism may require surgical intervention.
- In a 2-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females, respectively; less than the maximum recommended human dose of 20 mg/day on a body surface area (mg/m2) basis). Retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies). Retinal findings were not observed in a 39-week subcutaneous toxicity study of apomorphine in monkey at doses up to 1.5 mg/kg/day, a dose similar to the MRHD on a mg/m2 basis. The clinical significance of the finding in rat has not been established but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice.
- In placebo-controlled trials, most patients received only one subcutaneous dose of Apomorphine. All patients received concomitant levodopa and 86% received a concomitant dopamine agonist. All patients had some degree of spontaneously occurring periods of hypomobility ("off episodes") at baseline.
- The most common adverse reactions (Apomorphine incidence at least 10% greater than placebo incidence) observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities.
Table 1 presents the most common adverse reactions reported by Apomorphine-naïve Parkinson's disease patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were treated for up to 4 weeks (Study 1). Individual Apomorphine doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms.
- Patients treated with Apomorphine subcutaneous injections during clinical studies, 26% of patients had injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). In addition to those in Table 1, the most common adverse reactions in pooled Apomorphine trials (occurring in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, Parkinson's disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, ecchymosis, constipation, diarrhea, weakness, and dehydration.
## Postmarketing Experience
There is limited information regarding Apomorphine Postmarketing Experience in the drug label.
# Drug Interactions
- Based on reports of profound hypotension and loss of consciousness when Apomorphine was administered with ondansetron, the concomitant use of Apomorphine with 5HT3 antagonists, including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated.
- The following adverse events were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n = 94) compared to patients not receiving these concomitant drugs (n = 456): hypotension 10% vs 4%, myocardial infarction 3% vs 1%, serious pneumonia 5% vs 3%, serious falls 9% vs 3%, and bone and joint injuries 6% vs 2%. The mechanism underlying many of these events is unknown, but may represent increased hypotension.
- Since Apomorphine is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Apomorphine. Patients with major psychotic disorders, treated with neuroleptics, should be treated with dopamine agonists only if the potential benefits outweigh the risks.
- Caution should be exercised when prescribing Apomorphine concomitantly with drugs that prolong the QT/QTc interval.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Apomorphine has been shown to be teratogenic in rabbits and embryolethal in rats when given at clinically relevant doses. Apomorphine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- No adverse developmental effects were observed when apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) was administered by subcutaneous injection to pregnant rat throughout organogenesis; the highest dose tested (3 mg/kg/day) is 1.5 times the MRHD (20 mg/day) on a mg/m2 basis. Administration of apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) by subcutaneous injection to pregnant rabbits throughout organogenesis resulted in an increased incidence of malformations of the heart and/or great vessels at the mid and high doses tested; the no-effect dose is less than the MRHD on a mg/m2 basis.
- Apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day), administered by subcutaneous injection to females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose tested. There were no effects on developmental parameters or reproductive performance in surviving offspring. The no-effect dose for developmental toxicity (1 mg/kg/day) is less than the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apomorphine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Apomorphine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Apomorphine, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- In the Apomorphine clinical development program, there were 239 patients less than age 65 treated with Apomorphine and 311 patients who were age 65 years of age or older. Confusion and hallucinations were reported more frequently with patients age 65 and older compared to patients with less than age 65. Serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased disability) were also more common in patients age 65 and older. Patients age 65 and older were more likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory disorders, and have gastrointestinal events. Patients age 65 and above were also more likely to discontinue Apomorphine treatment as a result of one or more adverse reactions.
### Gender
There is no FDA guidance on the use of Apomorphine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Apomorphine with respect to specific racial populations.
### Renal Impairment
- The starting Apomorphine dose should be reduced in patients with mild or moderate renal impairment because the concentration and exposure (Cmax and AUC) are increased in these patients. Studies in subjects with severe renal impairment have not been conducted .
### Hepatic Impairment
- Caution should be exercised when administrating Apomorphine to patients with mild and moderate hepatic impairment due to the increased Cmax and AUC in these patients. Studies of subjects with severe hepatic impairment have not been conducted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Apomorphine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Apomorphine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### Monitoring
There is limited information regarding Apomorphine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Apomorphine and IV administrations.
# Overdosage
A 62-year-old man accidentally injected 25 mg of Apomorphine subcutaneously. After 3 minutes, the patient felt nauseated and lost consciousness for 20 minutes. Afterwards, he was alert with a heart rate 40/minute and a supine blood pressure of 90/50. He recovered completely within an hour.
# Pharmacology
## Mechanism of Action
- Apomorphine is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C receptors. The precise mechanism of action of Apomorphine as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic] dopamine D2-type receptors within the caudate-putamen in the brain.
## Structure
- Apomorphine (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C17H17NO2 ∙ HCL ∙ ½ H2O. Its structural formula and molecular weight are:
## Pharmacodynamics
- In a placebo-controlled study in which patients received increasing single doses of Apomorphine from 2 mg to up to 10 mg, the mean difference in QTc (measured by Holter monitor) between Apomorphine and placebo was 0 msec at 4 mg, 1 msec at 6 mg, and 7 msec at 8 mg. Too few patients received a 10 mg dose to be able to adequately characterize the change in QTc interval at that dose.
- In a controlled trial in which patients were administered placebo or a single dose of Apomorphine (mean dose of 5.2 mg; range of 2 mg to 10 mg), the mean difference between Apomorphine and placebo in the change in QTc was about 3 msec at 20 minutes and 90 minutes. In the entire database, 2 patients (one at 2 mg and 6 mg, one at 6 mg) exhibited large QTc increments (> 60 msecs from pre-dose) and had QTc intervals greater than 500 msecs acutely after dosing. Doses of 6 mg or less thus are associated with minimal increases in QTc.
Dose-dependent mean decrements in systolic blood pressure ranged from 5 mmHg after 2 mg to 16 mmHg after 10 mg. Dose-dependent mean decrements in diastolic blood pressure ranged from 3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 20 minutes, and were maximal between 20 and 40 minutes after dosing. Lesser, but still noteworthy blood pressure decrements persisted up to at least 90 minutes after dosing.
## Pharmacokinetics
- Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 minutes to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. *Apomorphine exhibits linear pharmacokinetics over a dose range of 2 mg to 8 mg following a single subcutaneous injection of Apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease.
- The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later.
- The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 minutes to 60 minutes)he route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid autooxidation.
## Nonclinical Toxicology
- Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1 mg/kg/day, 0.3 mg/kg/day, 0.8 mg/kg/day) and female (0.3 mg/kg/day, 0.8 mg/kg/day, 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 22 months or 23 months, respectively. In males, there was an increase in Leydig cell tumors at the highest dose tested, which is less than the MRHD (20 mg) on a mg/m2 basis. This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell tumors in rats are not relevant to humans. No drug-related tumors were observed in females; the highest dose tested is similar to the MRHD on a mg/m2 basis.
- In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to 20 mg/kg/day (male) or 40 mg/kg/day (female).
- Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in vivo micronucleus assay in mice.
- Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) to male and female rats prior to and throughout the mating period and continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in cynomolgus monkey at all subcutaneous dose tested (0.3 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day); the lowest dose tested is less than the MRHD on a mg/m2 basis.
- In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of 0.2 mg/kg, 0.8 mg/kg, and 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose tested.
# Clinical Studies
The effectiveness of Apomorphine in the acute symptomatic treatment of the recurring episodes of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes), in patients with advanced Parkinson's disease was established in three randomized, controlled trials of Apomorphine given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of Parkinson's disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a concomitant catechol-ortho-methyl transferase COMT) inhibitor, and 10% were using a concomitant monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to Apomorphine (i.e., Apomorphine naïve) and Studies 2 and 3 were conducted in patients with at least 3 months of Apomorphine use immediately prior to study enrollment. Almost all patients without prior exposure to Apomorphine began taking an antiemetic (trimethobenzamide) three days prior to starting Apomorphine and 50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after initiating Apomorphine.
The change from baseline in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson's disease
### Study Nº1
- Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with advanced Parkinson's disease who had at least 2 hours of "off" time per day despite an optimized oral regimen for Parkinson's disease including levodopa and an oral dopaminergic agonist. Patients with atypical Parkinson's disease, psychosis, dementia, hypotension, or those taking dopamine antagonists were excluded from participation. In an office setting, hypomobility was allowed to occur by withholding the patients' Parkinson's disease medications overnight. The following morning, patients (in a hypomobile state) were started on study treatment in a 2:1 ratio (2 mg of Apomorphine or placebo given subcutaneously). At least 2 hours after the first dose, patients were given additional doses of study medication until they achieved a "therapeutic response" (defined as a response similar to the patient's response to their usual dose of levodopa) or until 10 mg of Apomorphine or placebo equivalent was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 mg, 6 mg, 8 mg, 10 mg of Apomorphine) or placebo equivalent.
Of the 20 patients randomized to Apomorphine 18 achieved a "therapeutic response" at about 20 minutes. The mean Apomorphine dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached a "therapeutic response." The mean change-from-baseline for UPDRS Part III score for Apomorphine group (highest dose) was statistically significant compared to that for the placebo group (Table 2).
### Study Nº2
- Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson's disease who had been using Apomorphine for at least 3 months. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received either a single dose of subcutaneous Apomorphine (at their usual dose) and placebo on different days in random order. UPDRS Part III scores were evaluated over time. The mean dose of Apomorphine was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 5 mg, 8 mg, and 10 mg). The mean change-from-baseline UPDRS Part III score for the Apomorphine group was statistically significant compared to that for the placebo group (Table 3).
### Study Nº3
- Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (Apomorphine-35; Placebo-27) with Parkinson's disease who had been using Apomorphine for at least 3 months. Patients were randomized to one of the following 4 treatments dosed once by subcutaneous administration: Apomorphine at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual Apomorphine dose, Apomorphine at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the usual Apomorphine dose + 0.2 mL. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received the randomized treatment. Apomorphine doses ranged between 2 mg – 10 mg. The mean change-from-baseline for the Apomorphine group for UPDRS Part III scores at 20 minutes post dosing was statistically significant compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in UPDRS Motor Scores over time for pooled Apomorphine and placebo administration.
# How Supplied
Apomorphine is supplied as a 10 mg/mL clear, colorless, sterile, solution in 3 mL (30 mg) glass cartridges.
- NDC 27505-004-05: Cartons of five 3 mL cartridges
- Apomorphine Pen: The pen injector is provided in a package with six needles and a carrying case.
## Storage
Store at 25°C (77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Apomorphine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Apomorphine hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Apokyn
# Look-Alike Drug Names
There is limited information regarding Apomorphine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Apomorphine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Apomorphine is a non-ergoline dopamine agonist that is FDA approved for the treatment of advanced Parkinson's disease. Common adverse reactions include yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Apomorphine should be initiated with the use of a concomitant antiemetic. Oral trimethobenzamide (300 mg three times a day) should be started 3 days prior to the initial dose of Apomorphine and continued at least during the first two months of therapy. Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated.
- The recommended starting dose of Apomorphine is 0.2 mL (2 mg). Titrate on the basis of effectiveness and tolerance, up to a maximum recommended dose of 0.6 mL (6 mg). There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average frequency of dosing in the development program was 3 times per day. There is limited experience with single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses greater than 2 mL (20 mg).
- Begin dosing when patients are in an "off" state. The initial dose should be a 0.2 mL (2 mg) test dose in a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who develop clinically significant orthostatic hypotension in response to this test dose of Apomorphine should not be considered candidates for treatment with Apomorphine.
- If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 0.2 mL (2 mg), used on an as needed basis to treat recurring "off" episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.
- The general principle guiding subsequent dosing (described in detail below) is to determine that the patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose.
- If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of 0.4 mL (4 mg) may be administered under medical supervision, at least 2-hours after the initial test dose, at the next observed "off" period. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring "off" episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.
- If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be administered during a separate "off" period under medical supervision, at least 2-hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing "off" episodes. If needed, and the 0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an out-patient basis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Apomorphine hydrochloride in adult patients.
### Non–Guideline-Supported Use
- Dosage
Subcutaneous injections: 0.25 to 1 milligram/day[1].
Sublingual: 2mg [2]
- Subcutaneous injections: 0.25 to 1 milligram/day[1].
- Sublingual: 2mg [2]
- Dosage: Subcutaneous injections of 12 to 18 milligrams/night[3].
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Apomorphine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Apomorphine hydrochloride in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Apomorphine hydrochloride in pediatric patients.
# Contraindications
Apomorphine is contraindicated in patients:
- Using concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron. There have been reports of profound hypotension and loss of consciousness when Apomorphine was administered with ondansetron.
- With hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema to apomorphine or to any of the excipients including a sulfite (i.e., sodium metabisulfite). Patients with a sulfite sensitivity may experience various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. Patients who experience any hypersensitivity/allergic reaction to Apomorphine should avoid taking Apomorphine again.
# Warnings
- Following intravenous administration of Apomorphine, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, Apomorphine should not be administered intravenously.
- Apomorphine causes severe nausea and vomiting when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an antiemetic, for three days prior to study enrollment, and were then encouraged to continue trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical studies, 31% and 11% of the Apomorphine-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued Apomorphine due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing Apomorphine The average time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years).
- The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) to reduce the incidence of nausea and/or vomiting in Apomorphine-treated patients has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with Parkinson's disease and should be avoided.
- There have been reports in the literature of patients treated with Apomorphine subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with Apomorphine and it is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not give such a history. Somnolence was reported in 35% of patients treated with Apomorphine and in none of the patients in the placebo group. Prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Before initiating treatment with Apomorphine, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with Apomorphine, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation (e.g., conversations, eating, etc.), Apomorphine should ordinarily be discontinued. If a decision is made to continue Apomorphine patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- In clinical studies, approximately 2% of Apomorphine-treated patients experienced syncope.
- Dopamine agonists, including Apomorphine, may cause orthostatic hypotension at any time but especially during dose escalation. Patients with Parkinson's disease may also have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.
- Patients undergoing titration of Apomorphine showed an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (≥ 20 mmHg decrease) when evaluated at various times after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension (≥ 30 mmHg decrease and systolic BP ≤ 90 mmHg) after subcutaneous apomorphine injection. In clinical trials of Apomorphine in patients with advanced Parkinson's disease, 59 of 550 patients (11%) had orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 4 patients (< 1%) and resulted in withdrawal of Apomorphine in 10 patients (2%). These events occurred both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other significant adverse events seen (e.g., falls), is unknown. Apomorphine causes dose-related decreases in systolic blood pressure (SBP) and diastolic blood pressure (DBP).
- The hypotensive effects of Apomorphine may be increased by the concomitant use of alcohol, antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid alcohol when using Apomorphine. Check blood pressure for hypotension and orthostatic hypotension in patients Apomorphine with concomitant antihypertensive medications and/or vasodilators.
- Patients with Parkinson's disease (PD) are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat PD. Subcutaneous Apomorphine might increase the risk of falling by simultaneously lowering blood pressure and altering mobility. In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of patients had falls that were considered serious.
- In clinical studies, hallucinations were reported by 14% of the Apomorphine-treated patients. In one randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10% of patients treated with Apomorphine and 0% of patients treated with placebo. Hallucinations resulted in discontinuation of Apomorphine in 1% of patients.
- Post marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing the dose of Apomorphine. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium.
- Patients with a major psychotic disorder should ordinarily not be treated with Apomorphine because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Apomorphine.
- Apomorphine may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical studies, dyskinesia or worsening of dyskinesia was reported in 24% of patients. Overall, 2% of Apomorphine-treated patients withdrew from studies due to dyskinesias.
- Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges and the inability to control these urges while taking one or more of the medications, including Apomorphine, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Apomorphine Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Apomorphine.
- In clinical studies, 4% of patients treated with Apomorphine experienced angina, myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close proximity to Apomorphine dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. Apomorphine has been shown to reduce resting systolic and diastolic blood pressure and may have the potential to exacerbate coronary (and cerebral) ischemia in patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, prescribers should re-evaluate the continued use of Apomorphine.
- There is a small dose related prolongation of QTc interval with doses of Apomorphine greater than 6 mg. Doses greater than 6 mg do not provide additional clinical benefit and are not recommended. Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes has not been observed in association with the use of Apomorphine at recommended doses in clinical studies, experience is too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes. The risks and benefits of Apomorphine treatment should be considered prior to initiating treatment with Apomorphine in patients with risk factors for prolonged QTc.
- A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Apomorphine for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, whether other, nonergot derived dopamine agonists, such as Apomorphine can cause these reactions is unknown.
- Apomorphine may cause prolonged painful erections in some patients. In clinical studies, painful erections were reported by 3 of 361 Apomorphine-treated men, and one patient withdrew from Apomorphine therapy because of priapism. Although no patients in the clinical studies required surgical intervention, severe priapism may require surgical intervention.
- In a 2-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females, respectively; less than the maximum recommended human dose of 20 mg/day on a body surface area (mg/m2) basis). Retinal atrophy/degeneration has been observed in albino rats treated with other dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies). Retinal findings were not observed in a 39-week subcutaneous toxicity study of apomorphine in monkey at doses up to 1.5 mg/kg/day, a dose similar to the MRHD on a mg/m2 basis. The clinical significance of the finding in rat has not been established but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice.
- In placebo-controlled trials, most patients received only one subcutaneous dose of Apomorphine. All patients received concomitant levodopa and 86% received a concomitant dopamine agonist. All patients had some degree of spontaneously occurring periods of hypomobility ("off episodes") at baseline.
- The most common adverse reactions (Apomorphine incidence at least 10% greater than placebo incidence) observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities.
Table 1 presents the most common adverse reactions reported by Apomorphine-naïve Parkinson's disease patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were treated for up to 4 weeks (Study 1). Individual Apomorphine doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms.
- Patients treated with Apomorphine subcutaneous injections during clinical studies, 26% of patients had injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). In addition to those in Table 1, the most common adverse reactions in pooled Apomorphine trials (occurring in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, Parkinson's disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, ecchymosis, constipation, diarrhea, weakness, and dehydration.
## Postmarketing Experience
There is limited information regarding Apomorphine Postmarketing Experience in the drug label.
# Drug Interactions
- Based on reports of profound hypotension and loss of consciousness when Apomorphine was administered with ondansetron, the concomitant use of Apomorphine with 5HT3 antagonists, including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated.
- The following adverse events were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n = 94) compared to patients not receiving these concomitant drugs (n = 456): hypotension 10% vs 4%, myocardial infarction 3% vs 1%, serious pneumonia 5% vs 3%, serious falls 9% vs 3%, and bone and joint injuries 6% vs 2%. The mechanism underlying many of these events is unknown, but may represent increased hypotension.
- Since Apomorphine is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Apomorphine. Patients with major psychotic disorders, treated with neuroleptics, should be treated with dopamine agonists only if the potential benefits outweigh the risks.
- Caution should be exercised when prescribing Apomorphine concomitantly with drugs that prolong the QT/QTc interval.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Apomorphine has been shown to be teratogenic in rabbits and embryolethal in rats when given at clinically relevant doses. Apomorphine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- No adverse developmental effects were observed when apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) was administered by subcutaneous injection to pregnant rat throughout organogenesis; the highest dose tested (3 mg/kg/day) is 1.5 times the MRHD (20 mg/day) on a mg/m2 basis. Administration of apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) by subcutaneous injection to pregnant rabbits throughout organogenesis resulted in an increased incidence of malformations of the heart and/or great vessels at the mid and high doses tested; the no-effect dose is less than the MRHD on a mg/m2 basis.
- Apomorphine (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day), administered by subcutaneous injection to females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose tested. There were no effects on developmental parameters or reproductive performance in surviving offspring. The no-effect dose for developmental toxicity (1 mg/kg/day) is less than the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apomorphine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Apomorphine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Apomorphine, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- In the Apomorphine clinical development program, there were 239 patients less than age 65 treated with Apomorphine and 311 patients who were age 65 years of age or older. Confusion and hallucinations were reported more frequently with patients age 65 and older compared to patients with less than age 65. Serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased disability) were also more common in patients age 65 and older. Patients age 65 and older were more likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory disorders, and have gastrointestinal events. Patients age 65 and above were also more likely to discontinue Apomorphine treatment as a result of one or more adverse reactions.
### Gender
There is no FDA guidance on the use of Apomorphine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Apomorphine with respect to specific racial populations.
### Renal Impairment
- The starting Apomorphine dose should be reduced in patients with mild or moderate renal impairment because the concentration and exposure (Cmax and AUC) are increased in these patients. Studies in subjects with severe renal impairment have not been conducted .
### Hepatic Impairment
- Caution should be exercised when administrating Apomorphine to patients with mild and moderate hepatic impairment due to the increased Cmax and AUC in these patients. Studies of subjects with severe hepatic impairment have not been conducted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Apomorphine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Apomorphine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### Monitoring
There is limited information regarding Apomorphine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Apomorphine and IV administrations.
# Overdosage
A 62-year-old man accidentally injected 25 mg of Apomorphine subcutaneously. After 3 minutes, the patient felt nauseated and lost consciousness for 20 minutes. Afterwards, he was alert with a heart rate 40/minute and a supine blood pressure of 90/50. He recovered completely within an hour.
# Pharmacology
## Mechanism of Action
- Apomorphine is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C receptors. The precise mechanism of action of Apomorphine as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic] dopamine D2-type receptors within the caudate-putamen in the brain.
## Structure
- Apomorphine (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C17H17NO2 ∙ HCL ∙ ½ H2O. Its structural formula and molecular weight are:
## Pharmacodynamics
- In a placebo-controlled study in which patients received increasing single doses of Apomorphine from 2 mg to up to 10 mg, the mean difference in QTc (measured by Holter monitor) between Apomorphine and placebo was 0 msec at 4 mg, 1 msec at 6 mg, and 7 msec at 8 mg. Too few patients received a 10 mg dose to be able to adequately characterize the change in QTc interval at that dose.
- In a controlled trial in which patients were administered placebo or a single dose of Apomorphine (mean dose of 5.2 mg; range of 2 mg to 10 mg), the mean difference between Apomorphine and placebo in the change in QTc was about 3 msec at 20 minutes and 90 minutes. In the entire database, 2 patients (one at 2 mg and 6 mg, one at 6 mg) exhibited large QTc increments (> 60 msecs from pre-dose) and had QTc intervals greater than 500 msecs acutely after dosing. Doses of 6 mg or less thus are associated with minimal increases in QTc.
Dose-dependent mean decrements in systolic blood pressure ranged from 5 mmHg after 2 mg to 16 mmHg after 10 mg. Dose-dependent mean decrements in diastolic blood pressure ranged from 3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 20 minutes, and were maximal between 20 and 40 minutes after dosing. Lesser, but still noteworthy blood pressure decrements persisted up to at least 90 minutes after dosing.
## Pharmacokinetics
- Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 minutes to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. *Apomorphine exhibits linear pharmacokinetics over a dose range of 2 mg to 8 mg following a single subcutaneous injection of Apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease.
- The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later.
- The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 minutes to 60 minutes)he route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid autooxidation.
## Nonclinical Toxicology
- Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1 mg/kg/day, 0.3 mg/kg/day, 0.8 mg/kg/day) and female (0.3 mg/kg/day, 0.8 mg/kg/day, 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 22 months or 23 months, respectively. In males, there was an increase in Leydig cell tumors at the highest dose tested, which is less than the MRHD (20 mg) on a mg/m2 basis. This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell tumors in rats are not relevant to humans. No drug-related tumors were observed in females; the highest dose tested is similar to the MRHD on a mg/m2 basis.
- In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to 20 mg/kg/day (male) or 40 mg/kg/day (female).
- Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in vivo micronucleus assay in mice.
- Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) to male and female rats prior to and throughout the mating period and continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in cynomolgus monkey at all subcutaneous dose tested (0.3 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day); the lowest dose tested is less than the MRHD on a mg/m2 basis.
- In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of 0.2 mg/kg, 0.8 mg/kg, and 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose tested.
# Clinical Studies
The effectiveness of Apomorphine in the acute symptomatic treatment of the recurring episodes of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes), in patients with advanced Parkinson's disease was established in three randomized, controlled trials of Apomorphine given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of Parkinson's disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a concomitant catechol-ortho-methyl transferase COMT) inhibitor, and 10% were using a concomitant monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to Apomorphine (i.e., Apomorphine naïve) and Studies 2 and 3 were conducted in patients with at least 3 months of Apomorphine use immediately prior to study enrollment. Almost all patients without prior exposure to Apomorphine began taking an antiemetic (trimethobenzamide) three days prior to starting Apomorphine and 50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after initiating Apomorphine.
The change from baseline in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson's disease
### Study Nº1
- Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with advanced Parkinson's disease who had at least 2 hours of "off" time per day despite an optimized oral regimen for Parkinson's disease including levodopa and an oral dopaminergic agonist. Patients with atypical Parkinson's disease, psychosis, dementia, hypotension, or those taking dopamine antagonists were excluded from participation. In an office setting, hypomobility was allowed to occur by withholding the patients' Parkinson's disease medications overnight. The following morning, patients (in a hypomobile state) were started on study treatment in a 2:1 ratio (2 mg of Apomorphine or placebo given subcutaneously). At least 2 hours after the first dose, patients were given additional doses of study medication until they achieved a "therapeutic response" (defined as a response similar to the patient's response to their usual dose of levodopa) or until 10 mg of Apomorphine or placebo equivalent was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 mg, 6 mg, 8 mg, 10 mg of Apomorphine) or placebo equivalent.
Of the 20 patients randomized to Apomorphine 18 achieved a "therapeutic response" at about 20 minutes. The mean Apomorphine dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached a "therapeutic response." The mean change-from-baseline for UPDRS Part III score for Apomorphine group (highest dose) was statistically significant compared to that for the placebo group (Table 2).
### Study Nº2
- Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson's disease who had been using Apomorphine for at least 3 months. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received either a single dose of subcutaneous Apomorphine (at their usual dose) and placebo on different days in random order. UPDRS Part III scores were evaluated over time. The mean dose of Apomorphine was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 5 mg, 8 mg, and 10 mg). The mean change-from-baseline UPDRS Part III score for the Apomorphine group was statistically significant compared to that for the placebo group (Table 3).
### Study Nº3
- Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (Apomorphine-35; Placebo-27) with Parkinson's disease who had been using Apomorphine for at least 3 months. Patients were randomized to one of the following 4 treatments dosed once by subcutaneous administration: Apomorphine at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual Apomorphine dose, Apomorphine at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the usual Apomorphine dose + 0.2 mL. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received the randomized treatment. Apomorphine doses ranged between 2 mg – 10 mg. The mean change-from-baseline for the Apomorphine group for UPDRS Part III scores at 20 minutes post dosing was statistically significant compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in UPDRS Motor Scores over time for pooled Apomorphine and placebo administration.
# How Supplied
Apomorphine is supplied as a 10 mg/mL clear, colorless, sterile, solution in 3 mL (30 mg) glass cartridges.
- NDC 27505-004-05: Cartons of five 3 mL cartridges
- Apomorphine Pen: The pen injector is provided in a package with six needles and a carrying case.
## Storage
Store at 25°C (77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Apomorphine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Apomorphine hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Apokyn
# Look-Alike Drug Names
There is limited information regarding Apomorphine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/APO-Go | |
925bab0cccafc3c04a4de8386cb32d3d8a708a29 | wikidoc | Aquaporin 1 | Aquaporin 1
Aquaporin 1 is a protein that in humans is encoded by the AQP1 gene.
AQP1 is a widely expressed water channel, whose physiological function has been most thoroughly characterized in the kidney. It is found in the basolateral and apical plasma membranes of the proximal tubules, the descending limb of the loop of Henle, and in the descending portion of the vasa recta. Additionally, it is found in red blood cells, vascular endothelium, the gastrointestinal tract, sweat glands, and lungs.
It is not regulated by vasopressin (ADH).
# Function
Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). This gene encodes an aquaporin which functions as a molecular water channel protein. It is a homotetramer with 6 bilayer spanning domains and N-glycosylation sites. The protein physically resembles channel proteins and is abundant in erythrocytes and renal tubes. The gene encoding this aquaporin is a possible candidate for disorders involving imbalance in ocular fluid movement. | Aquaporin 1
Aquaporin 1 is a protein that in humans is encoded by the AQP1 gene.
AQP1 is a widely expressed water channel, whose physiological function has been most thoroughly characterized in the kidney. It is found in the basolateral and apical plasma membranes of the proximal tubules, the descending limb of the loop of Henle, and in the descending portion of the vasa recta. Additionally, it is found in red blood cells, vascular endothelium, the gastrointestinal tract, sweat glands, and lungs.
It is not regulated by vasopressin (ADH).
# Function
Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). This gene encodes an aquaporin which functions as a molecular water channel protein. It is a homotetramer with 6 bilayer spanning domains and N-glycosylation sites. The protein physically resembles channel proteins and is abundant in erythrocytes and renal tubes. The gene encoding this aquaporin is a possible candidate for disorders involving imbalance in ocular fluid movement.[1] | https://www.wikidoc.org/index.php/AQP1 | |
7ddae9713f659325479047992e1dcb4aad5ec928 | wikidoc | ASPM (gene) | ASPM (gene)
Abnormal spindle-like microcephaly-associated protein also known as abnormal spindle protein homolog or Asp homolog is a protein that in humans is encoded by the ASPM gene. ASPM is located on chromosome 1, band q31 (1q31). Defective forms of the ASPM gene are associated with autosomal recessive primary microcephaly.
"ASPM" is an acronym for "Abnormal Spindle-like, Microcephaly-associated", which reflects its being an ortholog to the Drosophila melanogaster "abnormal spindle" (asp) gene. The expressed protein product of the asp gene is essential for normal mitotic spindle function in embryonic neuroblasts and regulation of neurogenesis.
A new allele of ASPM arose sometime in the past 14,000 years (mean estimate 5,800 years), during the Holocene, it seems to have swept through much of the European and Middle-Eastern population. Although the new allele is evidently beneficial, researchers do not know what it does.
# Animal studies
The mouse gene, Aspm, is expressed in the primary sites of prenatal cerebral cortical neurogenesis. The difference between Aspm and ASPM is a single, large insertion coding for so-called IQ domains. Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation. The function is conserved, the C. elegans protein ASPM-1 was shown to be localized to spindle asters, where it regulates spindle organization and rotation by interacting with calmodulin, dynein and NuMA-related LIN-5.
# Evolution
A new allele (version) of ASPM appeared sometime within the last 14,100 years, with a mean estimate of 5,800 years ago. The new allele has a frequency of about 50% in populations of the Middle East and Europe, it is less frequent in East Asia, and has low frequencies among Sub-Saharan African populations. It is also found with an unusually high percentage among the people of Papua New Guinea, with a 59.4% occurrence.
The mean estimated age of the ASPM allele of 5,800 years ago, roughly correlates with the development of written language, spread of agriculture and development of cities. Currently, two alleles of this gene exist: the older (pre-5,800 years ago) and the newer (post-5,800 years ago). About 10% of humans have two copies of the new ASPM allele, while about 50% have two copies of the old allele. The other 40% of humans have one copy of each. Of those with an instance of the new allele, 50% of them are an identical copy. The allele affects genotype over a large (62 kbp) region, a so called selective sweep which signals a rapid spread of a mutation (such as the new ASPM) through the population; this indicates that the mutation is somehow advantageous to the individual.
Testing the IQ of those with and without new ASPM allele has shown no difference in average IQ, providing no evidence to support the notion that the gene increases intelligence. However statistical analysis has shown that the older forms of the gene are found more heavily in populations that speak tonal languages like Chinese or many Sub-Saharan African languages.
Other genes related to brain development appear to have come under selective pressure in different populations.
The DAB1 gene, involved in organizing cell layers in the cerebral cortex, shows evidence of a selective sweep in the Chinese. The SV2B gene, which encodes a synaptic vesicle protein, likewise shows evidence of a selective sweep in African-Americans. | ASPM (gene)
Abnormal spindle-like microcephaly-associated protein also known as abnormal spindle protein homolog or Asp homolog is a protein that in humans is encoded by the ASPM gene.[1] ASPM is located on chromosome 1, band q31 (1q31).[2] Defective forms of the ASPM gene are associated with autosomal recessive primary microcephaly.[1][3]
"ASPM" is an acronym for "Abnormal Spindle-like, Microcephaly-associated", which reflects its being an ortholog to the Drosophila melanogaster "abnormal spindle" (asp) gene. The expressed protein product of the asp gene is essential for normal mitotic spindle function in embryonic neuroblasts and regulation of neurogenesis.[2][4]
A new allele of ASPM arose sometime in the past 14,000 years (mean estimate 5,800 years), during the Holocene, it seems to have swept through much of the European and Middle-Eastern population. Although the new allele is evidently beneficial, researchers do not know what it does.
# Animal studies
The mouse gene, Aspm, is expressed in the primary sites of prenatal cerebral cortical neurogenesis. The difference between Aspm and ASPM is a single, large insertion coding for so-called IQ domains.[5] Studies in mice also suggest a role of the expressed Aspm gene product in mitotic spindle regulation.[6] The function is conserved, the C. elegans protein ASPM-1 was shown to be localized to spindle asters, where it regulates spindle organization and rotation by interacting with calmodulin, dynein and NuMA-related LIN-5.[7]
# Evolution
A new allele (version) of ASPM appeared sometime within the last 14,100 years, with a mean estimate of 5,800 years ago. The new allele has a frequency of about 50% in populations of the Middle East and Europe, it is less frequent in East Asia, and has low frequencies among Sub-Saharan African populations.[8] It is also found with an unusually high percentage among the people of Papua New Guinea, with a 59.4% occurrence.[9]
The mean estimated age of the ASPM allele of 5,800 years ago, roughly correlates with the development of written language, spread of agriculture and development of cities.[10] Currently, two alleles of this gene exist: the older (pre-5,800 years ago) and the newer (post-5,800 years ago). About 10% of humans have two copies of the new ASPM allele, while about 50% have two copies of the old allele. The other 40% of humans have one copy of each. Of those with an instance of the new allele, 50% of them are an identical copy.[11] The allele affects genotype over a large (62 kbp) region, a so called selective sweep which signals a rapid spread of a mutation (such as the new ASPM) through the population; this indicates that the mutation is somehow advantageous to the individual.[9][12]
Testing the IQ of those with and without new ASPM allele has shown no difference in average IQ, providing no evidence to support the notion that the gene increases intelligence.[12][13][14] However statistical analysis has shown that the older forms of the gene are found more heavily in populations that speak tonal languages like Chinese or many Sub-Saharan African languages.[15]
Other genes related to brain development appear to have come under selective pressure in different populations.
The DAB1 gene, involved in organizing cell layers in the cerebral cortex, shows evidence of a selective sweep in the Chinese. The SV2B gene, which encodes a synaptic vesicle protein, likewise shows evidence of a selective sweep in African-Americans.[16][17] | https://www.wikidoc.org/index.php/ASPM_(gene) | |
489e73d33f7ae91ecb05e16b68247161301d78b0 | wikidoc | AT-10 resin | AT-10 resin
# Overview
AT-10 is a synthetic resin, mainly used in the manufacture of ultra-thin condoms. It has a higher strength in thinner sheets than other materials such as natural latex.
AT-10 is not stretchable, but does cling to skin to form a "wrap". It is well suited to condom manufacture as it:
- can be made into very thin sheets, circa 15 micrometres thick
- is hypoallergenic so does not have the potential to cause allergic reactions on contact with skin like natural latex
- allows body heat to pass through quickly
- is strong at relatively thin levels
- is non-porous
- does not degrade when exposed to common oils, such as oil based lubricants | AT-10 resin
# Overview
AT-10 is a synthetic resin, mainly used in the manufacture of ultra-thin condoms. It has a higher strength in thinner sheets than other materials such as natural latex.
AT-10 is not stretchable, but does cling to skin to form a "wrap". It is well suited to condom manufacture as it:
- can be made into very thin sheets, circa 15 micrometres thick
- is hypoallergenic so does not have the potential to cause allergic reactions on contact with skin like natural latex
- allows body heat to pass through quickly
- is strong at relatively thin levels
- is non-porous
- does not degrade when exposed to common oils, such as oil based lubricants
# External links
- Pasante Unique condoms an example of the ultra-thin condoms made from AT10 Resin.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/AT-10_Resin | |
e224db3d7f1dfb6760d0d8fc725122ba94c16e88 | wikidoc | AVERT Trial | AVERT Trial
# Objective
To compare the outcome of aggressive lipid lowering to that of angioplasty in stable coronary artery disease patients, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of LDL-C of at least 115 mg/dL who were referred for percutaneous revascularization.
# Methods
Atorvastatin versus Revascularization Treatment (AVERT) trial was a randomized comparative study that enrolled 341 patients with stable CAD. All the patients were randomly assigned to treatment with either atorvastatin 80 mg per day or percutaneous revascularization procedure (angioplasty) followed by usual care. The follow-up period was 18 months.
# Results
At the end of follow-up period atorvastatin was associated with 36% lower incidence of ischemic events compared to angioplasty. Also, patients who received atorvastatin had a significantly longer time to the first ischemic event.
# Conclusion
Aggressive lipid lowering therapy with atorvastatin is at least as effective as angioplasty in reducing the incidence of ischemic events in low-risk patients with stable CAD. | AVERT Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To compare the outcome of aggressive lipid lowering to that of angioplasty in stable coronary artery disease patients, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of LDL-C of at least 115 mg/dL who were referred for percutaneous revascularization.
# Methods
Atorvastatin versus Revascularization Treatment (AVERT) trial was a randomized comparative study that enrolled 341 patients with stable CAD. All the patients were randomly assigned to treatment with either atorvastatin 80 mg per day or percutaneous revascularization procedure (angioplasty) followed by usual care. The follow-up period was 18 months.
# Results
At the end of follow-up period atorvastatin was associated with 36% lower incidence of ischemic events compared to angioplasty. Also, patients who received atorvastatin had a significantly longer time to the first ischemic event.
# Conclusion
Aggressive lipid lowering therapy with atorvastatin is at least as effective as angioplasty in reducing the incidence of ischemic events in low-risk patients with stable CAD.[1][2] | https://www.wikidoc.org/index.php/AVERT_Trial | |
4d90a402a9f13b4be200fefc93bb0fc73a16f70d | wikidoc | Abel's test | Abel's test
In mathematics, Abel's test (also known as Abel's criterion) is a method of testing for the convergence of an infinite series. The test is named after mathematician Niels Abel. There are two slightly different versions of Abel's test – one is used with series of real numbers, and the other is used with power series in complex analysis.
# Abel's test in real analysis
Given two sequences of real numbers, \{a_n\} and \{b_n\}, if the sequences satisfy
- \sum^{\infty}_{n=1}a_n converges
- \lbrace b_n \rbrace\, is monotonic and \lim_{n \rightarrow \infty} b_n \ne \infty
then the series
converges.
# Abel's test in complex analysis
A closely related convergence test, also known as Abel's test, can often be used to establish the convergence of a power series on the boundary of its circle of convergence. Specifically, Abel's test states that if
\lim_{n\rightarrow\infty} a_n = 0\,
and the series
f(z) = \sum_{n=0}^\infty a_nz^n\,
converges when |z| 1, and the coefficients {an} are positive real numbers decreasing monotonically toward the limit zero for n > m (for large enough n, in other words), then the power series for f(z) converges everywhere on the unit circle, except when z = 1. Abel's test cannot be applied when z = 1, so convergence at that single point must be investigated separately. Notice that Abel's test can also be applied to a power series with radius of convergence R ≠ 1 by a simple change of variables ζ = z/R.
Proof of Abel's test: Suppose that z is a point on the unit circle, z ≠ 1. Then
z = e^{i\theta} \quad\Rightarrow\quad z^{\frac{1}{2}} - z^{-\frac{1}{2}} =
2i\sin{\textstyle \frac{\theta}{2}} \ne 0
so that, for any two positive integers p > q > m, we can write
\begin{align}
2i\sin{\textstyle \frac{\theta}{2}}\left(S_p - S_q\right) & =
\sum_{n=q+1}^p a_n \left(z^{n+\frac{1}{2}} - z^{n-\frac{1}{2}}\right)\\
& = \left -
a_{q+1}z^{q+\frac{1}{2}} + a_pz^{p+\frac{1}{2}}\,
\end{align}
where Sp and Sq are partial sums:
S_p = \sum_{n=0}^p a_nz^n.\,
But now, since |z| = 1 and the an are monotonically decreasing positive real numbers when n > m, we can also write
\begin{align}
\left| 2i\sin{\textstyle \frac{\theta}{2}}\left(S_p - S_q\right)\right| & =
\left| \sum_{n=q+1}^p a_n \left(z^{n+\frac{1}{2}} - z^{n-\frac{1}{2}}\right)\right| \\
& \le \left +
\left| a_{q+1}z^{q+\frac{1}{2}}\right| + \left| a_pz^{p+\frac{1}{2}}\right| \\
& = \left +a_{q+1} + a_p \\
& = a_{q+1} - a_p + a_{q+1} + a_p = 2a_{q+1}\,
\end{align}
Now we can apply Cauchy's criterion to conclude that the power series for f(z) converges at the chosen point z ≠ 1, because sin(½θ) ≠ 0 is a fixed quantity, and aq+1 can be made smaller than any given ε > 0 by choosing a large enough q. | Abel's test
In mathematics, Abel's test (also known as Abel's criterion) is a method of testing for the convergence of an infinite series. The test is named after mathematician Niels Abel. There are two slightly different versions of Abel's test – one is used with series of real numbers, and the other is used with power series in complex analysis.
# Abel's test in real analysis
Given two sequences of real numbers, <math>\{a_n\}</math> and <math>\{b_n\}</math>, if the sequences satisfy
- <math> \sum^{\infty}_{n=1}a_n </math> converges
- <math>\lbrace b_n \rbrace\,</math> is monotonic and <math>\lim_{n \rightarrow \infty} b_n \ne \infty</math>
then the series
converges.
# Abel's test in complex analysis
A closely related convergence test, also known as Abel's test, can often be used to establish the convergence of a power series on the boundary of its circle of convergence. Specifically, Abel's test states that if
\lim_{n\rightarrow\infty} a_n = 0\,
</math>
and the series
f(z) = \sum_{n=0}^\infty a_nz^n\,
</math>
converges when |z| < 1 and diverges when |z| > 1, and the coefficients {an} are positive real numbers decreasing monotonically toward the limit zero for n > m (for large enough n, in other words), then the power series for f(z) converges everywhere on the unit circle, except when z = 1. Abel's test cannot be applied when z = 1, so convergence at that single point must be investigated separately. Notice that Abel's test can also be applied to a power series with radius of convergence R ≠ 1 by a simple change of variables ζ = z/R.[1]
Proof of Abel's test: Suppose that z is a point on the unit circle, z ≠ 1. Then
z = e^{i\theta} \quad\Rightarrow\quad z^{\frac{1}{2}} - z^{-\frac{1}{2}} =
2i\sin{\textstyle \frac{\theta}{2}} \ne 0
</math>
so that, for any two positive integers p > q > m, we can write
\begin{align}
2i\sin{\textstyle \frac{\theta}{2}}\left(S_p - S_q\right) & =
\sum_{n=q+1}^p a_n \left(z^{n+\frac{1}{2}} - z^{n-\frac{1}{2}}\right)\\
& = \left[\sum_{n=q+2}^p \left(a_{n-1} - a_n\right) z^{n-\frac{1}{2}}\right] -
a_{q+1}z^{q+\frac{1}{2}} + a_pz^{p+\frac{1}{2}}\,
\end{align}
</math>
where Sp and Sq are partial sums:
S_p = \sum_{n=0}^p a_nz^n.\,
</math>
But now, since |z| = 1 and the an are monotonically decreasing positive real numbers when n > m, we can also write
\begin{align}
\left| 2i\sin{\textstyle \frac{\theta}{2}}\left(S_p - S_q\right)\right| & =
\left| \sum_{n=q+1}^p a_n \left(z^{n+\frac{1}{2}} - z^{n-\frac{1}{2}}\right)\right| \\
& \le \left[\sum_{n=q+2}^p \left| \left(a_{n-1} - a_n\right) z^{n-\frac{1}{2}}\right|\right] +
\left| a_{q+1}z^{q+\frac{1}{2}}\right| + \left| a_pz^{p+\frac{1}{2}}\right| \\
& = \left[\sum_{n=q+2}^p \left(a_{n-1} - a_n\right)\right] +a_{q+1} + a_p \\
& = a_{q+1} - a_p + a_{q+1} + a_p = 2a_{q+1}\,
\end{align}
</math>
Now we can apply Cauchy's criterion to conclude that the power series for f(z) converges at the chosen point z ≠ 1, because sin(½θ) ≠ 0 is a fixed quantity, and aq+1 can be made smaller than any given ε > 0 by choosing a large enough q.
# External links
- Proof (for real series) at PlanetMath.org
# Notes
- ↑ (Moretti, 1964, p. 91) | https://www.wikidoc.org/index.php/Abel%27s_test | |
15326b77403ed41e129073e957cfc752764fdfdd | wikidoc | Abemaciclib | Abemaciclib
# Disclaimer
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# Overview
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) that is FDA approved for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Common adverse reactions include diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
- In combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
- As monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
- 150 mg taken orally twice daily.
- 500 mg of fulverstrant is administered on Days 1, 15, and 29; and once monthly thereafter.
- 200 mg taken orally twice daily.
- Continue treatment until disease progression or unacceptable toxicity. Abemaciclib may be taken with or without food.
- Instruct patients to take their doses of abemaciclib at approximately the same times every day.
- If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Abemaciclib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Diarrhea occurred in 81% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 90% of patients receiving abemaciclib alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and in 20% of patients receiving abemaciclib alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.
- Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue abemaciclib until toxicity resolves to ≤Grade 1, and then resume abemaciclib at the next lower dose.
- Neutropenia occurred in 41% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 37% of patients receiving abemaciclib alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and in 27% of patients receiving abemaciclib in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1 was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.
- Monitor complete blood counts prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
- Febrile neutropenia has been reported in <1% of patients exposed to abemaciclib in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.
- In MONARCH 3, Grade ≥3 increases in ALT (6% versus 2%) and AST (3% versus 1%) were reported in the abemaciclib and placebo arms, respectively. In MONARCH 2, Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the abemaciclib and placebo arms, respectively.
- In MONARCH 3, for patients receiving abemaciclib plus an aromatase inhibitor with Grade ≥3 ALT increased, median time to onset was 61 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 2, for patients receiving abemaciclib plus fulvestrant with Grade ≥3 ALT increased, median time to onset was 57 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 3, for patients receiving abemaciclib plus an aromatase inhibitor with Grade ≥3 AST increased, median time to onset was 71 days, and median time to resolution was 15 days. In MONARCH 2, for patients receiving abemaciclib plus fulvestrant with Grade ≥3 AST increased, median time to onset was 185 days, and median time to resolution was 13 days.
- Monitor liver function tests (LFTs) prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.
- In MONARCH 3, venous thromboembolic events were reported in 5% of patients treated with abemaciclib plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo. In MONARCH 2, venous thromboembolic events were reported in 5% of patients treated with abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported.
- Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.
- Based on findings from animal studies and the mechanism of action, abemaciclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with abemaciclib and for at least 3 weeks after the last dose.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### MONARCH 3: Abemaciclib in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy
- Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting.
- MONARCH 3 was a study of 488 women receiving abemaciclib plus an aromatase inhibitor or placebo plus an aromatase inhibitor. Patients were randomly assigned to receive 150 mg of abemaciclib or placebo orally twice daily, plus physician's choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the abemaciclib arm and 13.9 months for the placebo arm. Median dose compliance was 98% for the abemaciclib arm and 99% for the placebo arm.
- Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 13% of patients receiving abemaciclib plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. Abemaciclib dose reductions due to neutropenia of any grade occurred in 11% of patients receiving abemaciclib plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.
- Permanent treatment discontinuation due to an adverse event was reported in 13% of patients receiving abemaciclib plus an aromatase inhibitor and in 3% placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving abemaciclib plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%).
- Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of abemaciclib plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving abemaciclib plus an aromatase inhibitor included: 3 (0.9%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE event, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction.
- The most common adverse reactions reported (≥20%) in the abemaciclib arm and ≥2% than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Diarrhea incidence was greatest during the first month of abemaciclib dosing. The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions. Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days.
- Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with abemaciclib plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.
- Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.
- The safety of abemaciclib (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to abemaciclib in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of abemaciclib plus fulvestrant in MONARCH 2.
- Median duration of treatment was 12 months for patients receiving abemaciclib plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.
- Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus fulvestrant. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 19% of patients receiving abemaciclib plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving abemaciclib plus fulvestrant compared to no patients receiving placebo plus fulvestrant.
- Permanent study treatment discontinuation due to an adverse event were reported in 9% of patients receiving abemaciclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving abemaciclib plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).
- Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of abemaciclib plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving abemaciclib plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.
- The most common adverse reactions reported (≥20%) in the abemaciclib arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.
- Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.
- Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting
- Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer. Patients received 200 mg abemaciclib orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.
- Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each) abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).
- Deaths during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection.
- The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.
## Postmarketing Experience
There is limited information regarding Abemaciclib Postmarketing Experience in the drug label.
# Drug Interactions
- Strong CYP3A Inhibitors
- Strong CYP3A Inducers
- Strong CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity.
Ketoconazole
- Avoid concomitant use of Ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold.
- In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily with concomitant use of other strong CYP3A inhibitors. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily with concomitant use of other strong CYP3A inhibitors. If a patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor. Patients should avoid grapefruit products.
- Coadministration of abemaciclib with rifampin, a strong CYP3A inducer, decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong CYP3A inducers and consider alternative agents.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Based on findings in animals and its mechanism of action, abemaciclib can cause fetal harm when administered to a pregnant woman. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abemaciclib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abemaciclib during labor and delivery.
### Nursing Mothers
- There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from abemaciclib, advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose.
### Pediatric Use
- The safety and effectiveness of abemaciclib have not been established in pediatric patients.
### Geriatic Use
- Of the 900 patients who received abemaciclib in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of abemaciclib were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Abemaciclib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abemaciclib with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault ). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown.
### Hepatic Impairment
- No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B).
- Reduce the dosing frequency when administering abemaciclib to patients with severe hepatic impairment (Child-Pugh C).
### Females of Reproductive Potential and Males
Pregnancy Testing
- Based on animal studies, abemaciclib can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with abemaciclib.
Contraception
- Abemaciclib can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during abemaciclib treatment and for at least 3 weeks after the last dose.
Infertility
- Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential.
### Immunocompromised Patients
There is no FDA guidance one the use of Abemaciclib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- When used in combination with fulvestrant or an aromatase inhibitor, the recommended dose of abemaciclib is 150 mg taken orally twice daily.
- When given with abemaciclib, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.
- When given with abemaciclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29; and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant. Pre/perimenopausal women treated with the combination of abemaciclib plus fulvestrant should be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards.
- When used as monotherapy, the recommended dose of abemaciclib is 200 mg taken orally twice daily.
- Continue treatment until disease progression or unacceptable toxicity. Abemaciclib may be taken with or without food.
- Instruct patients to take their doses of abemaciclib at approximately the same times every day.
- If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact.
### Monitoring
- Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.
- With concomitant use of other strong CYP3A inhibitors, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily. If a patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor.
- For patients with severe hepatic impairment (Child Pugh-C), reduce the abemaciclib dosing frequency to once daily.
# IV Compatibility
There is limited information regarding the compatibility of Abemaciclib and IV administrations.
# Overdosage
- There is no known antidote for abemaciclib. The treatment of overdose of abemaciclib should consist of general supportive measures.
# Pharmacology
## Mechanism of Action
- Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.
## Structure
- Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C27H32F2N8 and a molecular weight 506.59.
- The chemical name for abemaciclib is 2-Pyrimidinamine, N--2-pyridinyl]-5-fluoro-4--. Abemaciclib has the following structure:
## Pharmacodynamics
- Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.
## Pharmacokinetics
- The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including metastatic breast cancer, and in healthy subjects.
- Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively.
- The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).
Effect of Food
- A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%.
- In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV).
- In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations.
- The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV).
- Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.
- After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.
Age, Gender, and Body Weight
- Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib.
Patients with Renal Impairment
- In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min ≤ CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown.
Patients with Hepatic Impairment
- Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10). In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.
Effects of Other Drugs on abemaciclib
- Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold.
- Itraconazole (a strong CYP3A inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18 and M20) by 2.2-fold. Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a single 50 mg dose of abemaciclib (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold relative to abemaciclib alone in cancer patients.
- Moderate CYP3A Inhibitors: Diltiazem and verapamil (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold and 1.3-fold, respectively.
- Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 67% in healthy subjects.
- Moderate CYP3A Inducers: The effect of moderate CYP3A inducers on the pharmacokinetics of abemaciclib is unknown.
- Loperamide: Co-administration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant.
- Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, or exemestane on abemaciclib pharmacokinetics.
Effects of abemaciclib on Other Drugs
- Loperamide: In a clinical drug interaction study in healthy subjects, coadministration of a single 8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant.
- Metformin: In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.
- Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, or exemestane.
In Vitro Studies
- Transporter Systems: abemaciclib and its major active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage. The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K. Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3.
- Abemaciclib is a substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3.
- Abemaciclib inhibits P-gp and BCRP. The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown.
- CYP Metabolic Pathways: abemaciclib and its major active metabolites, M2 and M20, do not induce CYP1A2, CYP2B6, or CYP3A at clinically relevant concentrations. Abemaciclib and its major active metabolites, M2 and M20, down regulate mRNA of CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4. The mechanism of this down regulation and its clinical relevance are not understood. However, abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a result of autoinhibition of its metabolism was not observed.
- P-gp and BCRP Inhibitors: In vitro, abemaciclib is a substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been conducted with abemaciclib.
- Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes. Abemaciclib was not clastogenic in an in vivo rat bone marrow micronucleus assay.
- Studies to assess the effects of abemaciclib on fertility have not been performed. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis. These doses in rats and dogs resulted in approximately 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose.
# Clinical Studies
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease setting.
- MONARCH 3 was a randomized (2:1), double-blinded, placebo-controlled, multicenter study in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with a nonsteroidal aromatase inhibitor as initial endocrine-based therapy, including patients not previously treated with systemic therapy for breast cancer.
- Randomization was stratified by disease site (visceral, bone only, or other) and by prior (neo)adjuvant endocrine therapy (aromatase inhibitor versus other versus no prior endocrine therapy). A total of 493 patients were randomized to receive 150 mg abemaciclib or placebo orally twice daily, plus physician's choice of letrozole (80% of patients) or anastrozole (20% of patients). Patient median age was 63 years (range, 32-88 years) and the majority were White (58%) or Asian (30%). A total of 51% had received prior systemic therapy and 39% of patients had received chemotherapy, 53% had visceral disease, and 22% had bone-only disease.
- Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.
- MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multicenter study in women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. A total of 669 patients were randomized to receive abemaciclib or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.
- Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.
- Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting.
- MONARCH 1 (NCT02102490) was a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg abemaciclib orally twice daily on a continuous schedule until development of progressive disease or unmanageable toxicity.
- Patient median age was 58 years (range, 36-89 years), and the majority of patients were White (85%). Patients had an Eastern Cooperative Oncology Group performance status of 0 (55% of patients) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of patients had had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received a taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting.
# How Supplied
- 50 mg dose pack (14 tablets) – each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily)
- 100 mg dose pack (14 tablets) – each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily)
- 150 mg dose pack (14 tablets) – each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily)
- 200 mg dose pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily)
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Diarrhea
- Abemaciclib may cause diarrhea, which may be severe in some cases.
- Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.
- Encourage patients to increase oral fluids.
- If diarrhea does not resolve with antidiarrheal therapy within 24 hours to ≤Grade 1, suspend abemaciclib dosing.
### Neutropenia
- Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection.
### Hepatotoxicity
- Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity.
### Venous Thromboembolism
- Advise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia.
### Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during abemaciclib therapy and for at least 3 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy.
### Lactation
- Advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose.
### Drug Interactions
- Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors.
- Grapefruit may interact with abemaciclib. Advise patients not to consume grapefruit products while on treatment with abemaciclib.
- Advise patients to avoid concomitant use of CYP3A inducers and to consider alternative agents.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
### Dosing
- Instruct patients to take the doses of abemaciclib at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing).
- If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.
- Advise the patient that abemaciclib may be taken with or without food.
# Precautions with Alcohol
Alcohol-Abemaciclib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Verzenio
# Look-Alike Drug Names
There is limited information regarding Abemaciclib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Abemaciclib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]
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# Overview
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) that is FDA approved for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Common adverse reactions include diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
- In combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
- As monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
- 150 mg taken orally twice daily.
- 500 mg of fulverstrant is administered on Days 1, 15, and 29; and once monthly thereafter.
- 200 mg taken orally twice daily.
- Continue treatment until disease progression or unacceptable toxicity. Abemaciclib may be taken with or without food.
- Instruct patients to take their doses of abemaciclib at approximately the same times every day.
- If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Abemaciclib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding abemaciclib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Diarrhea occurred in 81% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 90% of patients receiving abemaciclib alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and in 20% of patients receiving abemaciclib alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.
- Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue abemaciclib until toxicity resolves to ≤Grade 1, and then resume abemaciclib at the next lower dose.
- Neutropenia occurred in 41% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and 37% of patients receiving abemaciclib alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving abemaciclib plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving abemaciclib plus fulvestrant in MONARCH 2, and in 27% of patients receiving abemaciclib in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1 was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.
- Monitor complete blood counts prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
- Febrile neutropenia has been reported in <1% of patients exposed to abemaciclib in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.
- In MONARCH 3, Grade ≥3 increases in ALT (6% versus 2%) and AST (3% versus 1%) were reported in the abemaciclib and placebo arms, respectively. In MONARCH 2, Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the abemaciclib and placebo arms, respectively.
- In MONARCH 3, for patients receiving abemaciclib plus an aromatase inhibitor with Grade ≥3 ALT increased, median time to onset was 61 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 2, for patients receiving abemaciclib plus fulvestrant with Grade ≥3 ALT increased, median time to onset was 57 days, and median time to resolution to Grade <3 was 14 days. In MONARCH 3, for patients receiving abemaciclib plus an aromatase inhibitor with Grade ≥3 AST increased, median time to onset was 71 days, and median time to resolution was 15 days. In MONARCH 2, for patients receiving abemaciclib plus fulvestrant with Grade ≥3 AST increased, median time to onset was 185 days, and median time to resolution was 13 days.
- Monitor liver function tests (LFTs) prior to the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.
- In MONARCH 3, venous thromboembolic events were reported in 5% of patients treated with abemaciclib plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo. In MONARCH 2, venous thromboembolic events were reported in 5% of patients treated with abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported.
- Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.
- Based on findings from animal studies and the mechanism of action, abemaciclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose.
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with abemaciclib and for at least 3 weeks after the last dose.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### MONARCH 3: Abemaciclib in Combination with an Aromatase Inhibitor (Anastrozole or Letrozole) as Initial Endocrine-Based Therapy
- Postmenopausal Women with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer with no prior systemic therapy in this disease setting.
- MONARCH 3 was a study of 488 women receiving abemaciclib plus an aromatase inhibitor or placebo plus an aromatase inhibitor. Patients were randomly assigned to receive 150 mg of abemaciclib or placebo orally twice daily, plus physician's choice of anastrozole or letrozole once daily. Median duration of treatment was 15.1 months for the abemaciclib arm and 13.9 months for the placebo arm. Median dose compliance was 98% for the abemaciclib arm and 99% for the placebo arm.
- Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus anastrozole or letrozole. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 13% of patients receiving abemaciclib plus an aromatase inhibitor compared to 2% of patients receiving placebo plus an aromatase inhibitor. Abemaciclib dose reductions due to neutropenia of any grade occurred in 11% of patients receiving abemaciclib plus an aromatase inhibitor compared to 0.6% of patients receiving placebo plus an aromatase inhibitor.
- Permanent treatment discontinuation due to an adverse event was reported in 13% of patients receiving abemaciclib plus an aromatase inhibitor and in 3% placebo plus an aromatase inhibitor. Adverse reactions leading to permanent discontinuation for patients receiving abemaciclib plus an aromatase inhibitor were diarrhea (2%), ALT increased (2%), infection (1%), venous thromboembolic events (VTE) (1%), neutropenia (0.9%), renal impairment (0.9%), AST increased (0.6%), dyspnea (0.6%), pulmonary fibrosis (0.6%) and anemia, rash, weight decreased and thrombocytopenia (each 0.3%).
- Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 11 cases (3%) of abemaciclib plus an aromatase inhibitor treated patients versus 3 cases (2%) of placebo plus an aromatase inhibitor treated patients. Causes of death for patients receiving abemaciclib plus an aromatase inhibitor included: 3 (0.9%) patient deaths due to underlying disease, 3 (0.9%) due to lung infection, 3 (0.9%) due to VTE event, 1 (0.3%) due to pneumonitis, and 1 (0.3%) due to cerebral infarction.
- The most common adverse reactions reported (≥20%) in the abemaciclib arm and ≥2% than the placebo arm were diarrhea, neutropenia, fatigue, infections, nausea, abdominal pain, anemia, vomiting, alopecia, decreased appetite, and leukopenia. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, increased ALT, and anemia. Diarrhea incidence was greatest during the first month of abemaciclib dosing. The median time to onset of the first diarrhea event was 8 days, and the median durations of diarrhea for Grades 2 and for Grade 3 were 11 days and 8 days, respectively. Most diarrhea events recovered or resolved (88%) with supportive treatment and/or dose reductions. Nineteen percent of patients with diarrhea required a dose omission and 13% required a dose reduction. The median time to the first dose reduction due to diarrhea was 38 days.
- Additional adverse reactions in MONARCH 3 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, and pelvic venous thrombosis), which were reported in 5% of patients treated with abemaciclib plus anastrozole or letrozole as compared to 0.6% of patients treated with anastrozole or letrozole plus placebo.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. Across the clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.
- Women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.
- The safety of abemaciclib (150 mg twice daily) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in MONARCH 2. The data described below reflect exposure to abemaciclib in 441 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of abemaciclib plus fulvestrant in MONARCH 2.
- Median duration of treatment was 12 months for patients receiving abemaciclib plus fulvestrant and 8 months for patients receiving placebo plus fulvestrant.
- Dose reductions due to an adverse reaction occurred in 43% of patients receiving abemaciclib plus fulvestrant. Adverse reactions leading to dose reductions in ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reductions due to diarrhea of any grade occurred in 19% of patients receiving abemaciclib plus fulvestrant compared to 0.4% of patients receiving placebo and fulvestrant. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving abemaciclib plus fulvestrant compared to no patients receiving placebo plus fulvestrant.
- Permanent study treatment discontinuation due to an adverse event were reported in 9% of patients receiving abemaciclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Adverse reactions leading to permanent discontinuation for patients receiving abemaciclib plus fulvestrant were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).
- Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of abemaciclib plus fulvestrant treated patients versus 10 cases (5%) of placebo plus fulvestrant treated patients. Causes of death for patients receiving abemaciclib plus fulvestrant included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.
- The most common adverse reactions reported (≥20%) in the abemaciclib arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.
- Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with abemaciclib plus fulvestrant as compared to 0.9% of patients treated with fulvestrant plus placebo.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based on creatinine, may be considered to determine whether renal function is impaired.
- Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting
- Safety data below are based on MONARCH 1, a single-arm, open-label, multicenter study in 132 women with measurable HR-positive, HER2-negative metastatic breast cancer. Patients received 200 mg abemaciclib orally twice daily until development of progressive disease or unmanageable toxicity. Median duration of treatment was 4.5 months.
- Ten patients (8%) discontinued study treatment from adverse reactions due to (1 patient each) abdominal pain, arterial thrombosis, aspartate aminotransferase (AST) increased, blood creatinine increased, chronic kidney disease, diarrhea, ECG QT prolonged, fatigue, hip fracture, and lymphopenia. Forty-nine percent of patients had dose reductions due to an adverse reaction. The most frequent adverse reactions that led to dose reductions were diarrhea (20%), neutropenia (11%), and fatigue (9%).
- Deaths during treatment or during the 30-day follow up were reported in 2% of patients. Cause of death in these patients was due to infection.
- The most common reported adverse reactions (≥20%) were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. Severe (Grade 3 and 4) neutropenia was observed in patients receiving abemaciclib.
- Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function. In clinical studies, increases in serum creatinine (mean increase, 0.2-0.3 mg/dL) occurred within the first 28-day cycle of abemaciclib dosing, remained elevated but stable through the treatment period, and were reversible upon treatment discontinuation. Alternative markers such as BUN, cystatin C, or calculated GFR, which are not based on creatinine, may be considered to determine whether renal function is impaired.
## Postmarketing Experience
There is limited information regarding Abemaciclib Postmarketing Experience in the drug label.
# Drug Interactions
- Strong CYP3A Inhibitors
- Strong CYP3A Inducers
- Strong CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity.
Ketoconazole
- Avoid concomitant use of Ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold.
- In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily with concomitant use of other strong CYP3A inhibitors. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily with concomitant use of other strong CYP3A inhibitors. If a patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor. Patients should avoid grapefruit products.
- Coadministration of abemaciclib with rifampin, a strong CYP3A inducer, decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of strong CYP3A inducers and consider alternative agents.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Based on findings in animals and its mechanism of action, abemaciclib can cause fetal harm when administered to a pregnant woman. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abemaciclib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abemaciclib during labor and delivery.
### Nursing Mothers
- There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed infants from abemaciclib, advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose.
### Pediatric Use
- The safety and effectiveness of abemaciclib have not been established in pediatric patients.
### Geriatic Use
- Of the 900 patients who received abemaciclib in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) Grade 3 or 4 in patients ≥65 years of age across MONARCH 1, 2, and 3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased. No overall differences in safety or effectiveness of abemaciclib were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Abemaciclib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abemaciclib with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr ≥30-89 mL/min, estimated by Cockcroft-Gault [C-G]). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown.
### Hepatic Impairment
- No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B).
- Reduce the dosing frequency when administering abemaciclib to patients with severe hepatic impairment (Child-Pugh C).
### Females of Reproductive Potential and Males
Pregnancy Testing
- Based on animal studies, abemaciclib can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with abemaciclib.
Contraception
- Abemaciclib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during abemaciclib treatment and for at least 3 weeks after the last dose.
Infertility
- Based on findings in animals, abemaciclib may impair fertility in males of reproductive potential.
### Immunocompromised Patients
There is no FDA guidance one the use of Abemaciclib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- When used in combination with fulvestrant or an aromatase inhibitor, the recommended dose of abemaciclib is 150 mg taken orally twice daily.
- When given with abemaciclib, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.
- When given with abemaciclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29; and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant. Pre/perimenopausal women treated with the combination of abemaciclib plus fulvestrant should be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards.
- When used as monotherapy, the recommended dose of abemaciclib is 200 mg taken orally twice daily.
- Continue treatment until disease progression or unacceptable toxicity. Abemaciclib may be taken with or without food.
- Instruct patients to take their doses of abemaciclib at approximately the same times every day.
- If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact.
### Monitoring
- Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.
- With concomitant use of other strong CYP3A inhibitors, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily. If a patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor.
- For patients with severe hepatic impairment (Child Pugh-C), reduce the abemaciclib dosing frequency to once daily.
# IV Compatibility
There is limited information regarding the compatibility of Abemaciclib and IV administrations.
# Overdosage
- There is no known antidote for abemaciclib. The treatment of overdose of abemaciclib should consist of general supportive measures.
# Pharmacology
## Mechanism of Action
- Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.
## Structure
- Abemaciclib is a kinase inhibitor for oral administration. It is a white to yellow powder with the empirical formula C27H32F2N8 and a molecular weight 506.59.
- The chemical name for abemaciclib is 2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-. Abemaciclib has the following structure:
## Pharmacodynamics
- Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.
## Pharmacokinetics
- The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including metastatic breast cancer, and in healthy subjects.
- Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively.
- The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).
Effect of Food
- A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%.
- In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV).
- In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations.
- The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV).
- Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway. Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.
- After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.
Age, Gender, and Body Weight
- Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib.
Patients with Renal Impairment
- In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min ≤ CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib. The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown.
Patients with Hepatic Impairment
- Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10). In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.
Effects of Other Drugs on abemaciclib
- Strong CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold.
- Itraconazole (a strong CYP3A inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18 and M20) by 2.2-fold. Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A inhibitor) with a single 50 mg dose of abemaciclib (0.3 times the approved recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold relative to abemaciclib alone in cancer patients.
- Moderate CYP3A Inhibitors: Diltiazem and verapamil (moderate CYP3A inhibitors) are predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold and 1.3-fold, respectively.
- Strong CYP3A Inducers: Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by 67% in healthy subjects.
- Moderate CYP3A Inducers: The effect of moderate CYP3A inducers on the pharmacokinetics of abemaciclib is unknown.
- Loperamide: Co-administration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy subjects increased the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not considered clinically relevant.
- Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, or exemestane on abemaciclib pharmacokinetics.
Effects of abemaciclib on Other Drugs
- Loperamide: In a clinical drug interaction study in healthy subjects, coadministration of a single 8 mg dose of loperamide with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to loperamide alone. These increases in loperamide exposure are not considered clinically relevant.
- Metformin: In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22% relative to metformin alone. Abemaciclib reduced the renal clearance and renal secretion of metformin by 45% and 62%, respectively, relative to metformin alone, without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.
- Endocrine Therapies: In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the pharmacokinetics of fulvestrant, anastrozole, letrozole, or exemestane.
In Vitro Studies
- Transporter Systems: abemaciclib and its major active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at concentrations achievable at the approved recommended dosage. The observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K. Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3.
- Abemaciclib is a substrate of P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are not substrates of hepatic uptake transporters OCT1, organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3.
- Abemaciclib inhibits P-gp and BCRP. The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown.
- CYP Metabolic Pathways: abemaciclib and its major active metabolites, M2 and M20, do not induce CYP1A2, CYP2B6, or CYP3A at clinically relevant concentrations. Abemaciclib and its major active metabolites, M2 and M20, down regulate mRNA of CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4. The mechanism of this down regulation and its clinical relevance are not understood. However, abemaciclib is a substrate of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a result of autoinhibition of its metabolism was not observed.
- P-gp and BCRP Inhibitors: In vitro, abemaciclib is a substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the pharmacokinetics of abemaciclib has not been studied.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been conducted with abemaciclib.
- Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes. Abemaciclib was not clastogenic in an in vivo rat bone marrow micronucleus assay.
- Studies to assess the effects of abemaciclib on fertility have not been performed. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis. These doses in rats and dogs resulted in approximately 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose.
# Clinical Studies
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with no prior systemic therapy in this disease setting.
- MONARCH 3 was a randomized (2:1), double-blinded, placebo-controlled, multicenter study in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with a nonsteroidal aromatase inhibitor as initial endocrine-based therapy, including patients not previously treated with systemic therapy for breast cancer.
- Randomization was stratified by disease site (visceral, bone only, or other) and by prior (neo)adjuvant endocrine therapy (aromatase inhibitor versus other versus no prior endocrine therapy). A total of 493 patients were randomized to receive 150 mg abemaciclib or placebo orally twice daily, plus physician's choice of letrozole (80% of patients) or anastrozole (20% of patients). Patient median age was 63 years (range, 32-88 years) and the majority were White (58%) or Asian (30%). A total of 51% had received prior systemic therapy and 39% of patients had received chemotherapy, 53% had visceral disease, and 22% had bone-only disease.
- Patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.
- MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multicenter study in women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). Primary endocrine therapy resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy or progressive disease within the first 6 months of first line endocrine therapy for metastatic breast cancer. A total of 669 patients were randomized to receive abemaciclib or placebo orally twice daily plus intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.
- Patient median age was 60 years (range, 32-91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.
- Patients with HR-positive, HER2-negative breast cancer who received prior endocrine therapy and 1-2 chemotherapy regimens in the metastatic setting.
- MONARCH 1 (NCT02102490) was a single-arm, open-label, multicenter study in women with measurable HR-positive, HER2-negative metastatic breast cancer whose disease progressed during or after endocrine therapy, had received a taxane in any setting, and who received 1 or 2 prior chemotherapy regimens in the metastatic setting. A total of 132 patients received 200 mg abemaciclib orally twice daily on a continuous schedule until development of progressive disease or unmanageable toxicity.
- Patient median age was 58 years (range, 36-89 years), and the majority of patients were White (85%). Patients had an Eastern Cooperative Oncology Group performance status of 0 (55% of patients) or 1 (45%). The median duration of metastatic disease was 27.6 months. Ninety percent (90%) of patients had visceral metastases, and 51% of patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of patients had had one line of chemotherapy in the metastatic setting. Sixty-nine percent (69%) of patients had received a taxane-based regimen in the metastatic setting and 55% had received capecitabine in the metastatic setting.
# How Supplied
- 50 mg dose pack (14 tablets) – each blister pack contains 14 tablets (50 mg per tablet) (50 mg twice daily)
- 100 mg dose pack (14 tablets) – each blister pack contains 14 tablets (100 mg per tablet) (100 mg twice daily)
- 150 mg dose pack (14 tablets) – each blister pack contains 14 tablets (150 mg per tablet) (150 mg twice daily)
- 200 mg dose pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (200 mg twice daily)
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Diarrhea
- Abemaciclib may cause diarrhea, which may be severe in some cases.
- Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.
- Encourage patients to increase oral fluids.
- If diarrhea does not resolve with antidiarrheal therapy within 24 hours to ≤Grade 1, suspend abemaciclib dosing.
### Neutropenia
- Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection.
### Hepatotoxicity
- Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity.
### Venous Thromboembolism
- Advise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia.
### Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during abemaciclib therapy and for at least 3 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy.
### Lactation
- Advise lactating women not to breastfeed during abemaciclib treatment and for at least 3 weeks after the last dose.
### Drug Interactions
- Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors.
- Grapefruit may interact with abemaciclib. Advise patients not to consume grapefruit products while on treatment with abemaciclib.
- Advise patients to avoid concomitant use of CYP3A inducers and to consider alternative agents.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.
### Dosing
- Instruct patients to take the doses of abemaciclib at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing).
- If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.
- Advise the patient that abemaciclib may be taken with or without food.
# Precautions with Alcohol
Alcohol-Abemaciclib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Verzenio
# Look-Alike Drug Names
There is limited information regarding Abemaciclib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Abemaciclib | |
c3c8d8124260e8de99fe13130cdfb16c3848573d | wikidoc | Abiogenesis | Abiogenesis
In the natural sciences, abiogenesis, the question of the origin of life, is the study of how life on Earth might have emerged from non-life. Scientific consensus is that abiogenesis occurred sometime between 4.4 billion years ago, when water vapor first liquefied, and 2.7 billion years ago, when the ratio of stable isotopes of carbon (12C and 13C), iron (56Fe, 57Fe, and 58Fe) and sulfur (32S, 33S, 34S, and 36S) points to a biogenic origin of minerals and sediments and molecular biomarkers indicate photosynthesis.
This topic also includes panspermia and other exogenic theories regarding possible extra-planetary or extraterrestrial origins of life, thought to have possibly occurred sometime over the last 13.7 billion years in the evolution of the Universe since the Big Bang.
Origin of life studies is a limited field of research despite its profound impact on biology and human understanding of the natural world. Progress in this field is generally slow and sporadic, though it still draws the attention of many due to the eminence of the question being investigated. Several theories have been proposed, most notably the iron-sulfur world theory (metabolism first) and the RNA world hypothesis (genetics first).
# History of the concept in science
Until the early 19th century people frequently believed in spontaneous generation of life from non-living matter.
## Spontaneous generation
Classical notions of abiogenesis, now more precisely known as spontaneous generation, held that complex, living organisms are generated by decaying organic substances, e.g. that mice spontaneously appear in stored grain or maggots spontaneously appear in meat.
According to Aristotle it was a readily observable truth that aphids arise from the dew which falls on plants, fleas from putrid matter, mice from dirty hay, and crocodiles from rotting logs at the bottom of bodies of water, and so forth. In the 17th century such assumptions started to be questioned; such as that by Sir Thomas Browne in his Pseudodoxia Epidemica, subtitled Enquiries into Very many Received Tenets, and Commonly Presumed Truths, of 1646, an attack on false beliefs and "vulgar errors." His conclusions were not widely accepted, e.g. his contemporary, Alexander Ross wrote: "To question this (i.e., spontaneous generation) is to question reason, sense and experience. If he doubts of this let him go to Egypt, and there he will find the fields swarming with mice, begot of the mud of Nylus, to the great calamity of the inhabitants."
In 1546 the physician Girolamo Fracastoro theorized that epidemic diseases were caused by tiny, invisible particles or "spores", which might not be living creatures, but this was not widely accepted. Next, Robert Hooke published the first drawings of a microorganism in 1665. He is also credited for naming the cell which he discovered while observing cork samples.
Then in 1676 Anthony van Leeuwenhoek discovered microorganisms that, based on his drawings and descriptions are thought to have been protozoa and bacteria. This sparked a renewal in interest in the microscopic world.
The first step was taken by the Italian Francesco Redi, who, in 1668, proved that no maggots appeared in meat when flies were prevented from laying eggs. From the 17th century onwards it was gradually shown that, at least in the case of all the higher and readily visible organisms, the previous sentiment regarding spontaneous generation was false. The alternative seemed to be omne vivum ex ovo: that every living thing came from a pre-existing living thing (literally, from an egg).
In 1768 Lazzaro Spallanzani proved that microbes came from the air, and could be killed by boiling. Yet it was not until 1861 that Louis Pasteur performed a series of careful experiments which proved that organisms such as bacteria and fungi do not appear in nutrient rich media of their own accord in non-living material, and which supported cell theory.
## Darwin and Pasteur
By the middle of the 19th century Pasteur and other scientists demonstrated that living organisms did not arise spontaneously from non-living matter; the question therefore arose of how life might have come about within a naturalistic framework. In a letter to Joseph Dalton Hooker on February 1, 1871, Charles Darwin made the suggestion that the original spark of life may have begun in a "warm little pond, with all sorts of ammonia and phosphoric salts, lights, heat, electricity, etc. present, so that a protein compound was chemically formed ready to undergo still more complex changes". He went on to explain that "at the present day such matter would be instantly devoured or absorbed, which would not have been the case before living creatures were formed." In other words, the presence of life itself makes the search for the origin of life dependent on the sterile conditions of the laboratory.
## Haldane and Oparin
No real progress was made until 1924 when Aleksandr Ivanovich Oparin experimentally showed that atmospheric oxygen prevented the synthesis of the organic molecules that are the necessary building blocks for the evolution of life. In his The Origin of Life on Earth, Oparin argued that a "primeval soup" of organic molecules could be created in an oxygen-less atmosphere through the action of sunlight. These would combine in ever-more complex fashions until they dissolved into a coacervate droplet. These droplets would "grow" by fusion with other droplets, and "reproduce" through fission into daughter droplets, and so have a primitive metabolism in which those factors which promote "cell integrity" survive, those that do not become extinct. Many modern theories of the origin of life still take Oparin's ideas as a starting point.
Around the same time J. B. S. Haldane also suggested that the earth's pre-biotic oceans – very different from their modern counterparts – would have formed a "hot dilute soup" in which organic compounds, the building blocks of life, could have formed. This idea was called biopoiesis or biopoesis, the process of living matter evolving from self-replicating but nonliving molecules.
# Early conditions
Morse and MacKenzie have suggested that oceans may have appeared first in the Hadean era, as soon as 200 million years after the Earth was formed, in a hot (100 °C) reducing environment, and that the pH of about 5.8 rose rapidly towards neutral. This has been supported by Wilde who has pushed the date of the zircon crystals found in the metamorphosed quartzite of Mount Narryer in Western Australia, previously thought to be 4.1–4.2 billion years old, to 4.404 billion years. This means that oceans and continental crust existed within 150 million years of Earth's formation. Despite this, the Hadean environment was one highly hazardous to life. Frequent collisions with large objects, up to 500 kilometres in diameter, would have been sufficient to vaporise the ocean within a few months of impact, with hot steam mixed with rock vapour leading to high altitude clouds completely covering the planet. After a few months the height of these clouds began to decrease but the cloud base would still have been elevated for about the next thousand years. After that, it began to rain at low altitude. For another two thousand years rains slowly draw down the height of the clouds, returning the oceans to their original depth only 3,000 years after the impact event. The possible Late Heavy Bombardment possibly caused by the movements in position of the Gaseous Giant planets, that pockmarked the moon, and other inner planets (Mercury, Mars, and presumably Earth and Venus), between 3.8 and 4.1 billion years would likely have sterilised the planet if life had already evolved by that time.
Examining the time interval that could have existed between devastating environmental insults by impact exceeded the timescale for establishing self-replicating protoorganisms, the interval in time when life might first have bootstrapped itself into existence can be found for different early environments. The study by Maher and Stephenson shows that if the deep marine hydrothermal setting provides a suitable site for the origin of life, abiogenesis could have happened as early as 4000 to 4200 Myr ago, whereas if it occurred at the surface of the earth abiogenesis could only have occurred between 3700 and 4000 Myr.
Other research suggests a colder start to life. Research by Stanley Miller showed the ingredients adenine and guanine require freezing conditions to synthesize, but cytosine and uracil require boiling temperatures. Based on his research he suggested a beginning of life involving freezing conditions and exploding meteorites. A new article in Discover Magazine points to research by Stanley Miller indicating the formation of seven different amino acids and 11 types of nucleobases in ice when ammonia and cyanide were left in the Antarctic ice from 1972–1997, and research by Hauke Trinks showing the formation of RNA molecules 400 bases long under freezing conditions using an RNA template, a single-strand chain of RNA that guides the formation of a new strand of RNA. As that new RNA strand grows, it adheres to the template. The explanation given for the unusual speed of these reactions at such a low temperature is eutectic freezing. As an ice crystal forms, it stays pure: Only molecules of water join the growing crystal, while impurities like salt or cyanide are excluded. These impurities become crowded in microscopic pockets of liquid within the ice, and this crowding causes the molecules to collide more often.
Evidence of the early appearance of life comes from the Isua supercrustal belt in Western Greenland and from similar formations in the nearby Akilia Islands. Carbon entering into rock formations has a concentration of elemental δ13C of about −5.5, where because of a preferential biotic uptake of 12C, biomass has a δ13C of between −20 and −30. These isotopic fingerprints are preserved in the sediments, and Mojzis has used this technique to suggest that life existed on the planet already by 3.85 billion years ago. Lazcano and Miller (1994) suggest that the rapidity of the evolution of life is dictated by the rate of recirculating water through mid-ocean submarine vents. Complete recirculation takes 10 million years, thus any organic compounds produced by then would be altered or destroyed by temperatures exceeding 300 °C. They estimate that the development of a 100 kilobase genome of a DNA/protein primitive heterotroph into a 7000 gene filamentous cyanobacterium would have required only 7 million years.
# Current models
There is no truly "standard model" of the origin of life. But most currently accepted models build in one way or another upon a number of discoveries about the origin of molecular and cellular components for life, which are listed in a rough order of postulated emergence:
- Plausible pre-biotic conditions result in the creation of certain basic small molecules (monomers) of life, such as amino acids. This was demonstrated in the Miller-Urey experiment by Stanley L. Miller and Harold C. Urey in 1953.
- Phospholipids (of an appropriate length) can spontaneously form lipid bilayers, a basic component of the cell membrane.
- The polymerization of nucleotides into random RNA molecules might have resulted in self-replicating ribozymes (RNA world hypothesis).
- Selection pressures for catalytic efficiency and diversity result in ribozymes which catalyse peptidyl transfer (hence formation of small proteins), since oligopeptides complex with RNA to form better catalysts. Thus the first ribosome is born, and protein synthesis becomes more prevalent.
- Proteins outcompete ribozymes in catalytic ability, and therefore become the dominant biopolymer. Nucleic acids are restricted to predominantly genomic use.
The origin of the basic biomolecules, while not settled, is less controversial than the significance and order of steps 2 and 3. The basic chemicals from which life was thought to have formed are:
- Methane (CH4),
- Ammonia (NH3),
- Water (H2O),
- Hydrogen sulfide (H2S),
- Carbon dioxide (CO2) or carbon monoxide (CO), and
- Phosphate (PO43-).
Molecular oxygen (O2) and ozone (O3) were either rare or absent.
As of 2008, no one has yet synthesized a "protocell" using basic components which would have the necessary properties of life (the so-called "bottom-up-approach"). Without such a proof-of-principle, explanations have tended to be short on specifics. However, some researchers are working in this field, notably Steen Rasmussen at Los Alamos National Laboratory and Jack Szostak at Harvard University. Others have argued that a "top-down approach" is more feasible. One such approach, attempted by Craig Venter and others at The Institute for Genomic Research, involves engineering existing prokaryotic cells with progressively fewer genes, attempting to discern at which point the most minimal requirements for life were reached. The biologist John Desmond Bernal, coined the term Biopoesis for this process, and suggested that there were a number of clearly defined "stages" that could be recognised in explaining the origin of life.
- Stage 1: The origin of biological monomers
- Stage 2: The origin of biological polymers
- Stage 3: The evolution from molecules to cell
Bernal suggested that Darwinian evolution may have commenced early, some time between Stage 1 and 2.
## Origin of organic molecules
There are three sources of organic molecules on the early Earth:
- organic synthesis by other energy sources (such as ultraviolet light or electrical discharges) (eg.Miller's experiments).
- delivery by extraterrestrial objects (eg carbonaceous chondrites);
- organic synthesis driven by impact shocks.
Recently estimates of these sources suggest that the heavy bombardment before 3.5 Gyr ago within the early atmosphere made available quantities of organics comparable to those produced by other energy sources.
### Miller's experiments (The Primordial Soup Theory)
In 1953 a graduate student, Stanley Miller, and his professor, Harold Urey, performed an experiment that proved organic molecules could have spontaneously formed on early Earth from inorganic precursors. The now-famous “Miller-Urey experiment” used a highly reduced mixture of gases – methane, ammonia and hydrogen – to form basic organic monomers, such as amino acids. Whether the mixture of gases used in the Miller-Urey experiment truly reflects the atmospheric content of early Earth is a controversial topic. Other less reducing gases produce a lower yield and variety. It was once thought that appreciable amounts of molecular oxygen were present in the prebiotic atmosphere, which would have essentially prevented the formation of organic molecules; however, the current scientific consensus is that such was not the case. See Oxygen Catastrophe.
Simple organic molecules are, of course, a long way from a fully functional self-replicating life form. But in an environment with no pre-existing life these molecules may have accumulated and provided a rich environment for chemical evolution ("soup theory"). On the other hand, the spontaneous formation of complex polymers from abiotically generated monomers under these conditions is not at all a straightforward process. Besides the necessary basic organic monomers, compounds that would have prohibited the formation of polymers were formed in high concentration during the experiments.
It can be argued that the most crucial challenge unanswered by this theory is how the relatively simple organic building blocks polymerise and form more complex structures, interacting in consistent ways to form a protocell. For example, in an aqueous environment hydrolysis of oligomers/polymers into their constituent monomers would be favored over the condensation of individual monomers into polymers. Also, the Miller experiment produces many substances that would undergo cross-reactions with the amino acids or terminate the peptide chain.
### The Deep Sea Vent Theory
The deep sea vent theory for the origin of life on Earth states that life may have began at the interface where chemically rich fluids, heated by some mechanisms like tidal forces of surrounding moons or planets, emerge from below the sea floor. Chemical energy is derived from the reduced gases by the redox reactions, such as hydrogen-sulfide and hydrogen coming out from the vent in contact with a suitable oxidant, such as carbon dioxide.
### Fox's experiments
In the 1950s and 1960s Sidney W. Fox, studied the spontaneous formation of peptide structures under conditions that might plausibly have existed early in Earth's history. He demonstrated that amino acids could spontaneously form small peptides. These amino acids and small peptides could be encouraged to form closed spherical membranes, called microspheres.
### Eigen's hypothesis
In the early 1970s the problem of the origin of life was approached by Manfred Eigen and Peter Schuster of the Max Planck Institute for Biophysical Chemistry. They examined the transient stages between the molecular chaos and a self-replicating hypercycle in a prebiotic soup.
In a hypercycle, the information storing system (possibly RNA) produces an enzyme, which catalyzes the formation of another information system, in sequence until the product of the last aids in the formation of the first information system. Mathematically treated, hypercycles could create quasispecies, which through natural selection entered into a form of Darwinian evolution. A boost to hypercycle theory was the discovery that RNA, in certain circumstances forms itself into ribozymes, capable of catalyzing their own chemical reactions. However, these reactions are limited to self-excisions (in which a longer RNA molecule becomes shorter), and much rarer small additions that are incapable of coding for any useful protein. The hypercycle theory is further degraded since the hypothetical RNA would require the existence of complex biochemicals such as nucleotides which are not formed under the conditions proposed by the Miller-Urey experiment.
### Wächtershäuser's hypothesis
Another possible answer to this polymerization conundrum was provided in 1980s by Günter Wächtershäuser, in his iron-sulfur world theory. In this theory, he postulated the evolution of (bio)chemical pathways as fundamentals of the evolution of life. Moreover, he presented a consistent system of tracing today's biochemistry back to ancestral reactions that provide alternative pathways to the synthesis of organic building blocks from simple gaseous compounds.
In contrast to the classical Miller experiments, which depend on external sources of energy (such as simulated lightning or UV irradiation), "Wächtershäuser systems" come with a built-in source of energy, sulfides of iron and other minerals (e.g. pyrite). The energy released from redox reactions of these metal sulfides is not only available for the synthesis of organic molecules, but also for the formation of oligomers and polymers. It is therefore hypothesized that such systems may be able to evolve into autocatalytic sets of self-replicating, metabolically active entities that would predate the life forms known today.
The experiment produced a relatively small yield of dipeptides (0.4% to 12.4%) and a smaller yield of tripeptides (0.10%) but the authors also noted that: "under these same conditions dipeptides hydrolysed rapidly."
### Radioactive beach theory
Zachary Adam at the University of Washington, Seattle, claims that stronger tidal processes from a much closer moon may have concentrated radioactive grains of uranium and other radioactive elements at the high water mark on primordial beaches where they may have been responsible for generating life's building blocks. According to computer models reported in Astrobiology, vol 7 p 852, a deposit of such radioactive materials could show the same self-sustaining nuclear reaction as that found in the Oklo uranium ore seam in Gabon. Such radioactive beach sand provides sufficient energy to generate organic molecules, such as amino acids and sugars from acetonitrile in water. Radioactive monazite also releases soluble phosphate into regions between sand-grains, making it biologically "accessible". Thus amino acids, sugars and soluble phosphates can all be simultaneously produced, according to Adam. Radioactive actinides, then in greater concentrations, could have formed part of organo-metallic complexes. These complexes could have been important early catalysts to living processes.
John Parnell of the University of Aberdeen suggests that such a process could provide part of the "crucible of life" on any early wet rocky planet, so long as the planet is large enough to have generated a system of plate tectonics which brings radioactive minerals to the surface. As the early Earth is believed to have many smaller "platelets" it would provide a suitable environment for such processes.
### Homochirality
Some process in chemical evolution must account for the origin of homochirality, i.e. all building blocks in living organisms having the same "handedness" (amino acids being left-handed, nucleic acid sugars (ribose and deoxyribose) being right-handed, and chiral phosphoglycerides). Chiral molecules can be synthesized, but in the absence of a chiral source or a chiral catalyst are formed in a 50/50 mixture of both enantiomers. This is called a racemic mixture. Clark has suggested that homochirality may have started in space, as the studies of the amino acids on the Murchison meteorite showed L-alanine to be more than twice as frequent as its D form, and L-glutamic acid was more than 3 times prevalent than its D counterpart. It is suggested that polarised light has the power to destroy one enantiomer within the proto-planetary disk. Noyes showed that beta decay caused the breakdown of D-leucine, in a racemic mixture, and that the presence of 14C, present in larger amounts in organic chemicals in the early Earth environment, could have been the cause. Robert M. Hazen reports upon experiments conducted in which various chiral crystal surfaces, act as sites for possible concentration and assembly of chiral monomer units into macromolecules. Once established, chirality would be selected for.
### Self-organization and replication
While features of self-organization and self-replication are often considered the hallmark of living systems, there are many instances of abiotic molecules exhibiting such characteristics under proper conditions. For example Martin and Russel show that physical compartmentation by cell membranes from the environment and self-organization of self-contained redox reactions are the most conserved attributes of living things, and they argue therefore that inorganic matter with such attributes would be life's most likely last common ancestor.
## From organic molecules to protocells
The question "How do simple organic molecules form a protocell?" is largely unanswered but there are many hypotheses. Some of these postulate the early appearance of nucleic acids ("genes-first") whereas others postulate the evolution of biochemical reactions and pathways first ("metabolism-first"). Recently, trends are emerging to create hybrid models that combine aspects of both.
### "Genes first" models: the RNA world
The RNA world hypothesis suggests that relatively short RNA molecules could have spontaneously formed that were capable of catalyzing their own continuing replication. It is difficult to gauge the probability of this formation. A number of theories of modes of formation have been put forward. Early cell membranes could have formed spontaneously from proteinoids, protein-like molecules that are produced when amino acid solutions are heated – when present at the correct concentration in aqueous solution, these form microspheres which are observed to behave similarly to membrane-enclosed compartments. Other possibilities include systems of chemical reactions taking place within clay substrates or on the surface of pyrite rocks. Factors supportive of an important role for RNA in early life include its ability to act both to store information and catalyse chemical reactions (as a ribozyme); its many important roles as an intermediate in the expression and maintenance of the genetic information (in the form of DNA) in modern organisms; and the ease of chemical synthesis of at least the components of the molecule under conditions approximating the early Earth. Relatively short RNA molecules which can duplicate others have been artificially produced in the lab.
Researchers have pointed out difficulties for the abiogenic synthesis of nucleotides from cytosine and uracil. Cytosine has a half-life of 19 days at 100 °C and 17,000 years in freezing water. Larralde et al, say that "the generally accepted prebiotic synthesis of ribose, the formose reaction, yields numerous sugars without any selectivity." and they conclude that their "results suggest that the backbone of the first genetic material could not have contained ribose or other sugars because of their instability." The ester linkage of ribose and phosphoric acid in RNA is known to be prone to hydrolysis.
A slightly different version of this hypothesis is that a different type of nucleic acid, such as PNA, TNA or GNA, was the first one to emerge as a self-reproducing molecule, to be replaced by RNA only later.
### "Metabolism first" models: iron-sulfur world and others
Several models reject the idea of the self-replication of a "naked-gene" and postulate the emergence of a primitive metabolism which could provide an environment for the later emergence of RNA replication.
One of the earliest incarnations of this idea was put forward in 1924 with Aleksandr Ivanovich Oparin's notion of primitive self-replicating vesicles which predated the discovery of the structure of DNA. More recent variants in the 1980s and 1990s include Günter Wächtershäuser's iron-sulfur world theory and models introduced by Christian de Duve based on the chemistry of thioesters. More abstract and theoretical arguments for the plausibility of the emergence of metabolism without the presence of genes include a mathematical model introduced by Freeman Dyson in the early 1980s and Stuart Kauffman's notion of collectively autocatalytic sets, discussed later in that decade.
However, the idea that a closed metabolic cycle, such as the reductive citric acid cycle, could form spontaneously (proposed by Günter Wächtershäuser) remains unsupported. According to Leslie Orgel, a leader in origin-of-life studies for the past several decades, there is reason to believe the assertion will remain so. In an article entitled "Self-Organizing Biochemical Cycles", Orgel summarizes his analysis of the proposal by stating, "There is at present no reason to expect that multistep cycles such as the reductive citric acid cycle will self-organize on the surface of FeS/FeS2 or some other mineral." It is possible that another type of metabolic pathway was used at the beginning of life. For example, instead of the reductive citric acid cycle, the "open" acetyl-CoA pathway (another one of the four recognised ways of carbon dioxide fixation in nature today) would be even more compatible with the idea of self-organisation on a metal sulfide surface. The key enzyme of this pathway, carbon monoxide dehydrogenase/acetyl-CoA synthase harbours mixed nickel-iron-sulfur clusters in its reaction centers and catalyses the formation of acetyl-CoA (which may be regarded as a modern form of acetyl-thiol) in a single step.
### Bubble Theory
Waves breaking on the shore create a delicate foam composed of bubbles. Winds sweeping across the ocean have a tendency to drive things to shore, much like driftwood collecting on the beach. It is possible that organic molecules were concentrated on the shorelines in much the same way. Shallow coastal waters also tend to be warmer, further concentrating the molecules through evaporation. While bubbles composed mostly of water burst quickly, water containing amphiphiles forms much more stable bubbles, lending more time to the particular bubble to perform these crucial experiments.
Amphiphiles are oily compounds containing a hydrophilic head on one or both ends of a hydrophobic molecule. Some amphiphiles have the tendency to spontaneously form membranes in water. A spherically closed membrane contains water and is a hypothetical precursor to the modern cell membrane. If a protein came along that increased the integrity of its parent bubble, then that bubble had an advantage, and was placed at the top of the natural selection waiting list. Primitive reproduction can be envisioned when the bubbles burst, releasing the results of the experiment into the surrounding medium. Once enough of the 'right stuff' was released into the medium, the development of the first prokaryotes, eukaryotes, and multicellular organisms could be achieved.
Similarly, bubbles formed entirely out of protein-like molecules, called microspheres, will form spontaneously under the right conditions. But they are not a likely precursor to the modern cell membrane, as cell membranes are composed primarily of lipid compounds rather than amino-acid compounds (for types of membrane spheres associated with abiogenesis, see protobionts, micelle, coacervate).
A recent model by Fernando and Rowe suggests that the enclosure of an autocatalytic non-enzymatic metabolism within protocells may have been one way of avoiding the side-reaction problem that is typical of metabolism first models.
# Other models
## Autocatalysis
British ethologist Richard Dawkins wrote about autocatalysis as a potential explanation for the origin of life in his 2004 book The Ancestor's Tale. Autocatalysts are substances which catalyze the production of themselves, and therefore have the property of being a simple molecular replicator. In his book, Dawkins cites experiments performed by Julius Rebek and his colleagues at the Scripps Research Institute in California in which they combined amino adenosine and pentafluorophenyl ester with the autocatalyst amino adenosine triacid ester (AATE). One system from the experiment contained variants of AATE which catalysed the synthesis of themselves. This experiment demonstrated the possibility that autocatalysts could exhibit competition within a population of entities with heredity, which could be interpreted as a rudimentary form of natural selection.
## Clay theory
A model for the origin of life based on clay was forwarded by Dr A. Graham Cairns-Smith of the University of Glasgow in 1985 and adopted as a plausible illustration by several other scientists, including Richard Dawkins. Clay theory postulates that complex organic molecules arose gradually on a pre-existing, non-organic replication platform — silicate crystals in solution. Complexity in companion molecules developed as a function of selection pressures on types of clay crystal is then exapted to serve the replication of organic molecules independently of their silicate "launch stage".
Cairns-Smith is a staunch critic of other models of chemical evolution. However, he admits, that like many models of the origin of life, his own also has its shortcomings (Horgan 1991).
In 2007, Kahr and colleagues reported their experiments to examine the idea that crystals can act as a source of transferable information, using crystals of potassium hydrogen phthalate. "Mother" crystals with imperfections were cleaved and used as seeds to grow "daughter" crystals from solution. They then examined the distribution of imperfections in the crystal system and found that the imperfections in the mother crystals were indeed reproduced in the daughters. The daughter crystals had many additional imperfections. For a gene-like behavior the additional imperfections should be much less than the parent ones, thus Kahr concludes that the crystals "were not faithful enough to store and transfer information form one generation to the next".
## "Deep-hot biosphere" model of Gold
The discovery of nanobes (filamental structures that are smaller than bacteria, but that may contain DNA in deep rocks) in the late 1990s has been informally linked with led to a controversial theory put forward by Thomas Gold in the 1970s that life first developed not on the surface of the Earth, but several kilometers below the surface.
It is now reasonably well established that microbial life is plentiful at shallow depths in the Earth (up to five kilometers below the surface) in the form of extremophile archaea, rather than the better-known eubacteria (which live in more accessible conditions). It is claimed that discovery of microbial life below the surface of another body in our solar system would lend significant credence to this theory. Thomas Gold also asserted that a trickle of food from a deep, unreachable, source is needed for survival because life arising in a puddle of organic material is likely to consume all of its food and become extinct. Gold's theory is that that flow of food is due to out-gassing of primordial methane from the Earth's mantle; more conventional explanations of the food supply of deep microbes (away from sedimentary carbon compounds) is that the organisms subsist on hydrogen released by an interaction between water and (reduced) iron compounds in rocks
## "Primitive" extraterrestrial life
An alternative to Earthly abiogenesis is the hypothesis that primitive life may have originally formed extraterrestrially, either in space or on a nearby planet (Mars). (Note that exogenesis is related to, but not the same as, the notion of panspermia). A supporter of this theory was Francis Crick.
Organic compounds are relatively common in space, especially in the outer solar system where volatiles are not evaporated by solar heating. Comets are encrusted by outer layers of dark material, thought to be a tar-like substance composed of complex organic material formed from simple carbon compounds after reactions initiated mostly by irradiation by ultraviolet light. It is supposed that a rain of material from comets could have brought significant quantities of such complex organic molecules to Earth.
An alternative but related hypothesis, proposed to explain the presence of life on Earth so soon after the planet had cooled down, with apparently very little time for prebiotic evolution, is that life formed first on early Mars. Due to its smaller size Mars cooled before Earth (a difference of hundreds of millions of years), allowing prebiotic processes there while Earth was still too hot. Life was then transported to the cooled Earth when crustal material was blasted off Mars by asteroid and comet impacts. Mars continued to cool faster and eventually became hostile to the continued evolution or even existence of life (it lost its atmosphere due to low volcanism), Earth is following the same fate as Mars, but at a slower rate.
Neither hypothesis actually answers the question of how life first originated, but merely shifts it to another planet or a comet. However, the advantage of an extraterrestrial origin of primitive life is that life is not required to have evolved on each planet it occurs on, but rather in a single location, and then spread about the galaxy to other star systems via cometary and/or meteorite impact. Evidence to support the plausibility of the concept is scant, but it finds support in recent study of Martian meteorites found in Antarctica and in studies of extremophile microbes. Additional support comes from a recent discovery of a bacterial ecosytem whose energy source is radioactivity.
## Lipid World
There is a theory that ascribes the first self-replicating object to be lipid-like. It is known that phospholipids form bilayers in water while under agitation– the same structure as in cell membranes. These molecules were not present on early earth, however other amphiphilic long chain molecules also form membranes. Furthermore, these bodies may expand (by insertion of additional lipids), and under excessive expansion may undergo spontaneous splitting which preserves the same size and composition of lipids in the two progenies. The main idea in this theory is that the molecular composition of the lipid bodies is the preliminary way for information storage, and evolution led to the appearance of polymer entities such as RNA or DNA that may store information favorably. Still, no biochemical mechanism has been offered to support the Lipid World theory.
## Polyphosphate model
The problem with most scenarios of abiogenesis is that the thermodynamic equilibrium of amino acid versus peptides is in the direction of separate amino acids. What has been missing is some force that drives polymerization. The resolution of this problem may well be in the properties of polyphosphates. Polyphosphates are formed by polymerization of ordinary monophosphate ions PO4−3 by ultraviolet light. Polyphosphates cause polymerization of amino acids into peptides. Ample ultraviolet light must have existed in the early oceans. The key issue seems to be that calcium reacts with soluble phosphate to form insoluble calcium phosphate (apatite), so some plausible mechanism must be found to keep free calcium ions from solution.
## PAH world hypothesis
Other sources of complex molecules have been postulated, including extraterrestrial stellar or interstellar origin. For example, from spectral analyses, organic molecules are known to be present in comets and meteorites. In 2004, a team detected traces of polycyclic aromatic hydrocarbons (PAH's) in a nebula. Those are the most complex molecules so far found in space. The use of PAH's has also been proposed as a precursor to the RNA world in the PAH world hypothesis.
## Multiple genesis
Different forms of life may have appeared quasi-simultaneously in the early history of Earth. The other forms may be extinct, leaving distinctive fossils through their different biochemistry (e.g., using arsenic instead of phosphorus), survive as extremophiles, or simply be unnoticed through their being analogous to organisms of the current life tree. Hartman for example combines a number of theories together, by proposing that:
The first organisms were self-replicating iron-rich clays which fixed carbon dioxide into oxalic and other dicarboxylic acids. This system of replicating clays and their metabolic phenotype then evolved into the sulfide rich region of the hotspring acquiring the ability to fix nitrogen. Finally phosphate was incorporated into the evolving system which allowed the synthesis of nucleotides and phospholipids. If biosynthesis recapitulates biopoesis, then the synthesis of amino acids preceded the synthesis of the purine and pyrimidine bases. Furthermore the polymerization of the amino acid thioesters into polypeptides preceded the directed polymerization of amino acid esters by polynucleotides. | Abiogenesis
In the natural sciences, abiogenesis, the question of the origin of life, is the study of how life on Earth might have emerged from non-life. Scientific consensus is that abiogenesis occurred sometime between 4.4 billion years ago, when water vapor first liquefied,[2] and 2.7 billion years ago, when the ratio of stable isotopes of carbon (12C and 13C), iron (56Fe, 57Fe, and 58Fe) and sulfur (32S, 33S, 34S, and 36S) points to a biogenic origin of minerals and sediments[3][4] and molecular biomarkers indicate photosynthesis.[5][6]
This topic also includes panspermia and other exogenic theories regarding possible extra-planetary or extraterrestrial origins of life, thought to have possibly occurred sometime over the last 13.7 billion years in the evolution of the Universe since the Big Bang.[7]
Origin of life studies is a limited field of research despite its profound impact on biology and human understanding of the natural world. Progress in this field is generally slow and sporadic, though it still draws the attention of many due to the eminence of the question being investigated. Several theories have been proposed, most notably the iron-sulfur world theory (metabolism first) and the RNA world hypothesis (genetics first).[8]
# History of the concept in science
Until the early 19th century people frequently believed in spontaneous generation of life from non-living matter.
## Spontaneous generation
Classical notions of abiogenesis, now more precisely known as spontaneous generation, held that complex, living organisms are generated by decaying organic substances, e.g. that mice spontaneously appear in stored grain or maggots spontaneously appear in meat.
According to Aristotle it was a readily observable truth that aphids arise from the dew which falls on plants, fleas from putrid matter, mice from dirty hay, and crocodiles from rotting logs at the bottom of bodies of water, and so forth. In the 17th century such assumptions started to be questioned; such as that by Sir Thomas Browne in his Pseudodoxia Epidemica, subtitled Enquiries into Very many Received Tenets, and Commonly Presumed Truths, of 1646, an attack on false beliefs and "vulgar errors." His conclusions were not widely accepted, e.g. his contemporary, Alexander Ross wrote: "To question this (i.e., spontaneous generation) is to question reason, sense and experience. If he doubts of this let him go to Egypt, and there he will find the fields swarming with mice, begot of the mud of Nylus, to the great calamity of the inhabitants."[9]
In 1546 the physician Girolamo Fracastoro theorized that epidemic diseases were caused by tiny, invisible particles or "spores", which might not be living creatures, but this was not widely accepted. Next, Robert Hooke published the first drawings of a microorganism in 1665. He is also credited for naming the cell which he discovered while observing cork samples.
Then in 1676 Anthony van Leeuwenhoek discovered microorganisms that, based on his drawings and descriptions are thought to have been protozoa and bacteria. This sparked a renewal in interest in the microscopic world.[10]
The first step was taken by the Italian Francesco Redi, who, in 1668, proved that no maggots appeared in meat when flies were prevented from laying eggs. From the 17th century onwards it was gradually shown that, at least in the case of all the higher and readily visible organisms, the previous sentiment regarding spontaneous generation was false. The alternative seemed to be omne vivum ex ovo: that every living thing came from a pre-existing living thing (literally, from an egg).
In 1768 Lazzaro Spallanzani proved that microbes came from the air, and could be killed by boiling. Yet it was not until 1861 that Louis Pasteur performed a series of careful experiments which proved that organisms such as bacteria and fungi do not appear in nutrient rich media of their own accord in non-living material, and which supported cell theory.
## Darwin and Pasteur
By the middle of the 19th century Pasteur and other scientists demonstrated that living organisms did not arise spontaneously from non-living matter; the question therefore arose of how life might have come about within a naturalistic framework. In a letter to Joseph Dalton Hooker on February 1, 1871,[11] Charles Darwin made the suggestion that the original spark of life may have begun in a "warm little pond, with all sorts of ammonia and phosphoric salts, lights, heat, electricity, etc. present, so that a protein compound was chemically formed ready to undergo still more complex changes". He went on to explain that "at the present day such matter would be instantly devoured or absorbed, which would not have been the case before living creatures were formed."[12] In other words, the presence of life itself makes the search for the origin of life dependent on the sterile conditions of the laboratory.
## Haldane and Oparin
No real progress was made until 1924 when Aleksandr Ivanovich Oparin experimentally showed that atmospheric oxygen prevented the synthesis of the organic molecules that are the necessary building blocks for the evolution of life. In his The Origin of Life on Earth,[13][14] Oparin argued that a "primeval soup" of organic molecules could be created in an oxygen-less atmosphere through the action of sunlight. These would combine in ever-more complex fashions until they dissolved into a coacervate droplet. These droplets would "grow" by fusion with other droplets, and "reproduce" through fission into daughter droplets, and so have a primitive metabolism in which those factors which promote "cell integrity" survive, those that do not become extinct. Many modern theories of the origin of life still take Oparin's ideas as a starting point.
Around the same time J. B. S. Haldane also suggested that the earth's pre-biotic oceans – very different from their modern counterparts – would have formed a "hot dilute soup" in which organic compounds, the building blocks of life, could have formed. This idea was called biopoiesis or biopoesis, the process of living matter evolving from self-replicating but nonliving molecules.[15]
# Early conditions
Morse and MacKenzie[16] have suggested that oceans may have appeared first in the Hadean era, as soon as 200 million years after the Earth was formed, in a hot (100 °C) reducing environment, and that the pH of about 5.8 rose rapidly towards neutral. This has been supported by Wilde[17] who has pushed the date of the zircon crystals found in the metamorphosed quartzite of Mount Narryer in Western Australia, previously thought to be 4.1–4.2 billion years old, to 4.404 billion years. This means that oceans and continental crust existed within 150 million years of Earth's formation. Despite this, the Hadean environment was one highly hazardous to life. Frequent collisions with large objects, up to 500 kilometres in diameter, would have been sufficient to vaporise the ocean within a few months of impact, with hot steam mixed with rock vapour leading to high altitude clouds completely covering the planet. After a few months the height of these clouds began to decrease but the cloud base would still have been elevated for about the next thousand years. After that, it began to rain at low altitude. For another two thousand years rains slowly draw down the height of the clouds, returning the oceans to their original depth only 3,000 years after the impact event.[18] The possible Late Heavy Bombardment possibly caused by the movements in position of the Gaseous Giant planets, that pockmarked the moon, and other inner planets (Mercury, Mars, and presumably Earth and Venus), between 3.8 and 4.1 billion years would likely have sterilised the planet if life had already evolved by that time.
Examining the time interval that could have existed between devastating environmental insults by impact exceeded the timescale for establishing self-replicating protoorganisms, the interval in time when life might first have bootstrapped itself into existence can be found for different early environments. The study by Maher and Stephenson[19] shows that if the deep marine hydrothermal setting provides a suitable site for the origin of life, abiogenesis could have happened as early as 4000 to 4200 Myr ago, whereas if it occurred at the surface of the earth abiogenesis could only have occurred between 3700 and 4000 Myr.
Other research suggests a colder start to life. Research by Stanley Miller showed the ingredients adenine and guanine require freezing conditions to synthesize, but cytosine and uracil require boiling temperatures.[20] Based on his research he suggested a beginning of life involving freezing conditions and exploding meteorites.[21] A new article in Discover Magazine points to research by Stanley Miller indicating the formation of seven different amino acids and 11 types of nucleobases in ice when ammonia and cyanide were left in the Antarctic ice from 1972–1997,[22] and research by Hauke Trinks showing the formation of RNA molecules 400 bases long under freezing conditions using an RNA template, a single-strand chain of RNA that guides the formation of a new strand of RNA. As that new RNA strand grows, it adheres to the template.[23] The explanation given for the unusual speed of these reactions at such a low temperature is eutectic freezing. As an ice crystal forms, it stays pure: Only molecules of water join the growing crystal, while impurities like salt or cyanide are excluded. These impurities become crowded in microscopic pockets of liquid within the ice, and this crowding causes the molecules to collide more often.[24]
Evidence of the early appearance of life comes from the Isua supercrustal belt in Western Greenland and from similar formations in the nearby Akilia Islands. Carbon entering into rock formations has a concentration of elemental δ13C of about −5.5, where because of a preferential biotic uptake of 12C, biomass has a δ13C of between −20 and −30. These isotopic fingerprints are preserved in the sediments, and Mojzis[25] has used this technique to suggest that life existed on the planet already by 3.85 billion years ago. Lazcano and Miller (1994) suggest that the rapidity of the evolution of life is dictated by the rate of recirculating water through mid-ocean submarine vents. Complete recirculation takes 10 million years, thus any organic compounds produced by then would be altered or destroyed by temperatures exceeding 300 °C. They estimate that the development of a 100 kilobase genome of a DNA/protein primitive heterotroph into a 7000 gene filamentous cyanobacterium would have required only 7 million years.[26]
# Current models
There is no truly "standard model" of the origin of life. But most currently accepted models build in one way or another upon a number of discoveries about the origin of molecular and cellular components for life, which are listed in a rough order of postulated emergence:
- Plausible pre-biotic conditions result in the creation of certain basic small molecules (monomers) of life, such as amino acids. This was demonstrated in the Miller-Urey experiment by Stanley L. Miller and Harold C. Urey in 1953.
- Phospholipids (of an appropriate length) can spontaneously form lipid bilayers, a basic component of the cell membrane.
- The polymerization of nucleotides into random RNA molecules might have resulted in self-replicating ribozymes (RNA world hypothesis).
- Selection pressures for catalytic efficiency and diversity result in ribozymes which catalyse peptidyl transfer (hence formation of small proteins), since oligopeptides complex with RNA to form better catalysts. Thus the first ribosome is born, and protein synthesis becomes more prevalent.
- Proteins outcompete ribozymes in catalytic ability, and therefore become the dominant biopolymer. Nucleic acids are restricted to predominantly genomic use.
The origin of the basic biomolecules, while not settled, is less controversial than the significance and order of steps 2 and 3. The basic chemicals from which life was thought to have formed are:
- Methane (CH4),
- Ammonia (NH3),
- Water (H2O),
- Hydrogen sulfide (H2S),
- Carbon dioxide (CO2) or carbon monoxide (CO), and
- Phosphate (PO43-).
Molecular oxygen (O2) and ozone (O3) were either rare or absent.
As of 2008, no one has yet synthesized a "protocell" using basic components which would have the necessary properties of life (the so-called "bottom-up-approach"). Without such a proof-of-principle, explanations have tended to be short on specifics. However, some researchers are working in this field, notably Steen Rasmussen at Los Alamos National Laboratory and Jack Szostak at Harvard University. Others have argued that a "top-down approach" is more feasible. One such approach, attempted by Craig Venter and others at The Institute for Genomic Research, involves engineering existing prokaryotic cells with progressively fewer genes, attempting to discern at which point the most minimal requirements for life were reached. The biologist John Desmond Bernal, coined the term Biopoesis for this process, and suggested that there were a number of clearly defined "stages" that could be recognised in explaining the origin of life.
- Stage 1: The origin of biological monomers
- Stage 2: The origin of biological polymers
- Stage 3: The evolution from molecules to cell
Bernal suggested that Darwinian evolution may have commenced early, some time between Stage 1 and 2.
## Origin of organic molecules
There are three sources of organic molecules on the early Earth:
- organic synthesis by other energy sources (such as ultraviolet light or electrical discharges) (eg.Miller's experiments).
- delivery by extraterrestrial objects (eg carbonaceous chondrites);
- organic synthesis driven by impact shocks.
Recently estimates of these sources suggest that the heavy bombardment before 3.5 Gyr ago within the early atmosphere made available quantities of organics comparable to those produced by other energy sources.[27]
### Miller's experiments (The Primordial Soup Theory)
In 1953 a graduate student, Stanley Miller, and his professor, Harold Urey, performed an experiment that proved organic molecules could have spontaneously formed on early Earth from inorganic precursors. The now-famous “Miller-Urey experiment” used a highly reduced mixture of gases – methane, ammonia and hydrogen – to form basic organic monomers, such as amino acids. Whether the mixture of gases used in the Miller-Urey experiment truly reflects the atmospheric content of early Earth is a controversial topic. Other less reducing gases produce a lower yield and variety. It was once thought that appreciable amounts of molecular oxygen were present in the prebiotic atmosphere, which would have essentially prevented the formation of organic molecules; however, the current scientific consensus is that such was not the case. See Oxygen Catastrophe.
Simple organic molecules are, of course, a long way from a fully functional self-replicating life form. But in an environment with no pre-existing life these molecules may have accumulated and provided a rich environment for chemical evolution ("soup theory"). On the other hand, the spontaneous formation of complex polymers from abiotically generated monomers under these conditions is not at all a straightforward process. Besides the necessary basic organic monomers, compounds that would have prohibited the formation of polymers were formed in high concentration during the experiments.
It can be argued that the most crucial challenge unanswered by this theory is how the relatively simple organic building blocks polymerise and form more complex structures, interacting in consistent ways to form a protocell. For example, in an aqueous environment hydrolysis of oligomers/polymers into their constituent monomers would be favored over the condensation of individual monomers into polymers. Also, the Miller experiment produces many substances that would undergo cross-reactions with the amino acids or terminate the peptide chain.
### The Deep Sea Vent Theory
The deep sea vent theory for the origin of life on Earth states that life may have began at the interface where chemically rich fluids, heated by some mechanisms like tidal forces of surrounding moons or planets, emerge from below the sea floor. Chemical energy is derived from the reduced gases by the redox reactions, such as hydrogen-sulfide and hydrogen coming out from the vent in contact with a suitable oxidant, such as carbon dioxide[28].
### Fox's experiments
In the 1950s and 1960s Sidney W. Fox, studied the spontaneous formation of peptide structures under conditions that might plausibly have existed early in Earth's history. He demonstrated that amino acids could spontaneously form small peptides. These amino acids and small peptides could be encouraged to form closed spherical membranes, called microspheres.[29]
### Eigen's hypothesis
In the early 1970s the problem of the origin of life was approached by Manfred Eigen and Peter Schuster of the Max Planck Institute for Biophysical Chemistry. They examined the transient stages between the molecular chaos and a self-replicating hypercycle in a prebiotic soup.[30]
In a hypercycle, the information storing system (possibly RNA) produces an enzyme, which catalyzes the formation of another information system, in sequence until the product of the last aids in the formation of the first information system. Mathematically treated, hypercycles could create quasispecies, which through natural selection entered into a form of Darwinian evolution. A boost to hypercycle theory was the discovery that RNA, in certain circumstances forms itself into ribozymes, capable of catalyzing their own chemical reactions.[31] However, these reactions are limited to self-excisions (in which a longer RNA molecule becomes shorter), and much rarer small additions that are incapable of coding for any useful protein. The hypercycle theory is further degraded since the hypothetical RNA would require the existence of complex biochemicals such as nucleotides which are not formed under the conditions proposed by the Miller-Urey experiment.
### Wächtershäuser's hypothesis
Another possible answer to this polymerization conundrum was provided in 1980s by Günter Wächtershäuser, in his iron-sulfur world theory. In this theory, he postulated the evolution of (bio)chemical pathways as fundamentals of the evolution of life. Moreover, he presented a consistent system of tracing today's biochemistry back to ancestral reactions that provide alternative pathways to the synthesis of organic building blocks from simple gaseous compounds.
In contrast to the classical Miller experiments, which depend on external sources of energy (such as simulated lightning or UV irradiation), "Wächtershäuser systems" come with a built-in source of energy, sulfides of iron and other minerals (e.g. pyrite). The energy released from redox reactions of these metal sulfides is not only available for the synthesis of organic molecules, but also for the formation of oligomers and polymers. It is therefore hypothesized that such systems may be able to evolve into autocatalytic sets of self-replicating, metabolically active entities that would predate the life forms known today.
The experiment produced a relatively small yield of dipeptides (0.4% to 12.4%) and a smaller yield of tripeptides (0.10%) but the authors also noted that: "under these same conditions dipeptides hydrolysed rapidly."[32]
### Radioactive beach theory
Zachary Adam[33] at the University of Washington, Seattle, claims that stronger tidal processes from a much closer moon may have concentrated radioactive grains of uranium and other radioactive elements at the high water mark on primordial beaches where they may have been responsible for generating life's building blocks. According to computer models reported in Astrobiology, vol 7 p 852, a deposit of such radioactive materials could show the same self-sustaining nuclear reaction as that found in the Oklo uranium ore seam in Gabon. Such radioactive beach sand provides sufficient energy to generate organic molecules, such as amino acids and sugars from acetonitrile in water. Radioactive monazite also releases soluble phosphate into regions between sand-grains, making it biologically "accessible". Thus amino acids, sugars and soluble phosphates can all be simultaneously produced, according to Adam. Radioactive actinides, then in greater concentrations, could have formed part of organo-metallic complexes. These complexes could have been important early catalysts to living processes.
John Parnell of the University of Aberdeen suggests that such a process could provide part of the "crucible of life" on any early wet rocky planet, so long as the planet is large enough to have generated a system of plate tectonics which brings radioactive minerals to the surface. As the early Earth is believed to have many smaller "platelets" it would provide a suitable environment for such processes.
### Homochirality
Some process in chemical evolution must account for the origin of homochirality, i.e. all building blocks in living organisms having the same "handedness" (amino acids being left-handed, nucleic acid sugars (ribose and deoxyribose) being right-handed, and chiral phosphoglycerides). Chiral molecules can be synthesized, but in the absence of a chiral source or a chiral catalyst are formed in a 50/50 mixture of both enantiomers. This is called a racemic mixture. Clark has suggested that homochirality may have started in space, as the studies of the amino acids on the Murchison meteorite showed L-alanine to be more than twice as frequent as its D form, and L-glutamic acid was more than 3 times prevalent than its D counterpart. It is suggested that polarised light has the power to destroy one enantiomer within the proto-planetary disk. Noyes[34] showed that beta decay caused the breakdown of D-leucine, in a racemic mixture, and that the presence of 14C, present in larger amounts in organic chemicals in the early Earth environment, could have been the cause. Robert M. Hazen reports upon experiments conducted in which various chiral crystal surfaces, act as sites for possible concentration and assembly of chiral monomer units into macromolecules[35]. Once established, chirality would be selected for.[36]
### Self-organization and replication
Template:Sect-stub
While features of self-organization and self-replication are often considered the hallmark of living systems, there are many instances of abiotic molecules exhibiting such characteristics under proper conditions. For example Martin and Russel[37] show that physical compartmentation by cell membranes from the environment and self-organization of self-contained redox reactions are the most conserved attributes of living things, and they argue therefore that inorganic matter with such attributes would be life's most likely last common ancestor.
## From organic molecules to protocells
The question "How do simple organic molecules form a protocell?" is largely unanswered but there are many hypotheses. Some of these postulate the early appearance of nucleic acids ("genes-first") whereas others postulate the evolution of biochemical reactions and pathways first ("metabolism-first"). Recently, trends are emerging to create hybrid models that combine aspects of both.
### "Genes first" models: the RNA world
The RNA world hypothesis suggests that relatively short RNA molecules could have spontaneously formed that were capable of catalyzing their own continuing replication. It is difficult to gauge the probability of this formation. A number of theories of modes of formation have been put forward. Early cell membranes could have formed spontaneously from proteinoids, protein-like molecules that are produced when amino acid solutions are heated – when present at the correct concentration in aqueous solution, these form microspheres which are observed to behave similarly to membrane-enclosed compartments. Other possibilities include systems of chemical reactions taking place within clay substrates or on the surface of pyrite rocks. Factors supportive of an important role for RNA in early life include its ability to act both to store information and catalyse chemical reactions (as a ribozyme); its many important roles as an intermediate in the expression and maintenance of the genetic information (in the form of DNA) in modern organisms; and the ease of chemical synthesis of at least the components of the molecule under conditions approximating the early Earth. Relatively short RNA molecules which can duplicate others have been artificially produced in the lab.[38]
Researchers have pointed out difficulties for the abiogenic synthesis of nucleotides from cytosine and uracil.[39] Cytosine has a half-life of 19 days at 100 °C and 17,000 years in freezing water.[40] Larralde et al, say that "the generally accepted prebiotic synthesis of ribose, the formose reaction, yields numerous sugars without any selectivity."[41] and they conclude that their "results suggest that the backbone of the first genetic material could not have contained ribose or other sugars because of their instability." The ester linkage of ribose and phosphoric acid in RNA is known to be prone to hydrolysis.[42]
A slightly different version of this hypothesis is that a different type of nucleic acid, such as PNA, TNA or GNA, was the first one to emerge as a self-reproducing molecule, to be replaced by RNA only later.[43][44]
### "Metabolism first" models: iron-sulfur world and others
Several models reject the idea of the self-replication of a "naked-gene" and postulate the emergence of a primitive metabolism which could provide an environment for the later emergence of RNA replication.
One of the earliest incarnations of this idea was put forward in 1924 with Aleksandr Ivanovich Oparin's notion of primitive self-replicating vesicles which predated the discovery of the structure of DNA. More recent variants in the 1980s and 1990s include Günter Wächtershäuser's iron-sulfur world theory and models introduced by Christian de Duve based on the chemistry of thioesters. More abstract and theoretical arguments for the plausibility of the emergence of metabolism without the presence of genes include a mathematical model introduced by Freeman Dyson in the early 1980s and Stuart Kauffman's notion of collectively autocatalytic sets, discussed later in that decade.
However, the idea that a closed metabolic cycle, such as the reductive citric acid cycle, could form spontaneously (proposed by Günter Wächtershäuser) remains unsupported. According to Leslie Orgel, a leader in origin-of-life studies for the past several decades, there is reason to believe the assertion will remain so. In an article entitled "Self-Organizing Biochemical Cycles",[45] Orgel summarizes his analysis of the proposal by stating, "There is at present no reason to expect that multistep cycles such as the reductive citric acid cycle will self-organize on the surface of FeS/FeS2 or some other mineral." It is possible that another type of metabolic pathway was used at the beginning of life. For example, instead of the reductive citric acid cycle, the "open" acetyl-CoA pathway (another one of the four recognised ways of carbon dioxide fixation in nature today) would be even more compatible with the idea of self-organisation on a metal sulfide surface. The key enzyme of this pathway, carbon monoxide dehydrogenase/acetyl-CoA synthase harbours mixed nickel-iron-sulfur clusters in its reaction centers and catalyses the formation of acetyl-CoA (which may be regarded as a modern form of acetyl-thiol) in a single step.
### Bubble Theory
Waves breaking on the shore create a delicate foam composed of bubbles. Winds sweeping across the ocean have a tendency to drive things to shore, much like driftwood collecting on the beach. It is possible that organic molecules were concentrated on the shorelines in much the same way. Shallow coastal waters also tend to be warmer, further concentrating the molecules through evaporation. While bubbles composed mostly of water burst quickly, water containing amphiphiles forms much more stable bubbles, lending more time to the particular bubble to perform these crucial experiments.
Amphiphiles are oily compounds containing a hydrophilic head on one or both ends of a hydrophobic molecule. Some amphiphiles have the tendency to spontaneously form membranes in water. A spherically closed membrane contains water and is a hypothetical precursor to the modern cell membrane. If a protein came along that increased the integrity of its parent bubble, then that bubble had an advantage, and was placed at the top of the natural selection waiting list. Primitive reproduction can be envisioned when the bubbles burst, releasing the results of the experiment into the surrounding medium. Once enough of the 'right stuff' was released into the medium, the development of the first prokaryotes, eukaryotes, and multicellular organisms could be achieved.[46]
Similarly, bubbles formed entirely out of protein-like molecules, called microspheres, will form spontaneously under the right conditions. But they are not a likely precursor to the modern cell membrane, as cell membranes are composed primarily of lipid compounds rather than amino-acid compounds (for types of membrane spheres associated with abiogenesis, see protobionts, micelle, coacervate).
A recent model by Fernando and Rowe[47] suggests that the enclosure of an autocatalytic non-enzymatic metabolism within protocells may have been one way of avoiding the side-reaction problem that is typical of metabolism first models.
# Other models
## Autocatalysis
British ethologist Richard Dawkins wrote about autocatalysis as a potential explanation for the origin of life in his 2004 book The Ancestor's Tale. Autocatalysts are substances which catalyze the production of themselves, and therefore have the property of being a simple molecular replicator. In his book, Dawkins cites experiments performed by Julius Rebek and his colleagues at the Scripps Research Institute in California in which they combined amino adenosine and pentafluorophenyl ester with the autocatalyst amino adenosine triacid ester (AATE). One system from the experiment contained variants of AATE which catalysed the synthesis of themselves. This experiment demonstrated the possibility that autocatalysts could exhibit competition within a population of entities with heredity, which could be interpreted as a rudimentary form of natural selection.
## Clay theory
A model for the origin of life based on clay was forwarded by Dr A. Graham Cairns-Smith of the University of Glasgow in 1985 and adopted as a plausible illustration by several other scientists, including Richard Dawkins. Clay theory postulates that complex organic molecules arose gradually on a pre-existing, non-organic replication platform — silicate crystals in solution. Complexity in companion molecules developed as a function of selection pressures on types of clay crystal is then exapted to serve the replication of organic molecules independently of their silicate "launch stage".
Cairns-Smith is a staunch critic of other models of chemical evolution.[48] However, he admits, that like many models of the origin of life, his own also has its shortcomings (Horgan 1991).
In 2007, Kahr and colleagues reported their experiments to examine the idea that crystals can act as a source of transferable information, using crystals of potassium hydrogen phthalate. "Mother" crystals with imperfections were cleaved and used as seeds to grow "daughter" crystals from solution. They then examined the distribution of imperfections in the crystal system and found that the imperfections in the mother crystals were indeed reproduced in the daughters. The daughter crystals had many additional imperfections. For a gene-like behavior the additional imperfections should be much less than the parent ones, thus Kahr concludes that the crystals "were not faithful enough to store and transfer information form one generation to the next".[49][50]
## "Deep-hot biosphere" model of Gold
The discovery of nanobes (filamental structures that are smaller than bacteria, but that may contain DNA in deep rocks) in the late 1990s has been informally linked with led to a controversial theory put forward by Thomas Gold in the 1970s that life first developed not on the surface of the Earth, but several kilometers below the surface.[51]
It is now reasonably well established that microbial life is plentiful at shallow depths in the Earth (up to five kilometers below the surface)[51] in the form of extremophile archaea, rather than the better-known eubacteria (which live in more accessible conditions). It is claimed that discovery of microbial life below the surface of another body in our solar system would lend significant credence to this theory. Thomas Gold also asserted that a trickle of food from a deep, unreachable, source is needed for survival because life arising in a puddle of organic material is likely to consume all of its food and become extinct. Gold's theory is that that flow of food is due to out-gassing of primordial methane from the Earth's mantle; more conventional explanations of the food supply of deep microbes (away from sedimentary carbon compounds) is that the organisms subsist on hydrogen released by an interaction between water and (reduced) iron compounds in rocks
## "Primitive" extraterrestrial life
An alternative to Earthly abiogenesis is the hypothesis that primitive life may have originally formed extraterrestrially, either in space or on a nearby planet (Mars). (Note that exogenesis is related to, but not the same as, the notion of panspermia). A supporter of this theory was Francis Crick.
Organic compounds are relatively common in space, especially in the outer solar system where volatiles are not evaporated by solar heating. Comets are encrusted by outer layers of dark material, thought to be a tar-like substance composed of complex organic material formed from simple carbon compounds after reactions initiated mostly by irradiation by ultraviolet light. It is supposed that a rain of material from comets could have brought significant quantities of such complex organic molecules to Earth.
An alternative but related hypothesis, proposed to explain the presence of life on Earth so soon after the planet had cooled down, with apparently very little time for prebiotic evolution, is that life formed first on early Mars. Due to its smaller size Mars cooled before Earth (a difference of hundreds of millions of years), allowing prebiotic processes there while Earth was still too hot. Life was then transported to the cooled Earth when crustal material was blasted off Mars by asteroid and comet impacts. Mars continued to cool faster and eventually became hostile to the continued evolution or even existence of life (it lost its atmosphere due to low volcanism), Earth is following the same fate as Mars, but at a slower rate.
Neither hypothesis actually answers the question of how life first originated, but merely shifts it to another planet or a comet. However, the advantage of an extraterrestrial origin of primitive life is that life is not required to have evolved on each planet it occurs on, but rather in a single location, and then spread about the galaxy to other star systems via cometary and/or meteorite impact. Evidence to support the plausibility of the concept is scant, but it finds support in recent study of Martian meteorites found in Antarctica and in studies of extremophile microbes.[52] Additional support comes from a recent discovery of a bacterial ecosytem whose energy source is radioactivity.[53]
## Lipid World
There is a theory that ascribes the first self-replicating object to be lipid-like.[54] It is known that phospholipids form bilayers in water while under agitation– the same structure as in cell membranes. These molecules were not present on early earth, however other amphiphilic long chain molecules also form membranes. Furthermore, these bodies may expand (by insertion of additional lipids), and under excessive expansion may undergo spontaneous splitting which preserves the same size and composition of lipids in the two progenies. The main idea in this theory is that the molecular composition of the lipid bodies is the preliminary way for information storage, and evolution led to the appearance of polymer entities such as RNA or DNA that may store information favorably. Still, no biochemical mechanism has been offered to support the Lipid World theory.
## Polyphosphate model
The problem with most scenarios of abiogenesis is that the thermodynamic equilibrium of amino acid versus peptides is in the direction of separate amino acids. What has been missing is some force that drives polymerization. The resolution of this problem may well be in the properties of polyphosphates.[55][56] Polyphosphates are formed by polymerization of ordinary monophosphate ions PO4−3 by ultraviolet light. Polyphosphates cause polymerization of amino acids into peptides. Ample ultraviolet light must have existed in the early oceans. The key issue seems to be that calcium reacts with soluble phosphate to form insoluble calcium phosphate (apatite), so some plausible mechanism must be found to keep free calcium ions from solution.
## PAH world hypothesis
Other sources of complex molecules have been postulated, including extraterrestrial stellar or interstellar origin. For example, from spectral analyses, organic molecules are known to be present in comets and meteorites. In 2004, a team detected traces of polycyclic aromatic hydrocarbons (PAH's) in a nebula.[57] Those are the most complex molecules so far found in space. The use of PAH's has also been proposed as a precursor to the RNA world in the PAH world hypothesis.[58]
## Multiple genesis
Different forms of life may have appeared quasi-simultaneously in the early history of Earth.[59] The other forms may be extinct, leaving distinctive fossils through their different biochemistry (e.g., using arsenic instead of phosphorus), survive as extremophiles, or simply be unnoticed through their being analogous to organisms of the current life tree. Hartman[60] for example combines a number of theories together, by proposing that:
The first organisms were self-replicating iron-rich clays which fixed carbon dioxide into oxalic and other dicarboxylic acids. This system of replicating clays and their metabolic phenotype then evolved into the sulfide rich region of the hotspring acquiring the ability to fix nitrogen. Finally phosphate was incorporated into the evolving system which allowed the synthesis of nucleotides and phospholipids. If biosynthesis recapitulates biopoesis, then the synthesis of amino acids preceded the synthesis of the purine and pyrimidine bases. Furthermore the polymerization of the amino acid thioesters into polypeptides preceded the directed polymerization of amino acid esters by polynucleotides. | https://www.wikidoc.org/index.php/Abiogenesis | |
ce226693d2afee1f5d5992f7339361f94057c296 | wikidoc | Abiraterone | Abiraterone
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# Overview
Abiraterone is an antiandrogen that is FDA approved for the treatment of metastatic castration-resistant prostate cancer. Common adverse reactions include fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Abiraterone is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets.
- Hepatic Impairment
- In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of Abiraterone to 250 mg once daily. A once daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once daily in patients with moderate hepatic impairment and caution is advised. In patients with moderate hepatic impairment monitor ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. If elevations in ALT and/or AST greater than 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone and do not re-treat patients with Abiraterone.
- Do not use Abiraterone in patients with baseline severe hepatic impairment (Child-Pugh Class C).
- Hepatotoxicity
- For patients who develop hepatotoxicity during treatment with Abiraterone (ALT and/or AST greater than 5X ULN or bilirubin-total bilirubin greater than 3X ULN), interrupt treatment with Abiraterone. Treatment may be restarted at a reduced dose of 750 mg once daily following return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, monitor serum transaminases and bilirubin at a minimum of every two weeks for three months and monthly thereafter.
- If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced dose of 500 mg once daily following return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN.
- If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with Abiraterone. The safety of Abiraterone re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
- Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during Abiraterone treatment. Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the Abiraterone dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abiraterone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abiraterone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Abiraterone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abiraterone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abiraterone in pediatric patients.
# Contraindications
- Pregnancy
- Abiraterone can cause fetal harm when administered to a pregnant woman. Abiraterone is not indicated for use in women. Abiraterone is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.
# Warnings
### Precautions
- Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess
- Abiraterone may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with Abiraterone.
- Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use Abiraterone with caution in patients with a history of cardiovascular disease. The safety of Abiraterone in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Abiraterone.
- Adrenocortical Insufficiency
- Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking Abiraterone and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Abiraterone in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Abiraterone. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations.
- Hepatotoxicity
- In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received Abiraterone, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to cardiovascular disease increases occurred in 1% of patients taking Abiraterone. No deaths clearly related to Abiraterone were reported due to hepatotoxicity events.
- Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with Abiraterone, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Abiraterone dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt Abiraterone treatment and closely monitor liver function.
- Re-treatment with Abiraterone at a reduced dose level may take place only after return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN.
- The safety of Abiraterone re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
- Increased Abiraterone Exposures with Food
- Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. Abiraterone Cmax and AUC0–∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Abiraterone was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.
- The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
- The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
- Study 1: Metastatic CRPC Following Chemotherapy
- Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 XULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN.
- Table 1 shows adverse reactions on the Abiraterone arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with Abiraterone was 8 months.
- Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3–4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the Abiraterone arm.
- Study 2: Metastatic CRPC Prior to Chemotherapy
- Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.
- Table 3 shows adverse reactions on the Abiraterone arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with Abiraterone was 13.8 months.
- Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the Abiraterone arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the Abiraterone arm.
- Cardiovascular Adverse Reactions:
- In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with Abiraterone compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3–4 cardiac failure occurred in 1.6% of patients taking Abiraterone and led to 5 treatment discontinuations and 2 deaths. Grade 3–4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.
- In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the Abiraterone arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the Abiraterone arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the Abiraterone arms.
## Postmarketing Experience
- The following additional adverse reactions have been identified during post approval use of Abiraterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
# Drug Interactions
- Drugs that Inhibit or Induce CYP3A4 Enzymes
- Based on in vitro data, Abiraterone is a substrate of CYP3A4.
- In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during Abiraterone treatment. If a strong CYP3A4 inducer must be co-administered, increase the Abiraterone dosing frequency.
- In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
- Effects of Abiraterone on Drug Metabolizing Enzymes
- Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug.
- In vitro, Abiraterone inhibits CYP2C8. There are no clinical data on the use of Abiraterone with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Abiraterone can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with Abiraterone in pregnant women and Abiraterone is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. Abiraterone is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Abiraterone.
- In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6–17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abiraterone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abiraterone during labor and delivery.
### Nursing Mothers
- Abiraterone is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Abiraterone, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Abiraterone with respect to pediatric patients.
### Geriatic Use
- Of the total number of patients receiving Abiraterone in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Abiraterone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abiraterone with respect to specific racial populations.
### Renal Impairment
- In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of Abiraterone. No dosage adjustment is necessary for patients with renal impairment.
### Hepatic Impairment
- The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of Abiraterone increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.
- In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7 fold and the fraction of free drug increased 2 fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.
- No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of Abiraterone to 250 mg once daily. Do not use Abiraterone in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone treatment.
- For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Abiraterone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Abiraterone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly.
- Monitor for symptoms and signs of adrenocortical insufficiency.
# IV Compatibility
There is limited information regarding IV Compatibility of Abiraterone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Human experience of overdose with Abiraterone is limited.
### Management
- There is no specific antidote. In the event of an overdose, stop Abiraterone, undertake general supportive measures, including monitoring for pparrhythmias]] and cardiac failure and assess liver function.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Abiraterone in the drug label.
# Pharmacology
## Mechanism of Action
- Abiraterone acetate (Abiraterone) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
- CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals.
- Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.
- Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled phase 3 clinical trial. It is not necessary to monitor the effect of Abiraterone on serum testosterone levels.
- Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.
## Structure
- Abiraterone acetate, the active ingredient of Abiraterone is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each Abiraterone tablet contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is:
- Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.
- Inactive ingredients in the tablets are colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Abiraterone in the drug label.
## Pharmacokinetics
- Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (99% of the analyzed samples.
- Absorption
- Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate.
- At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ± SD) of Cmax were 226 ± 178 ng/mL and of AUC were 993 ± 639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC).
- Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. Abiraterone Cmax and AUC0–∞ were approximately 7- and 5-fold higher, respectively, when abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal. Given the normal variation in the content and composition of meals, taking Abiraterone with meals has the potential to result in increased and highly variable exposures. Therefore, no food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water.
- Distribution and Protein Binding
- Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. No studies have been conducted with other transporter proteins.
- Metabolism
- Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate.
- Excretion
- In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
- Patients with Hepatic Impairment
- The pharmacokinetics of abiraterone was examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to abiraterone after a single oral 1,000 mg dose given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.
- In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7 fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment.
- Patients with Renal Impairment
- The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg Abiraterone dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function.
- Drug Interactions
- In vitro studies with human hepatic microsomes showed that abiraterone is a strong inhibitor of CYP1A2, CYP2D6 and CYP2C8 and a moderate inhibitor of CYP2C9, CYP2C19 and CYP3A4/5.
- In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.
- In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.
- Abiraterone is a substrate of CYP3A4, in vitro. In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%.
- In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
- QT Prolongation
- In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received Abiraterone orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to abiraterone acetate cannot be excluded due to study design limitations
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.
- Abiraterone acetate and abiraterone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay.
- Abiraterone has the potential to impair reproductive function and fertility in humans based on findings in animals. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.
- In fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks at ≥30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. Female rats dosed for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.
- In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. A dose-dependent increase in cataracts was observed in rats at 26 weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC). In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or were partially resolved after a 4-week recovery period.
# Clinical Studies
- The efficacy and safety of Abiraterone in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.
- Study 1
- Patients with metastatic CRPC who had received prior docetaxel chemotherapy:
- A total of 1195 patients were randomized 2:1 to receive either Abiraterone orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal.
- The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39–95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0–1 and 45% had a Brief Pain Inventory-Short Form score of ≥4 (patient's reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.
- The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival in patients treated with Abiraterone compared to patients in the placebo arm (Table 5 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 5).
- Study 2
- Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy
- In Study 2, 1088 patients were randomized 1:1 to receive either Abiraterone at a dose of 1,000 mg once daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.
- Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with Abiraterone was 95.4% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0–1 (asymptomatic) in 66% of patients and 2–3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).
- Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.
- At the protocol pre-specified third interim analysis for overall survival, 37% (200 of 546) of patients treated with Abiraterone, compared with 43% (234 of 542) of patients treated with placebo, had died. Overall survival was longer for Abiraterone than placebo with a hazard ratio of 0.792 (95% CI: 0.655 – 0.956). The p-value was 0.0151 which did not meet the pre-specified value for statistical significance (Table 6 and Figure 2).
- At the pre-specified rPFS analysis, 150 (28%) patients treated with Abiraterone and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3).
- The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving Abiraterone and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: , p<0.0001).
- The median time to opiate use for prostate cancer pain was not reached for patients receiving Abiraterone and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: , p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the Abiraterone arm.
# How Supplied
- Abiraterone (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. Abiraterone 250 mg tablets are available in high-density polyethylene bottles of 120 tablets.
- NDC Number 57894-150-12
- Storage and Handling
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F).
- Based on its mechanism of action, Abiraterone may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle Abiraterone without protection, e.g., gloves.
## Storage
There is limited information regarding Abiraterone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that Abiraterone and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.
- Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with Abiraterone and prednisone.
- Patients should be informed that Abiraterone must not be taken with food and that no food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking Abiraterone with food causes increased exposure and this may result in adverse reactions.
- Patients should be informed that Abiraterone is taken once daily and prednisone is taken twice daily according to their physician's instructions.
- Patients should be informed that in the event of a missed daily dose of Abiraterone or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.
- Patients should be apprised of the common side effects associated with Abiraterone, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
- Patients should be advised that their liver function will be monitored using blood tests.
- Patients should be informed that Abiraterone may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Abiraterone without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with Abiraterone.
# Precautions with Alcohol
- Alcohol-Abiraterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZYTIGA®
# Look-Alike Drug Names
There is limited information regarding Abiraterone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Abiraterone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Abiraterone is an antiandrogen that is FDA approved for the treatment of metastatic castration-resistant prostate cancer. Common adverse reactions include fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Abiraterone is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets.
- Hepatic Impairment
- In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of Abiraterone to 250 mg once daily. A once daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once daily in patients with moderate hepatic impairment and caution is advised. In patients with moderate hepatic impairment monitor ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. If elevations in ALT and/or AST greater than 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone and do not re-treat patients with Abiraterone.
- Do not use Abiraterone in patients with baseline severe hepatic impairment (Child-Pugh Class C).
- Hepatotoxicity
- For patients who develop hepatotoxicity during treatment with Abiraterone (ALT and/or AST greater than 5X ULN or bilirubin-total bilirubin greater than 3X ULN), interrupt treatment with Abiraterone. Treatment may be restarted at a reduced dose of 750 mg once daily following return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, monitor serum transaminases and bilirubin at a minimum of every two weeks for three months and monthly thereafter.
- If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced dose of 500 mg once daily following return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN.
- If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with Abiraterone. The safety of Abiraterone re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
- Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during Abiraterone treatment. Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the Abiraterone dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abiraterone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abiraterone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Abiraterone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abiraterone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Abiraterone in pediatric patients.
# Contraindications
- Pregnancy
- Abiraterone can cause fetal harm when administered to a pregnant woman. Abiraterone is not indicated for use in women. Abiraterone is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.
# Warnings
### Precautions
- Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess
- Abiraterone may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with Abiraterone.
- Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use Abiraterone with caution in patients with a history of cardiovascular disease. The safety of Abiraterone in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Abiraterone.
- Adrenocortical Insufficiency
- Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking Abiraterone and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Abiraterone in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Abiraterone. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations.
- Hepatotoxicity
- In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received Abiraterone, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to cardiovascular disease increases occurred in 1% of patients taking Abiraterone. No deaths clearly related to Abiraterone were reported due to hepatotoxicity events.
- Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with Abiraterone, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Abiraterone dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt Abiraterone treatment and closely monitor liver function.
- Re-treatment with Abiraterone at a reduced dose level may take place only after return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN.
- The safety of Abiraterone re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.
- Increased Abiraterone Exposures with Food
- Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. Abiraterone Cmax and AUC0–∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Abiraterone was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.
- The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
- The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
- Study 1: Metastatic CRPC Following Chemotherapy
- Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 XULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN.
- Table 1 shows adverse reactions on the Abiraterone arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with Abiraterone was 8 months.
- Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3–4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the Abiraterone arm.
- Study 2: Metastatic CRPC Prior to Chemotherapy
- Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.
- Table 3 shows adverse reactions on the Abiraterone arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with Abiraterone was 13.8 months.
- Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the Abiraterone arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the Abiraterone arm.
- Cardiovascular Adverse Reactions:
- In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with Abiraterone compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3–4 cardiac failure occurred in 1.6% of patients taking Abiraterone and led to 5 treatment discontinuations and 2 deaths. Grade 3–4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.
- In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the Abiraterone arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the Abiraterone arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the Abiraterone arms.
## Postmarketing Experience
- The following additional adverse reactions have been identified during post approval use of Abiraterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
# Drug Interactions
- Drugs that Inhibit or Induce CYP3A4 Enzymes
- Based on in vitro data, Abiraterone is a substrate of CYP3A4.
- In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during Abiraterone treatment. If a strong CYP3A4 inducer must be co-administered, increase the Abiraterone dosing frequency.
- In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
- Effects of Abiraterone on Drug Metabolizing Enzymes
- Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug.
- In vitro, Abiraterone inhibits CYP2C8. There are no clinical data on the use of Abiraterone with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Abiraterone can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with Abiraterone in pregnant women and Abiraterone is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. Abiraterone is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Abiraterone.
- In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6–17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abiraterone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abiraterone during labor and delivery.
### Nursing Mothers
- Abiraterone is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Abiraterone, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Abiraterone with respect to pediatric patients.
### Geriatic Use
- Of the total number of patients receiving Abiraterone in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Abiraterone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abiraterone with respect to specific racial populations.
### Renal Impairment
- In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of Abiraterone. No dosage adjustment is necessary for patients with renal impairment.
### Hepatic Impairment
- The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of Abiraterone increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.
- In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7 fold and the fraction of free drug increased 2 fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.
- No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of Abiraterone to 250 mg once daily. Do not use Abiraterone in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone treatment.
- For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Abiraterone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Abiraterone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly.
- Monitor for symptoms and signs of adrenocortical insufficiency.
# IV Compatibility
There is limited information regarding IV Compatibility of Abiraterone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Human experience of overdose with Abiraterone is limited.
### Management
- There is no specific antidote. In the event of an overdose, stop Abiraterone, undertake general supportive measures, including monitoring for pparrhythmias]] and cardiac failure and assess liver function.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Abiraterone in the drug label.
# Pharmacology
## Mechanism of Action
- Abiraterone acetate (Abiraterone) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
- CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals.
- Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.
- Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled phase 3 clinical trial. It is not necessary to monitor the effect of Abiraterone on serum testosterone levels.
- Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.
## Structure
- Abiraterone acetate, the active ingredient of Abiraterone is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each Abiraterone tablet contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is:
- Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.
- Inactive ingredients in the tablets are colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Abiraterone in the drug label.
## Pharmacokinetics
- Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (<0.2 ng/mL) in >99% of the analyzed samples.
- Absorption
- Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate.
- At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ± SD) of Cmax were 226 ± 178 ng/mL and of AUC were 993 ± 639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC).
- Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. Abiraterone Cmax and AUC0–∞ were approximately 7- and 5-fold higher, respectively, when abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal. Given the normal variation in the content and composition of meals, taking Abiraterone with meals has the potential to result in increased and highly variable exposures. Therefore, no food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water.
- Distribution and Protein Binding
- Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. No studies have been conducted with other transporter proteins.
- Metabolism
- Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate.
- Excretion
- In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
- Patients with Hepatic Impairment
- The pharmacokinetics of abiraterone was examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to abiraterone after a single oral 1,000 mg dose given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.
- In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7 fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment.
- Patients with Renal Impairment
- The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg Abiraterone dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function.
- Drug Interactions
- In vitro studies with human hepatic microsomes showed that abiraterone is a strong inhibitor of CYP1A2, CYP2D6 and CYP2C8 and a moderate inhibitor of CYP2C9, CYP2C19 and CYP3A4/5.
- In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.
- In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.
- Abiraterone is a substrate of CYP3A4, in vitro. In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%.
- In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
- QT Prolongation
- In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received Abiraterone orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to abiraterone acetate cannot be excluded due to study design limitations
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.
- Abiraterone acetate and abiraterone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay.
- Abiraterone has the potential to impair reproductive function and fertility in humans based on findings in animals. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.
- In fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks at ≥30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. Female rats dosed for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.
- In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. A dose-dependent increase in cataracts was observed in rats at 26 weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC). In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or were partially resolved after a 4-week recovery period.
# Clinical Studies
- The efficacy and safety of Abiraterone in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.
- Study 1
- Patients with metastatic CRPC who had received prior docetaxel chemotherapy:
- A total of 1195 patients were randomized 2:1 to receive either Abiraterone orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal.
- The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39–95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0–1 and 45% had a Brief Pain Inventory-Short Form score of ≥4 (patient's reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.
- The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival in patients treated with Abiraterone compared to patients in the placebo arm (Table 5 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 5).
- Study 2
- Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy
- In Study 2, 1088 patients were randomized 1:1 to receive either Abiraterone at a dose of 1,000 mg once daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.
- Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with Abiraterone was 95.4% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0–1 (asymptomatic) in 66% of patients and 2–3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).
- Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.
- At the protocol pre-specified third interim analysis for overall survival, 37% (200 of 546) of patients treated with Abiraterone, compared with 43% (234 of 542) of patients treated with placebo, had died. Overall survival was longer for Abiraterone than placebo with a hazard ratio of 0.792 (95% CI: 0.655 – 0.956). The p-value was 0.0151 which did not meet the pre-specified value for statistical significance (Table 6 and Figure 2).
- At the pre-specified rPFS analysis, 150 (28%) patients treated with Abiraterone and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3).
- The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving Abiraterone and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p<0.0001).
- The median time to opiate use for prostate cancer pain was not reached for patients receiving Abiraterone and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the Abiraterone arm.
# How Supplied
- Abiraterone (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. Abiraterone 250 mg tablets are available in high-density polyethylene bottles of 120 tablets.
- NDC Number 57894-150-12
- Storage and Handling
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F).
- Based on its mechanism of action, Abiraterone may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle Abiraterone without protection, e.g., gloves.
## Storage
There is limited information regarding Abiraterone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that Abiraterone and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.
- Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with Abiraterone and prednisone.
- Patients should be informed that Abiraterone must not be taken with food and that no food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking Abiraterone with food causes increased exposure and this may result in adverse reactions.
- Patients should be informed that Abiraterone is taken once daily and prednisone is taken twice daily according to their physician's instructions.
- Patients should be informed that in the event of a missed daily dose of Abiraterone or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.
- Patients should be apprised of the common side effects associated with Abiraterone, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
- Patients should be advised that their liver function will be monitored using blood tests.
- Patients should be informed that Abiraterone may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Abiraterone without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with Abiraterone.
# Precautions with Alcohol
- Alcohol-Abiraterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZYTIGA®[1]
# Look-Alike Drug Names
There is limited information regarding Abiraterone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Abiraterone | |
b4835a4629363b89bc5fb8ab7f3445f475d90eca | wikidoc | Heart block | Heart block
# Overview
Heart block is defined as impaired or abnormal conduction of electrical impulses in the heart. With each heartbeat, an electrical signal spreads across the heart from the upper (atria) to the lower chambers (ventricles). As it travels, the signal causes the heart to contract and pump blood. This process repeats with each new heartbeat. Heart block occurs if the electrical signal is slowed or disrupted as it moves from the upper to the lower chambers of the heart. This abnormality can occur in the heart muscle (myocardium) or in the specialized electrical conduction system of the heart.
# Classification
A heart block can be a blockage at any level of the electrical conduction system of the heart:
- SA Nodal Block: Blocks that occur within the sinoatrial node (SA node) are described as SA nodal blocks.
- AV Nodal Block: Blocks that occur within the atrioventricular node (AV node) are described as AV nodal blocks.
- Infra-Hisian Block: Blocks that occur below the AV node are known as Infra-Hisian blocks (named after the bundle of His).
- Bundle Branch Block: Blocks that occur within the left or right bundle branches are known as bundle branch blocks.
- Hemiblock: Blocks that occur within the fascicles of the left bundle branch are known as hemiblocks.
Clinically speaking, most of the important heart blocks are AV nodal blocks and Infra-Hisian blocks.
## Types of SA nodal blocks
The SA nodal blocks rarely give symptoms. This is because if an individual had complete block at this level of the conduction system (which is uncommon), the secondary pacemaker of the heart would be at the AV node, which would fire at 40 to 60 beats a minute, which is enough to retain consciousness in the resting state.
Types of SA nodal blocks include:
- SA node Wenckebach (Mobitz type I)
- SA node Mobitz type II
- SA node exit block
In addition to the above blocks, the SA node can be suppressed by any other arrhythmia that reaches it. This includes retrograde conduction from the ventricles, ectopic atrial beats, atrial fibrillation, and atrial flutter.
The difference between SA node block and SA node suppression is that in SA node block an electrical impulse is generated by the SA node that doesn't make the atria contract. In SA node suppression, on the other hand, the SA node doesn't generate an electrical impulse because it is reset by the electrical impulse that enters the SA node.
## Types of AV nodal blocks
There are four basic types of AV nodal block:
- First degree AV block
- Second degree AV block
Type 1 second degree AV block (Mobitz I) (also known as Wenckebach phenomenon)
- Type 1 second degree AV block (Mobitz I) (also known as Wenckebach phenomenon)
- Third degree AV block (Complete heart block)
## Types of infrahisian block
Infrahisian block describes block of the distal conduction system. Types of infrahisian block include:
- Type 2 second degree heart block (Mobitz II)
- Left bundle branch block
Left anterior fascicular block
Left posterior fascicular block
- Left anterior fascicular block
- Left posterior fascicular block
- Right bundle branch block
Of these types of infrahisian block, Mobitz II heart block is considered most important because of the possible progression to complete heart block.
# Pathophysiology
Damage to the heart muscle and its electrical system by diseases, surgery, or medicines can cause acquired heart block. Heart block can be either congenital or acquired. Acquired heart block is more common than congenital heart block.
# Risk Factors
The risk factors for congenital and acquired heart block are different.
## Congenital Heart Block
- If a pregnant woman has an autoimmune disease, such as lupus, her fetus is at risk for heart block.
- Autoimmune diseases can cause the body to make proteins called antibodies that can cross the placenta. (The placenta is the organ that attaches the umbilical cord to the mother's womb.) These antibodies may damage the baby's heart and lead to congenital heart block.
- Congenital heart defects also may result in congenital heart block. These defects are problems with the heart's structure that are present at birth. Most of the time, doctors don't know what causes these defects.
- Heredity may play a role in certain heart defects. For example, a parent who has a congenital heart defect may be more likely than other people to have a child with the condition.
## Acquired Heart Block
- Acquired heart block can occur in people of any age. However, most types of the disorder are more common in older people. This is because many of the risk factors are more common in older people.
- People who have a history of heart disease or heart attacks are more likely to have heart block. Examples of heart disease that can lead to heart block include heart failure, coronary heart disease, and cardiomyopathy (heart muscle diseases).
- Other diseases also may raise the risk of heart block. These include sarcoidosis and the degenerative muscle disorders Lev's disease and Lenegre's disease.
- Exposure to toxic substances or taking certain medicines, such as digitalis, also can raise your risk of heart block.
- Well-trained athletes and young people are at higher risk for first-degree heart block caused by an overly active vagus nerve. You have one vagus nerve on each side of your body. These nerves run from your brain stem all the way to your abdomen. Activity in the vagus nerve slows the heart rate.
# Causes
## Life Threatening Causes
## Common Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Diagnosis
## Symptoms
Symptoms depend on the level of the heart block:
- First-degree heart block rarely causes symptoms.
- Symptoms of second- and third-degree heart block include:
- Chest pain
- Dizziness
- Fainting
- Fatigue
- Heart failure symptoms
- Light-headedness
- Pre-syncope
- Shortness of breath
- Syncope
### Contraindicated medications
Heart block is considered an absolute contraindication to the use of the following medications:
- Cyclobenzaprine | Heart block
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Heart block is defined as impaired or abnormal conduction of electrical impulses in the heart. With each heartbeat, an electrical signal spreads across the heart from the upper (atria) to the lower chambers (ventricles). As it travels, the signal causes the heart to contract and pump blood. This process repeats with each new heartbeat. Heart block occurs if the electrical signal is slowed or disrupted as it moves from the upper to the lower chambers of the heart. This abnormality can occur in the heart muscle (myocardium) or in the specialized electrical conduction system of the heart.
# Classification
A heart block can be a blockage at any level of the electrical conduction system of the heart:
- SA Nodal Block: Blocks that occur within the sinoatrial node (SA node) are described as SA nodal blocks.
- AV Nodal Block: Blocks that occur within the atrioventricular node (AV node) are described as AV nodal blocks.
- Infra-Hisian Block: Blocks that occur below the AV node are known as Infra-Hisian blocks (named after the bundle of His).
- Bundle Branch Block: Blocks that occur within the left or right bundle branches are known as bundle branch blocks.
- Hemiblock: Blocks that occur within the fascicles of the left bundle branch are known as hemiblocks.
Clinically speaking, most of the important heart blocks are AV nodal blocks and Infra-Hisian blocks.
## Types of SA nodal blocks
The SA nodal blocks rarely give symptoms. This is because if an individual had complete block at this level of the conduction system (which is uncommon), the secondary pacemaker of the heart would be at the AV node, which would fire at 40 to 60 beats a minute, which is enough to retain consciousness in the resting state.
Types of SA nodal blocks include:
- SA node Wenckebach (Mobitz type I)[1]
- SA node Mobitz type II
- SA node exit block
In addition to the above blocks, the SA node can be suppressed by any other arrhythmia that reaches it. This includes retrograde conduction from the ventricles, ectopic atrial beats, atrial fibrillation, and atrial flutter.
The difference between SA node block and SA node suppression is that in SA node block an electrical impulse is generated by the SA node that doesn't make the atria contract. In SA node suppression, on the other hand, the SA node doesn't generate an electrical impulse because it is reset by the electrical impulse that enters the SA node.
## Types of AV nodal blocks
There are four basic types of AV nodal block:
- First degree AV block
- Second degree AV block
Type 1 second degree AV block (Mobitz I) (also known as Wenckebach phenomenon)
- Type 1 second degree AV block (Mobitz I) (also known as Wenckebach phenomenon)
- Third degree AV block (Complete heart block)
## Types of infrahisian block
Infrahisian block describes block of the distal conduction system. Types of infrahisian block include:
- Type 2 second degree heart block (Mobitz II)
- Left bundle branch block
Left anterior fascicular block
Left posterior fascicular block
- Left anterior fascicular block
- Left posterior fascicular block
- Right bundle branch block
Of these types of infrahisian block, Mobitz II heart block is considered most important because of the possible progression to complete heart block.
# Pathophysiology
Damage to the heart muscle and its electrical system by diseases, surgery, or medicines can cause acquired heart block. Heart block can be either congenital or acquired. Acquired heart block is more common than congenital heart block.
# Risk Factors
The risk factors for congenital and acquired heart block are different.
## Congenital Heart Block
- If a pregnant woman has an autoimmune disease, such as lupus, her fetus is at risk for heart block.
- Autoimmune diseases can cause the body to make proteins called antibodies that can cross the placenta. (The placenta is the organ that attaches the umbilical cord to the mother's womb.) These antibodies may damage the baby's heart and lead to congenital heart block.
- Congenital heart defects also may result in congenital heart block. These defects are problems with the heart's structure that are present at birth. Most of the time, doctors don't know what causes these defects.
- Heredity may play a role in certain heart defects. For example, a parent who has a congenital heart defect may be more likely than other people to have a child with the condition.
## Acquired Heart Block
- Acquired heart block can occur in people of any age. However, most types of the disorder are more common in older people. This is because many of the risk factors are more common in older people.
- People who have a history of heart disease or heart attacks are more likely to have heart block. Examples of heart disease that can lead to heart block include heart failure, coronary heart disease, and cardiomyopathy (heart muscle diseases).
- Other diseases also may raise the risk of heart block. These include sarcoidosis and the degenerative muscle disorders Lev's disease and Lenegre's disease.
- Exposure to toxic substances or taking certain medicines, such as digitalis, also can raise your risk of heart block.
- Well-trained athletes and young people are at higher risk for first-degree heart block caused by an overly active vagus nerve. You have one vagus nerve on each side of your body. These nerves run from your brain stem all the way to your abdomen. Activity in the vagus nerve slows the heart rate.
# Causes
## Life Threatening Causes
## Common Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Diagnosis
## Symptoms
Symptoms depend on the level of the heart block:
- First-degree heart block rarely causes symptoms.
- Symptoms of second- and third-degree heart block include:
- Chest pain
- Dizziness
- Fainting
- Fatigue
- Heart failure symptoms
- Light-headedness
- Pre-syncope
- Shortness of breath
- Syncope
### Contraindicated medications
Heart block is considered an absolute contraindication to the use of the following medications:
- Cyclobenzaprine | https://www.wikidoc.org/index.php/Abnormal_conduction_of_the_impulses_through_the_heart | |
ec496c17dd99a327391027469c250d682f9bfe6e | wikidoc | Ejaculation | Ejaculation
Steven C. Campbell, M.D., Ph.D.
# Overview
Ejaculation is the ejecting of semen from the penis, and is usually accompanied by orgasm. It is usually the result of sexual stimulation, which may include prostate stimulation. Rarely, it is due to prostatic disease. Ejaculation may occur spontaneously during sleep (a nocturnal emission). Anejaculation is the condition of being unable to ejaculate.
# About
The process of ejaculation is a very intense sensation and the climax of the male orgasm (French "la petite mort" - the little death), which is extremely pleasurable and satisfying. Each spurt is associated with a wave of immense sexual pleasure, especially in the penis and loins. The first and second convulsions are usually the most intense in sensation, and produce the greatest quantity of semen. Thereafter, each contraction is associated with a diminishing volume of semen and a milder wave of pleasure. During sexual intercourse or masturbation, most males will find it difficult to resist the psychological temptation to continue the stimulation of the penis to the point of ejaculation once the feeling of orgasm becomes imminent.
Ejaculation has two phases: emission and ejaculation proper. The emission phase of the ejaculatory reflex is under control of the sympathetic nervous system, while the ejaculatory phase is under control of a spinal reflex at the level of the spinal nerves S2-4 via the pudendal nerve. During emission, the two ducts known as vas deferens contract to propel sperm from the epididymis where it was stored up to the ampullae at the top end of the vas deferens. The beginning of emission is typically experienced as a "point of no return," also known as point of ejaculatory inevitability. The sperm then passes through the ejaculatory ducts and is mixed with fluids from the seminal vesicles, the prostate, and the bulbourethral glands to form the semen, or ejaculate. During ejaculation proper, the semen is ejected through the urethra with rhythmic contractions.
These rhythmic contractions are part of the male orgasm. The typical male orgasm lasts about 17 seconds but can vary from a few seconds up to about a minute. After the start of orgasm, pulses of semen begin to flow from the urethra, reach a peak discharge and then diminish in flow. The typical orgasm consists of 10 to 15 contractions. The rate of contractions gradually slows during the orgasm. Initial contractions occur at an average interval of 0.6 seconds with an increasing increment of 0.1 second per contraction. Contractions of most men proceed at regular rhythmic intervals for the duration of the orgasm. Many men also experience additional irregular contractions at the conclusion of the orgasm.
Semen begins to spurt from the penis during the first or second contraction of orgasm. For most men the first spurt occurs during the second contraction. A small study of seven men found the initial spurt occurring on the first contraction for 2 men and occurring on the second contraction for 5 men. This same study showed between 26 and 60 percent of the contractions during orgasm were accompanied by a spurt of semen.
The force and amount of ejaculate vary widely from male to male. A normal ejaculation may contain anywhere from 1.5 to 5 milliliters. Adult ejaculate volume is affected by the amount of time that has passed since the previous ejaculation. Larger ejaculate volumes are seen with greater durations of abstinence. However, a recent Australian study has suggested a positive correlation between prostate cancer and infrequent ejaculation and/or prostate milking, which performs essentially the same function. That is, frequent masturbation appears to reduce the risk of prostate cancer. Frequent ejaculation is more easily obtained and sustained over time with the aid of masturbation and it is these ejaculations which are important, not the mechanism. Also, the duration of the stimulation leading up to the ejaculation can affect the volume. Abnormally low volume is known as hypospermia, though it is normal for the amount of ejaculate to diminish with age.
The number of sperm in an ejaculation also varies widely, depending on many factors, including the recentness of last ejaculation, the average warmth of the testicles, the degree and length of time of sexual excitement prior to ejaculation, the age, testosterone level, the nutrition and especially hydration and the total volume of seminal fluid. An unusually low sperm count, not the same as low semen volume, is known as oligospermia, and the absence of any sperm from the ejaculate is termed azoospermia.
Most men experience a lag time between the ability to ejaculate consecutively, and this lag time varies among men. Age also affects the recovery time; younger men typically recover faster than older men. During this refractory period it is difficult or impossible to attain an erection, because the sympathetic nervous system counteracts the effects of the parasympathetic nervous system.
There are wide variations in how long sexual stimulation can last before ejaculation occurs.
When a man ejaculates before he wants to it is called premature ejaculation. If a man is unable to ejaculate in a timely manner after prolonged sexual stimulation, in spite of his desire to do so, it is called delayed ejaculation or anorgasmia. An orgasm that is not accompanied by ejaculation is known as a dry orgasm.
# Ejaculate development during puberty
The first ejaculation in males occurs about 12 months after the onset of puberty. This first ejaculate volume is small. The typical ejaculation over the following three months produces less than 1 ml of semen. The semen produced during early puberty is also typically clear. After ejaculation this early semen remains jellylike and unlike semen from mature males fails to liquify. Most first ejaculations (90 percent) lack sperm. Of the few early ejaculations that do contain sperm, the majority of sperm (97%) lack motion. The remaining sperm (3%) have abnormal motion.
As the male proceeds through puberty, the semen develops mature characteristics with increasing quantities of normal sperm. Semen produced 12 to 14 months after the first ejaculation liquifies after a short period of time. Within 24 months of the first ejaculation, the semen volume and the quantity and characteristics of the sperm match that of adult male semen.
# Central nervous system control
To map the neuronal activation of the brain during the ejaculatory response, researchers have studied the expression of c-fos, a proto-oncogene expressed in neurons in response to stimulation by hormones and neurotransmitters Expression of c-fos in the following areas have been observed: ,
- medial preoptic area (MPOA)
- lateral septum, bed nucleus of the stria terminalis
- paraventricular nucleus of the hypothalamus (PVN)
- ventromedial hypothalamus, medial amygdala
- ventral premammillary nuclei
- ventral tegmentum
- central tegmental field
- mesencephalic central gray
- peripeduncular nuclei
- parvocellular subparafascicular nucleus (SPF) within the posterior thalamus
# Fertilization
During heterosexual intercourse, the vagina provides sexual stimulation to the penis, typically resulting in orgasm and ejaculation. Normally, ejaculation is required for emission of sperm; if ejaculation happens while the penis is either near or within the woman's vagina, sperm can then fertilize a woman's egg and impregnate her. However, almost all men produce a small amount of pre-ejaculate fluid when their penis is erect and they are sexually stimulated, and this pre-ejaculate may contain some sperm which can also lead to pregnancy. For this reason, coitus interruptus may still lead to unwanted pregnancies for couples engaging in vaginal intercourse if other forms of birth control are not used as well.
# Euphemisms
Because sexual topics are often an uncomfortable topic among peers, a huge variety of euphemisms and dysphemisms have been invented to describe ejaculation and semen. | Ejaculation
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Ejaculation is the ejecting of semen from the penis, and is usually accompanied by orgasm. It is usually the result of sexual stimulation, which may include prostate stimulation. Rarely, it is due to prostatic disease. Ejaculation may occur spontaneously during sleep (a nocturnal emission). Anejaculation is the condition of being unable to ejaculate.
# About
The process of ejaculation is a very intense sensation and the climax of the male orgasm (French "la petite mort" - the little death), which is extremely pleasurable and satisfying. Each spurt is associated with a wave of immense sexual pleasure, especially in the penis and loins. The first and second convulsions are usually the most intense in sensation, and produce the greatest quantity of semen. Thereafter, each contraction is associated with a diminishing volume of semen and a milder wave of pleasure. During sexual intercourse or masturbation, most males will find it difficult to resist the psychological temptation to continue the stimulation of the penis to the point of ejaculation once the feeling of orgasm becomes imminent.
Ejaculation has two phases: emission and ejaculation proper. The emission phase of the ejaculatory reflex is under control of the sympathetic nervous system, while the ejaculatory phase is under control of a spinal reflex at the level of the spinal nerves S2-4 via the pudendal nerve. During emission, the two ducts known as vas deferens contract to propel sperm from the epididymis where it was stored up to the ampullae at the top end of the vas deferens. The beginning of emission is typically experienced as a "point of no return," also known as point of ejaculatory inevitability. The sperm then passes through the ejaculatory ducts and is mixed with fluids from the seminal vesicles, the prostate, and the bulbourethral glands to form the semen, or ejaculate. During ejaculation proper, the semen is ejected through the urethra with rhythmic contractions.[1]
These rhythmic contractions are part of the male orgasm. The typical male orgasm lasts about 17 seconds but can vary from a few seconds up to about a minute. After the start of orgasm, pulses of semen begin to flow from the urethra, reach a peak discharge and then diminish in flow. The typical orgasm consists of 10 to 15 contractions. The rate of contractions gradually slows during the orgasm. Initial contractions occur at an average interval of 0.6 seconds with an increasing increment of 0.1 second per contraction. Contractions of most men proceed at regular rhythmic intervals for the duration of the orgasm. Many men also experience additional irregular contractions at the conclusion of the orgasm.[2]
Semen begins to spurt from the penis during the first or second contraction of orgasm. For most men the first spurt occurs during the second contraction. A small study of seven men found the initial spurt occurring on the first contraction for 2 men and occurring on the second contraction for 5 men. This same study showed between 26 and 60 percent of the contractions during orgasm were accompanied by a spurt of semen.[3]
The force and amount of ejaculate vary widely from male to male. A normal ejaculation may contain anywhere from 1.5 to 5 milliliters.[4] Adult ejaculate volume is affected by the amount of time that has passed since the previous ejaculation. Larger ejaculate volumes are seen with greater durations of abstinence. However, a recent Australian study has suggested a positive correlation between prostate cancer and infrequent ejaculation and/or prostate milking, which performs essentially the same function. That is, frequent masturbation appears to reduce the risk of prostate cancer. Frequent ejaculation is more easily obtained and sustained over time with the aid of masturbation and it is these ejaculations which are important, not the mechanism. [5] Also, the duration of the stimulation leading up to the ejaculation can affect the volume. Abnormally low volume is known as hypospermia, though it is normal for the amount of ejaculate to diminish with age.
The number of sperm in an ejaculation also varies widely, depending on many factors, including the recentness of last ejaculation, the average warmth of the testicles, the degree and length of time of sexual excitement prior to ejaculation, the age, testosterone level, the nutrition and especially hydration and the total volume of seminal fluid. An unusually low sperm count, not the same as low semen volume, is known as oligospermia, and the absence of any sperm from the ejaculate is termed azoospermia.
Most men experience a lag time between the ability to ejaculate consecutively, and this lag time varies among men. Age also affects the recovery time; younger men typically recover faster than older men. During this refractory period it is difficult or impossible to attain an erection, because the sympathetic nervous system counteracts the effects of the parasympathetic nervous system.
There are wide variations in how long sexual stimulation can last before ejaculation occurs.
When a man ejaculates before he wants to it is called premature ejaculation. If a man is unable to ejaculate in a timely manner after prolonged sexual stimulation, in spite of his desire to do so, it is called delayed ejaculation or anorgasmia. An orgasm that is not accompanied by ejaculation is known as a dry orgasm.
# Ejaculate development during puberty
The first ejaculation in males occurs about 12 months after the onset of puberty. This first ejaculate volume is small. The typical ejaculation over the following three months produces less than 1 ml of semen. The semen produced during early puberty is also typically clear. After ejaculation this early semen remains jellylike and unlike semen from mature males fails to liquify. Most first ejaculations (90 percent) lack sperm. Of the few early ejaculations that do contain sperm, the majority of sperm (97%) lack motion. The remaining sperm (3%) have abnormal motion. [6]
As the male proceeds through puberty, the semen develops mature characteristics with increasing quantities of normal sperm. Semen produced 12 to 14 months after the first ejaculation liquifies after a short period of time. Within 24 months of the first ejaculation, the semen volume and the quantity and characteristics of the sperm match that of adult male semen. [7]
# Central nervous system control
To map the neuronal activation of the brain during the ejaculatory response, researchers have studied the expression of c-fos, a proto-oncogene expressed in neurons in response to stimulation by hormones and neurotransmitters [8] Expression of c-fos in the following areas have been observed: [9],[10]
- medial preoptic area (MPOA)
- lateral septum, bed nucleus of the stria terminalis
- paraventricular nucleus of the hypothalamus (PVN)
- ventromedial hypothalamus, medial amygdala
- ventral premammillary nuclei
- ventral tegmentum
- central tegmental field
- mesencephalic central gray
- peripeduncular nuclei
- parvocellular subparafascicular nucleus (SPF) within the posterior thalamus
# Fertilization
During heterosexual intercourse, the vagina provides sexual stimulation to the penis, typically resulting in orgasm and ejaculation. Normally, ejaculation is required for emission of sperm; if ejaculation happens while the penis is either near or within the woman's vagina, sperm can then fertilize a woman's egg and impregnate her. However, almost all men produce a small amount of pre-ejaculate fluid when their penis is erect and they are sexually stimulated, and this pre-ejaculate may contain some sperm which can also lead to pregnancy. For this reason, coitus interruptus may still lead to unwanted pregnancies for couples engaging in vaginal intercourse if other forms of birth control are not used as well.
# Euphemisms
Because sexual topics are often an uncomfortable topic among peers, a huge variety of euphemisms and dysphemisms have been invented to describe ejaculation and semen. | https://www.wikidoc.org/index.php/Abnormal_ejaculation | |
93bc2e7c3c292b9a52b7b0d57786a1f3dc4a8770 | wikidoc | Abraham-men | Abraham-men
# Background
The Abraham-men (alternative spellings: Abram-Man or Abraham Cove) were a class of beggars claiming to be lunatics allowed out of restraint, in the Tudor and Stuart periods in England.
The phrase can be traced back as far as 1561, when it was given as one of The Fraternity of Vagabonds, by John Awdeley. It also appears in the taxonomy of rogues given by Thomas Harman, which was copied by later writers of rogue literature. It also appears in King Lear and John Fletcher's Beggar's Bush). It normally refers to the practice of beggars pretending that they were patients discharged from the Abraham ward at Bedlam. They were called anticks or God's minstrels, and later Poor Toms, from the popular song "Tom of Bedlam". John Aubrey the antiquary said they were common before the English Civil War, and wore a badge of tin on their left arms, an ox horn around their necks, a long staff and fantastical clothing. However, the badge seems to have been in myth. It may have been convenient theatrical property. In 1675 the governors of Bedlam issued a public notice:-
Bedlam specialised in the care of mental illness from 1403, and remained the only such hospital in England until the seventeenth century. There cannot have been many genuine ex-inmates. In 1598 there were only 20 patients there, one who had been there over 25 years and others for several years. | Abraham-men
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
The Abraham-men (alternative spellings: Abram-Man or Abraham Cove) were a class of beggars claiming to be lunatics allowed out of restraint, in the Tudor and Stuart periods in England.
The phrase can be traced back as far as 1561, when it was given as one of The Fraternity of Vagabonds, by John Awdeley. It also appears in the taxonomy of rogues given by Thomas Harman, which was copied by later writers of rogue literature. It also appears in King Lear and John Fletcher's Beggar's Bush). It normally refers to the practice of beggars pretending that they were patients discharged from the Abraham ward at Bedlam. They were called anticks or God's minstrels, and later Poor Toms, from the popular song "Tom of Bedlam". John Aubrey the antiquary said they were common before the English Civil War, and wore a badge of tin on their left arms, an ox horn around their necks, a long staff and fantastical clothing. However, the badge seems to have been in myth. It may have been convenient theatrical property. In 1675 the governors of Bedlam issued a public notice:-
Bedlam specialised in the care of mental illness from 1403, and remained the only such hospital in England until the seventeenth century. There cannot have been many genuine ex-inmates. In 1598 there were only 20 patients there, one who had been there over 25 years and others for several years. | https://www.wikidoc.org/index.php/Abraham-men | |
a03efd8aa2976dc641d9cd4e628848ebf8650223 | wikidoc | Abreugraphy | Abreugraphy
Synonyms and keywords: MMR, Miniature Mass Radiography
# Overview
Abreugraphy is a technique for mass screening of tuberculosis using a miniature (50 to 100 mm) photograph of the screen of a x-ray fluoroscopy of the thorax, first developed in 1935.
# Historical Perspective
Abreugraphy receives its name from its inventor, Dr. Manuel Dias de Abreu, a Brazilian physician and pulmonologist. It has received several different names, according to the country where it was adopted: mass radiography, miniature chest radiograph (United Kingdom and USA), roentgenfluorography (Germany), radiophotography (France), schermografia (Italy), photoradioscopy (Spain) and photofluorography (Sweden).
In many countries, miniature mass radiographs (MMR) was quickly adopted and extensively utilized in the 1950s. For example, in Brazil and in Japan, tuberculosis prevention laws went into effect, obligating ca. 60% of the population to undergo MMR screening. However, as a mass screening program for low-risk populations, the procedure was largely discontinued in the 1970s, following recommendation of the World Health Organization, due to three main reasons:
- The dramatic decrease of the general incidence of tuberculosis in developed countries (from 150 cases per 100,000 inhabitants in 1900, 70/100,000 in 1940 and 5/100,000 in 1950);
- Decreased benefits/cost ratio (a recent Canadian study has shown a cost of CD$ 236,496 per case in groups of immigrants with a low risk for tuberculosis, versus CD$ 3,943 per case in high risk groups);
- Risk of exposure to ionizing radiation doses, particularly among children, in the presence of extremely low yield rates of detection.
# Uses
MMR is still an easy and useful way to prevent transmission of the disease in certain situations, such as in prisons and for immigration applicants and foreign workers coming from countries with a higher risk for tuberculosis. Currently, 13 of the 26 European countries use MMR as the primary screening tool for this purpose. Examples of countries with permanent programs are Italy, Switzerland, Norway, Netherlands, Japan and the United Kingdom.
For example, a study in Switzerland between 1988 and 1990, employing abreugraphy to detect tuberculosis in 50,784 immigrants entering the canton of Vaud, discovered 674 foreign people with abnormalities. Of these, 256 had tuberculosis as the primary diagnosis and 34 were smear or culture-positive (5% of all radiological abnormalities).
Elderly populations are also a good target for MMR-based screening, because the radiation risk is less important and because they have a higher risk of tuberculosis (85 per 100,000 in developed countries, in the average). In Japan, for example, it is still used routinely, and the Japan Anti-Tuberculosis Association (JATA) reported the detection of 228 cases in 965,440 chest radiographs in 1996 alone .
MMR is most useful at detecting tuberculosis infection in the asymptomatic phase, and it should be combined with tuberculin skin tests and clinical questioning in order to be more effective. The sharp increase in tuberculosis in all countries with large exposure to HIV is probably mandating a return of MMR as a screening tool focusing on high-risk populations, such as homosexuals and intravenous drug users. New advances in digital radiography, coupled with much lower x-ray dosages may herald better MMR technologies. | Abreugraphy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: MMR, Miniature Mass Radiography
# Overview
Abreugraphy is a technique for mass screening of tuberculosis using a miniature (50 to 100 mm) photograph of the screen of a x-ray fluoroscopy of the thorax, first developed in 1935.
# Historical Perspective
Abreugraphy receives its name from its inventor, Dr. Manuel Dias de Abreu, a Brazilian physician and pulmonologist. It has received several different names, according to the country where it was adopted: mass radiography, miniature chest radiograph (United Kingdom and USA), roentgenfluorography (Germany), radiophotography (France), schermografia (Italy), photoradioscopy (Spain) and photofluorography (Sweden).
In many countries, miniature mass radiographs (MMR) was quickly adopted and extensively utilized in the 1950s. For example, in Brazil and in Japan, tuberculosis prevention laws went into effect, obligating ca. 60% of the population to undergo MMR screening. However, as a mass screening program for low-risk populations, the procedure was largely discontinued in the 1970s, following recommendation of the World Health Organization, due to three main reasons:
- The dramatic decrease of the general incidence of tuberculosis in developed countries (from 150 cases per 100,000 inhabitants in 1900, 70/100,000 in 1940 and 5/100,000 in 1950);
- Decreased benefits/cost ratio (a recent Canadian study [2] has shown a cost of CD$ 236,496 per case in groups of immigrants with a low risk for tuberculosis, versus CD$ 3,943 per case in high risk groups);
- Risk of exposure to ionizing radiation doses, particularly among children, in the presence of extremely low yield rates of detection.
# Uses
MMR is still an easy and useful way to prevent transmission of the disease in certain situations, such as in prisons and for immigration applicants and foreign workers coming from countries with a higher risk for tuberculosis. Currently, 13 of the 26 European countries use MMR as the primary screening tool for this purpose. Examples of countries with permanent programs are Italy, Switzerland, Norway, Netherlands, Japan and the United Kingdom. [1]
For example, a study in Switzerland [3] between 1988 and 1990, employing abreugraphy to detect tuberculosis in 50,784 immigrants entering the canton of Vaud, discovered 674 foreign people with abnormalities. Of these, 256 had tuberculosis as the primary diagnosis and 34 were smear or culture-positive (5% of all radiological abnormalities). [2]
Elderly populations are also a good target for MMR-based screening, because the radiation risk is less important and because they have a higher risk of tuberculosis (85 per 100,000 in developed countries, in the average). In Japan, for example, it is still used routinely, and the Japan Anti-Tuberculosis Association (JATA) reported the detection of 228 cases in 965,440 chest radiographs in 1996 alone [4].[3]
MMR is most useful at detecting tuberculosis infection in the asymptomatic phase, and it should be combined with tuberculin skin tests and clinical questioning in order to be more effective. The sharp increase in tuberculosis in all countries with large exposure to HIV is probably mandating a return of MMR as a screening tool focusing on high-risk populations, such as homosexuals and intravenous drug users. New advances in digital radiography, coupled with much lower x-ray dosages may herald better MMR technologies. | https://www.wikidoc.org/index.php/Abreugraphy | |
cd18a00ff920497cb6b63b52f960ef68a21f289a | wikidoc | Abstraction | Abstraction
Abstraction is the process or result of generalization by reducing the information content of a concept or an observable phenomenon, typically in order to retain only information which is relevant for a particular purpose. For example, abstracting a leather soccer ball to a ball retains only the information on general ball attributes and behaviour. Similarly, abstracting an emotional state to happiness reduces the amount of information conveyed about the emotional state. Computer scientists use abstraction to understand and solve problems and communicate their solutions with the computer in some particular computer language.
# Thought process
In philosophical terminology, abstraction is the thought process wherein ideas are distanced from objects.
Abstraction uses a strategy of simplification, wherein formerly concrete details are left ambiguous, vague, or undefined; thus effective communication about things in the abstract requires an intuitive or common experience between the communicator and the communication recipient.
For example, many different things can be red. Likewise, many things sit on surfaces (as in picture 1, to the right). The property of redness and the relation sitting-on are therefore abstractions of those objects. Specifically, the conceptual diagram graph 1 identifies only three boxes, two ellipses, and four arrows (and their nine labels), whereas the picture 1 shows much more pictorial detail, with the scores of implied relationships as implicit in the picture rather than with the nine explicit details in the graph.
Graph 1 details some explicit relationships between the objects of the diagram. For example the arrow between the agent and CAT:Elsie depicts an example of an is-a relationship, as does the arrow between the location and the MAT. The arrows between the gerund SITTING and the nouns agent and location express the diagram's basic relationship; "agent is SITTING on location"; Elsie is an instance of CAT.
Although the description sitting-on (graph 1) is more abstract than the graphic image of a cat sitting on a mat (picture 1), the delineation of abstract things from concrete things is somewhat ambiguous; this ambiguity or vagueness is characteristic of abstraction. Thus something as simple as a newspaper might be specified to six levels, as in Douglas R. Hofstadter's illustration of that ambiguity, with a progression from abstract to concrete in Gödel, Escher, Bach (1979):
(1) a publication
An abstraction can thus encapsulate each of these levels of detail with no loss of generality. But perhaps a detective or philosopher/scientist/engineer might seek to learn about some thing, at progressively deeper levels of detail, to solve a crime or a puzzle.
# Referents
Abstractions sometimes have ambiguous referents; for example, "happiness" (when used as an abstraction) can refer to as many things as there are people and events or states of being which make them happy. Likewise, "architecture" refers not only to the design of safe, functional buildings, but also to elements of creation and innovation which aim at elegant solutions to construction problems, to the use of space, and at its best, to the attempt to evoke an emotional response in the builders, owners, viewers and users of the building.
## Instantiation
Things that do not exist at any particular place and time are often considered abstract. By contrast, instances, or members, of such an abstract thing might exist in many different places and times. Those abstract things are then said to be multiply instantiated, in the sense of picture 1, picture 2, etc., shown above.
It is not sufficient, however, to define abstract ideas as those that can be instantiated and to define abstraction as the movement in the opposite direction to instantiation. Doing so would make the concepts 'cat' and 'telephone' abstract ideas since despite their varying appearances, a particular cat or a particular telephone is an instance of the concept "cat" or the concept "telephone". Although the concepts "cat" and "telephone" are abstractions, they are not abstract in the sense of the objects in graph 1 above.
We might look at other graphs, in a progression from cat to mammal to animal, and see that animal is more abstract than mammal; but on the other hand mammal is a harder idea to express, certainly in relation to marsupial.
## Physicality
A physical object (a possible referent of a concept or word) is considered concrete (not abstract) if it is a particular individual that occupies a particular place and time.
Abstract things are sometimes defined as those things that do not exist in reality or exist only as sensory experience, like the color red. That definition, however, suffers from the difficulty of deciding which things are real (i.e. which things exist in reality). For example, it is difficult to agree to whether concepts like God, the number three, and goodness are real, abstract, or both.
An approach to resolving such difficulty is to use predicates as a general term for whether things are variously real, abstract, concrete, or of a particular property (e.g. good). Questions about the properties of things are then propositions about predicates, which propositions remain to be evaluated by the investigator. In the graph 1 above, the graphical relationships like the arrows joining boxes and ellipses might denote predicates. Different levels of abstraction might be denoted by a progression of arrows joining boxes or ellipses in multiple rows, where the arrows point from one row to another, in a series of other graphs, say graph 2, etc.
# Abstraction used in philosophy
Abstraction in philosophy is the process (or, to some, the alleged process) in concept-formation of recognizing some set of common features in individuals, and on that basis forming a concept of that feature. The notion of abstraction is important to understanding some philosophical controversies surrounding empiricism and the problem of universals. It has also recently become popular in formal logic under predicate abstraction. Another philosophical tool for discussion of abstraction is Thought space.
## Ontological status
The way that physical objects, like rocks and trees, have being differs from the way that properties of abstract concepts or relations have being, for example the way the concrete, particular, individuals pictured in picture 1 exist differs from the way the concepts illustrated in graph 1 exist. That difference accounts for the ontological usefulness of the word "abstract". The word applies to properties and relations to mark the fact that, if they exist, they do not exist in space or time, but that instances of them can exist, potentially in many different places and times.
Perhaps confusingly, some philosophies refer to tropes (instances of properties) as abstract particulars. E.g., the particular redness of a particular apple is an abstract particular.
## In linguistics
Reification, also called hypostatization, might be considered a formal fallacy whenever an abstract concept, such as "society" or "technology" is treated as if it were a concrete object. In linguistics this is called metonymy, in which abstract concepts are referred to using the same sorts of nouns that signify concrete objects. Metonymy is an aspect of the English language and of other languages. It can blur the distinction between abstract and concrete things:
## Compression
An abstraction can be seen as a process of mapping multiple different pieces of constituent data to a single piece of abstract data based on similarities in the constituent data, for example many different physical cats map to the abstraction "CAT". This conceptual scheme emphasizes the inherent equality of both constituent and abstract data, thus avoiding problems arising from the distinction between "abstract" and "concrete". In this sense the process of abstraction entails the identification of similarities between objects and the process of associating these objects with an abstraction (which is itself an object).
Chains of abstractions can therefore be constructed moving from neural impulses arising from sensory perception to basic abstractions such as color or shape to experiential abstractions such as a specific cat to semantic abstractions such as the "idea" of a CAT to classes of objects such as "mammals" and even categories such as "object" as opposed to "action".
This conceptual scheme entails no specific hierarchical taxonomy (such as the one mentioned involving cats and mammals), only a progressive compression of detail.
# The neurology of abstraction
Some research into the human brain suggests that the left and right hemispheres differ in their handling of abstraction. For example, one meta-analysis reviewing human brain lesions has shown a left hemisphere bias during tool usage
# Abstraction in art
Most typically abstraction is used in the arts as a synonym for abstract art in general. Strictly speaking, it refers to art unconcerned with the literal depiction of things from the visible world--it can, however, refer to an object or image which has been distilled from the real world, or indeed, another work of art. Artwork that reshapes the natural world for expressive purposes is called abstract; that which derives from, but does not imitate a recognizable subject is called nonobjective abstraction. In the 20th century the trend toward abstraction coincided with advances in science, technology, and changes in urban life, eventually reflecting an interest in psychoanalytic theory. Later still, abstraction was manifest in more purely formal terms, such as color, freed from objective context, and a reduction of form to basic geometric designs.
In music, abstraction refers to the abandonment of tonality. Atonal music has no key signature, and lacking an externally imposed standard, is characterized by its internal relationships.
# Abstraction in psychology
Jung's definition of abstraction broadened its scope beyond the thinking process to include exactly four mutually exclusive, opposing complementary psychological functions: sensation, intuition, feeling, and thinking. Together they form a structural totality of the differentiating abstraction process. Abstraction operates in one of these opposing functions when it excludes the simultaneous influence of the other functions and other irrelevancies such as emotion. Abstraction requires selective use of this structural split of abilities in the psyche. The opposite of abstraction is concretism. Abstraction is one of Jung's 57 definitions in Chapter XI of Psychological Types.
There is an abstract thinking, just as there is abstract feeling, sensation and intuition. Abstract thinking singles out the rational, logical qualities ... Abstract feeling does the same with ... its feeling-values. ... I put abstract feelings on the same level as abstract thoughts. ... Abstract sensation would be aesthetic as opposed to sensuous sensation and abstract intuition would be symbolic as opposed to fantastic intuition. (Jung, (1971):par. 678).
# Origins
The first symbols of abstract thinking in humans can be traced to fossils dating between 50,000 and 100,000 years ago in Africa. | Abstraction
Abstraction is the process or result of generalization by reducing the information content of a concept or an observable phenomenon, typically in order to retain only information which is relevant for a particular purpose. For example, abstracting a leather soccer ball to a ball retains only the information on general ball attributes and behaviour. Similarly, abstracting an emotional state to happiness reduces the amount of information conveyed about the emotional state. Computer scientists use abstraction to understand and solve problems and communicate their solutions with the computer in some particular computer language.
# Thought process
In philosophical terminology, abstraction is the thought process wherein ideas[1] are distanced from objects.
Abstraction uses a strategy of simplification, wherein formerly concrete details are left ambiguous, vague, or undefined; thus effective communication about things in the abstract requires an intuitive or common experience between the communicator and the communication recipient.
For example, many different things can be red. Likewise, many things sit on surfaces (as in picture 1, to the right). The property of redness and the relation sitting-on are therefore abstractions of those objects. Specifically, the conceptual diagram graph 1 identifies only three boxes, two ellipses, and four arrows (and their nine labels), whereas the picture 1 shows much more pictorial detail, with the scores of implied relationships as implicit in the picture rather than with the nine explicit details in the graph.
Graph 1 details some explicit relationships between the objects of the diagram. For example the arrow between the agent and CAT:Elsie depicts an example of an is-a relationship, as does the arrow between the location and the MAT. The arrows between the gerund SITTING and the nouns agent and location express the diagram's basic relationship; "agent is SITTING on location"; Elsie is an instance of CAT.
Although the description sitting-on (graph 1) is more abstract than the graphic image of a cat sitting on a mat (picture 1), the delineation of abstract things from concrete things is somewhat ambiguous; this ambiguity or vagueness is characteristic of abstraction. Thus something as simple as a newspaper might be specified to six levels, as in Douglas R. Hofstadter's illustration of that ambiguity, with a progression from abstract to concrete in Gödel, Escher, Bach (1979):
(1) a publication
An abstraction can thus encapsulate each of these levels of detail with no loss of generality. But perhaps a detective or philosopher/scientist/engineer might seek to learn about some thing, at progressively deeper levels of detail, to solve a crime or a puzzle.
# Referents
Abstractions sometimes have ambiguous referents; for example, "happiness" (when used as an abstraction) can refer to as many things as there are people and events or states of being which make them happy. Likewise, "architecture" refers not only to the design of safe, functional buildings, but also to elements of creation and innovation which aim at elegant solutions to construction problems, to the use of space, and at its best, to the attempt to evoke an emotional response in the builders, owners, viewers and users of the building.
## Instantiation
Things that do not exist at any particular place and time are often considered abstract. By contrast, instances, or members, of such an abstract thing might exist in many different places and times. Those abstract things are then said to be multiply instantiated, in the sense of picture 1, picture 2, etc., shown above.
It is not sufficient, however, to define abstract ideas as those that can be instantiated and to define abstraction as the movement in the opposite direction to instantiation. Doing so would make the concepts 'cat' and 'telephone' abstract ideas since despite their varying appearances, a particular cat or a particular telephone is an instance of the concept "cat" or the concept "telephone". Although the concepts "cat" and "telephone" are abstractions, they are not abstract in the sense of the objects in graph 1 above.
We might look at other graphs, in a progression from cat to mammal to animal, and see that animal is more abstract than mammal; but on the other hand mammal is a harder idea to express, certainly in relation to marsupial.
## Physicality
A physical object (a possible referent of a concept or word) is considered concrete (not abstract) if it is a particular individual that occupies a particular place and time.
Abstract things are sometimes defined as those things that do not exist in reality or exist only as sensory experience, like the color red. That definition, however, suffers from the difficulty of deciding which things are real (i.e. which things exist in reality). For example, it is difficult to agree to whether concepts like God, the number three, and goodness are real, abstract, or both.
An approach to resolving such difficulty is to use predicates as a general term for whether things are variously real, abstract, concrete, or of a particular property (e.g. good). Questions about the properties of things are then propositions about predicates, which propositions remain to be evaluated by the investigator. In the graph 1 above, the graphical relationships like the arrows joining boxes and ellipses might denote predicates. Different levels of abstraction might be denoted by a progression of arrows joining boxes or ellipses in multiple rows, where the arrows point from one row to another, in a series of other graphs, say graph 2, etc.
# Abstraction used in philosophy
Abstraction in philosophy is the process (or, to some, the alleged process) in concept-formation of recognizing some set of common features in individuals, and on that basis forming a concept of that feature. The notion of abstraction is important to understanding some philosophical controversies surrounding empiricism and the problem of universals. It has also recently become popular in formal logic under predicate abstraction. Another philosophical tool for discussion of abstraction is Thought space.
## Ontological status
The way that physical objects, like rocks and trees, have being differs from the way that properties of abstract concepts or relations have being, for example the way the concrete, particular, individuals pictured in picture 1 exist differs from the way the concepts illustrated in graph 1 exist. That difference accounts for the ontological usefulness of the word "abstract". The word applies to properties and relations to mark the fact that, if they exist, they do not exist in space or time, but that instances of them can exist, potentially in many different places and times.
Perhaps confusingly, some philosophies refer to tropes (instances of properties) as abstract particulars. E.g., the particular redness of a particular apple is an abstract particular.
## In linguistics
Reification, also called hypostatization, might be considered a formal fallacy whenever an abstract concept, such as "society" or "technology" is treated as if it were a concrete object. In linguistics this is called metonymy, in which abstract concepts are referred to using the same sorts of nouns that signify concrete objects. Metonymy is an aspect of the English language and of other languages. It can blur the distinction between abstract and concrete things:
## Compression
An abstraction can be seen as a process of mapping multiple different pieces of constituent data to a single piece of abstract data based on similarities in the constituent data, for example many different physical cats map to the abstraction "CAT". This conceptual scheme emphasizes the inherent equality of both constituent and abstract data, thus avoiding problems arising from the distinction between "abstract" and "concrete". In this sense the process of abstraction entails the identification of similarities between objects and the process of associating these objects with an abstraction (which is itself an object).
Chains of abstractions can therefore be constructed moving from neural impulses arising from sensory perception to basic abstractions such as color or shape to experiential abstractions such as a specific cat to semantic abstractions such as the "idea" of a CAT to classes of objects such as "mammals" and even categories such as "object" as opposed to "action".
This conceptual scheme entails no specific hierarchical taxonomy (such as the one mentioned involving cats and mammals), only a progressive compression of detail.
# The neurology of abstraction
Some research into the human brain suggests that the left and right hemispheres differ in their handling of abstraction. For example, one meta-analysis reviewing human brain lesions has shown a left hemisphere bias during tool usage
[2].
# Abstraction in art
Most typically abstraction is used in the arts as a synonym for abstract art in general. Strictly speaking, it refers to art unconcerned with the literal depiction of things from the visible world[3]--it can, however, refer to an object or image which has been distilled from the real world, or indeed, another work of art. Artwork that reshapes the natural world for expressive purposes is called abstract; that which derives from, but does not imitate a recognizable subject is called nonobjective abstraction. In the 20th century the trend toward abstraction coincided with advances in science, technology, and changes in urban life, eventually reflecting an interest in psychoanalytic theory.[4] Later still, abstraction was manifest in more purely formal terms, such as color, freed from objective context, and a reduction of form to basic geometric designs. [5]
In music, abstraction refers to the abandonment of tonality. Atonal music has no key signature, and lacking an externally imposed standard, is characterized by its internal relationships.[6]
# Abstraction in psychology
Jung's definition of abstraction broadened its scope beyond the thinking process to include exactly four mutually exclusive, opposing complementary psychological functions: sensation, intuition, feeling, and thinking. Together they form a structural totality of the differentiating abstraction process. Abstraction operates in one of these opposing functions when it excludes the simultaneous influence of the other functions and other irrelevancies such as emotion. Abstraction requires selective use of this structural split of abilities in the psyche. The opposite of abstraction is concretism. Abstraction is one of Jung's 57 definitions in Chapter XI of Psychological Types.
There is an abstract thinking, just as there is abstract feeling, sensation and intuition. Abstract thinking singles out the rational, logical qualities ... Abstract feeling does the same with ... its feeling-values. ... I put abstract feelings on the same level as abstract thoughts. ... Abstract sensation would be aesthetic as opposed to sensuous sensation and abstract intuition would be symbolic as opposed to fantastic intuition. (Jung, [1921] (1971):par. 678).
# Origins
The first symbols of abstract thinking in humans can be traced to fossils dating between 50,000 and 100,000 years ago in Africa.[7][8] | https://www.wikidoc.org/index.php/Abstraction | |
4601d74bbffa44d62733811564e98e87f8c69370 | wikidoc | Acanthocyte | Acanthocyte
Acanthocyte is a general term meaning 'spiny cell'. AKA "spur cell" in more severe cases
- In human biology and medicine, the term refers to pathological red blood cells, which are coarse and irregularly crenelated resembling many-pointed stars. They are seen on blood films in, among others, lipid abnormalities, liver disease, chorea acanthocytosis, McLeod syndrome and several inherited neurological disorders, such as neuroacanthocytosis.
- In veterinary medicine, Acanthocytosis may be seen in dogs with liver disease or hemangiosarcoma.
- In mycology, the term also refers to stellate cells found on the hyphae of fungi of the genus Stropharia. Recent work, published in 2006, on those of Stropharia rugosoannulata has shown them to have nematode-killing properties.
- Acanthocytes
- Acanthocytes | Acanthocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Acanthocyte is a general term meaning 'spiny cell'. AKA "spur cell" in more severe cases
- In human biology and medicine, the term refers to pathological red blood cells, which are coarse and irregularly crenelated resembling many-pointed stars. They are seen on blood films in, among others, lipid abnormalities, liver disease, chorea acanthocytosis, McLeod syndrome and several inherited neurological disorders, such as neuroacanthocytosis.
- In veterinary medicine, Acanthocytosis may be seen in dogs with liver disease or hemangiosarcoma.
- In mycology, the term also refers to stellate cells found on the hyphae of fungi of the genus Stropharia. Recent work, published in 2006, on those of Stropharia rugosoannulata has shown them to have nematode-killing properties.[1]
- Acanthocytes
- Acanthocytes | https://www.wikidoc.org/index.php/Acanthocyte | |
435b6508bfa4bbbba61a4c152e5e373638186ee7 | wikidoc | Zafirlukast | Zafirlukast
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# Overview
Zafirlukast is a anti-Inflammatory , leukotriene pathway inhibitor that is FDA approved for the prophylaxis of and chronic treatment of asthma. Common adverse reactions include headache, nausea, diarrhea, abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
### Dosing Information
- Because food can reduce the bioavailability of zafirlukast, Zafirlukast should be taken at least 1 hour before or 2 hours after meals.
- The recommended dose of Zafirlukast in adults and children 12 years and older is 20 mg twice daily.
- Based on cross-study comparisons, the clearance of zafirlukast is reduced in elderly patients (65 years of age and older), such that Cmax and AUC are approximately twice those of younger adults. In clinical trials, a dose of 20 mg twice daily was not associated with an increase in the overall incidence of adverse events or withdrawals because of adverse events in elderly patients.
- Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis (see Contraindications). The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that the Cmax and AUC are approximately 50 - 60% greater than those of normal adults. Zafirlukast has not been evaluated in patients with hepatitis or in long-term studies of patients with cirrhosis.
- Dosage adjustment is not required for patients with renal impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zafirlukast in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zafirlukast in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
### Dosing Information
- The recommended dose of Zafirlukast in children 5 through 11 years of age is 10 mg twice daily.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zafirlukast in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zafirlukast in pediatric patients.
# Contraindications
- Zafirlukast is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients.
- Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis.
# Warnings
- Cases of life-threatening hepatic failure have been reported in patients treated with Zafirlukast. Cases of liver injury without other attributable cause have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of Zafirlukast (40 mg/day). In most, but not all post-marketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping Zafirlukast. In rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. In extremely rare post-marketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations.
- Physicians may consider the value of liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery.
- Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia) and to contact their physician immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.
- If liver dysfunction is suspected based upon clinical signs or symptoms (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver), Zafirlukast should be discontinued.
- Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, Zafirlukast therapy should not be resumed. Patients in whom Zafirlukast was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to Zafirlukast (see PRECAUTIONS, INFORMATION FOR PATIENTS and ADVERSE REACTIONS).
- Zafirlukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with Zafirlukast can be continued during acute exacerbations of asthma.
- Coadministration of zafirlukast with warfarin results in a clinically significant increase in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and Zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly.
### PRECAUTIONS
- In rare cases, patients with asthma on Zafirlukast may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that Zafirlukast may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see ADVERSE REACTIONS).
- Neuropsychiatric events have been reported in adult, adolescent and pediatric patients taking Zafirlukast. Post-marketing reports with Zafirlukast include insomnia and depression. The clinical details of some post-marketing reports involving Zafirlukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Zafirlukast if such events occur.
# Adverse Reactions
## Clinical Trials Experience
- The safety database for Zafirlukast consists of more than 4000 healthy volunteers and patients who received Zafirlukast, of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received Zafirlukast for 1 year or longer. The majority of the patients were 18 years of age or older; however, 222 patients between the age of 12 and 18 years received Zafirlukast.
- A comparison of adverse events reported by ≥1% of zafirlukast-treated patients, and at rates numerically greater than in placebo-treated patients, is shown for all trials in the table below.
- The frequency of less common adverse events was comparable between Zafirlukast and placebo.
- Rarely, elevations of one or more liver enzymes have occurred in patients receiving Zafirlukast in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of Zafirlukast (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all postmarketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping Zafirlukast. In rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death (see WARNINGS, HEPATOTOXICITY and PRECAUTIONS, INFORMATION FOR PATIENTS).
- In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. A similar finding was not observed in other age groups studied. These infections were mostly mild or moderate in intensity and predominantly affected the respiratory tract. Infections occurred equally in both sexes, were dose-proportional to total milligrams of zafirlukast exposure, and were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown.
- In rare cases, patients with asthma on Zafirlukast may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that Zafirlukast may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see PRECAUTIONS, EOSINOPHILIC CONDITIONS).
- Neuropsychiatric adverse events, including insomnia and depression, have been reported in association with Zafirlukast therapy (see PRECAUTIONS, NEUROPSYCHIATRIC EVENTS). Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have also been reported in association with Zafirlukast therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with Zafirlukast therapy.
- Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Zafirlukast to an existing theophylline regimen have been reported. The mechanism of the interaction between Zafirlukast and theophylline in these patients is unknown and not predicted by available in vitro metabolism data and the results of two clinical drug interaction studies.
- Zafirlukast has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with Zafirlukast 10 mg twice daily or higher for at least 6 months, and 113 of them were treated for one year or longer in clinical trials. The safety profile of Zafirlukast 10 mg twice daily-versus placebo in the 4- and 6-week double-blind trials was generally similar to that observed in the adult clinical trials with Zafirlukast 20 mg twice daily.
- In pediatric patients receiving Zafirlukast in multi-dose clinical trials, the following events occurred with a frequency of ≥ 2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: headache (4.5 vs. 4.2%) and abdominal pain (2.8 vs. 2.3%).
- The post-marketing experience in this age group is similar to that seen in adults, including hepatic dysfunction, which may lead to liver failure.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zafirlukast in the drug label.
# Drug Interactions
- In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+ 63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and Zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see WARNINGS, CONCOMITANT WARFARIN ADMINISTRATION). No formal drug-drug interaction studies with Zafirlukast and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme (eg, tolbutamide, phenytoin, carbamazepine) have been conducted; however, care should be exercised when Zafirlukast is coadministered with these drugs.
- In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state resulted in decreased mean plasma levels of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
- Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline.
- Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed.
- Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Zafirlukast to an existing theophylline regimen have been reported. The mechanism of the interaction between Zafirlukast and theophylline in these patients is unknown (see ADVERSE REACTIONS).
- Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%.
- In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.
- Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increasedplasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this interaction is unknown. Zafirlukast exposure is likely to be increased by other moderate and strong CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast.
- No other formal drug-drug interaction studies between Zafirlukast and marketed drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As Zafirlukast is known to be an inhibitor of CYP3A4 in vitro, it is reasonable to employ appropriate clinical monitoring when these drugs are coadministered with Zafirlukast.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- No teratogenicity was observed at oral doses up to 1600 mg/kg/day in mice (approximately 160 times the maximum recommended daily oral dose in adults on a mg/m2 basis), up to 2000 mg/kg/day in rats (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m2 basis) and up to 2000 mg/kg/day in cynomolgus monkeys (which resulted in approximately 20 times the exposure to drug plus metabolites compared to that from the maximum recommended daily oral dose in adults based on comparison of the AUC values). At an oral dose of 2000 mg/kg/day in rats, maternal toxicity and deaths were seen with increased incidence of early fetal resorption. Spontaneous abortions occurred in cynomolgus monkeys at the maternally toxic oral dose of 2000 mg/kg/day. There are no adequate and well-controlled trials in pregnant women. Because animal reproductive studies are not always predictive of human response, Zafirlukast should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zafirlukast in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zafirlukast during labor and delivery.
### Nursing Mothers
- Zafirlukast is excreted in breast milk. Following repeated 40 mg twice-a-day dosing in healthy women, average steady-state concentrations of zafirlukast in breast milk were 50 ng/mL compared to 255 ng/mL in plasma. Because of the potential for tumorigenicity shown for zafirlukast in mouse and rat studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects of zafirlukast, Zafirlukast should not be administered to mothers who are breast-feeding.
### Pediatric Use
- The safety of Zafirlukast at doses of 10 mg twice daily has been demonstrated in 205 pediatric patients 5 through 11 years of age in placebo-controlled trials lasting up to six weeks and with 179 patients in this age range participating in 52 weeks of treatment in an open-label extension.
- The effectiveness of Zafirlukast for the prophylaxis and chronic treatment of asthma in pediatric patients 5 through 11 years of age is based on an extrapolation of the demonstrated efficacy of Zafirlukast in adults with asthma and the likelihood that the disease course, and pathophysiology and the drug’s effect are substantially similar between the two populations. The recommended dose for the patients 5 through 11 years of age is based upon a cross-study comparison of the pharmacokinetics of zafirlukast in adults and pediatric subjects, and on the safety profile of zafirlukast in both adult and pediatric patients at doses equal to or higher than the recommended dose.
- The safety and effectiveness of zafirlukast for pediatric patients less than 5 years of age has not been established. The effect of Zafirlukast on growth in children has not been determined.
### Geriatic Use
- Based on cross-study comparison, the clearance of zafirlukast is reduced in patients 65 years of age and older such that Cmax and AUC are approximately 2- to 3-fold greater than those of younger patients (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY).
- A total of 8094 patients were exposed to zafirlukast in North American and European short-term placebo-controlled clinical trials. Of these, 243 patients were elderly (age 65 years and older). No overall difference in adverse events was seen in the elderly patients, except for an increase in the frequency of infections among zafirlukast-treated elderly patients compared to placebo-treated elderly patients (7.0% vs. 2.9%). The infections were not severe, occurred mostly in the lower respiratory tract, and did not necessitate withdrawal of therapy.
- An open-label, uncontrolled, 4-week trial of 3759 asthma patients compared the safety and efficacy of Zafirlukast 20 mg given twice daily in three patient age groups, adolescents (12-17 years), adults (18-65 years), and elderly (greater than 65 years). A higher percentage of elderly patients (n=384) reported adverse events when compared to adults and adolescents. These elderly patients showed less improvement in efficacy measures. In the elderly patients, adverse events occurring in greater than 1% of the population included headache (4.7%), diarrhea and nausea (1.8%), and pharyngitis (1.3%). The elderly reported the lowest percentage of infections of all three age groups in this study.
### Gender
There is no FDA guidance on the use of Zafirlukast with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zafirlukast with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zafirlukast in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zafirlukast in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zafirlukast in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zafirlukast in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Zafirlukast in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Zafirlukast in the drug label.
# Overdosage
- No deaths occurred at oral zafirlukast doses of 2000 mg/kg in mice (approximately 210 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis), 2000 mg/kg in rats (approximately 420 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis), and 500 mg/kg in dogs (approximately 350 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis).
- Overdosage with Zafirlukast has been reported in four patients surviving reported doses as high as 200 mg. The predominant symptoms reported following Zafirlukast overdose were rash and upset stomach. There were no acute toxic effects in humans that could be consistently ascribed to the administration of Zafirlukast. It is reasonable to employ the usual supportive measures in the event of an overdose; eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
# Pharmacology
## Mechanism of Action
- Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects.
- In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early- and late-phase response and the nonspecific hyperresponsiveness.
- In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.
## Structure
- Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. The molecular weight of zafirlukast is 575.7 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Zafirlukast in the drug label.
## Pharmacokinetics
- Zafirlukast is rapidly absorbed following oral administration. Peak plasma concentrations are generally achieved 3 hours after oral administration. The absolute bioavailability of zafirlukast is unknown. In two separate studies, one using a high fat and the other a high protein meal, administration of zafirlukast with food reduced the mean bioavailability by approximately 40%.
- Zafirlukast is more than 99% bound to plasma proteins, predominantly albumin. The degree of binding was independent of concentration in the clinically relevant range. The apparent steady-state volume of distribution (Vss/F) is approximately 70 L, suggesting moderate distribution into tissues. Studies in rats using radiolabeled zafirlukast indicate minimal distribution across the blood-brain barrier.
- Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9 (CYP2C9) pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved total plasma concentrations.
- The apparent oral clearance (CL/f) of zafirlukast is approximately 20 L/h. Studies in the rat and dog suggest that biliary excretion is the primary route of excretion. Following oral administration of radiolabeled zafirlukast to volunteers, urinary excretion accounts for approximately 10% of the dose and the remainder is excreted in feces. Zafirlukast is not detected in urine.
- In the pivotal bioequivalence study, the mean terminal half-life of zafirlukast is approximately 10 hours in both normal adult subjects and patients with asthma. In other studies, the mean plasma half-life of zafirlukast ranged from approximately 8 to 16 hours in both normal subjects and patients with asthma. The pharmacokinetics of zafirlukast are approximately linear over the range from 5 mg to 80 mg. Steady-state plasma concentrations of zafirlukast are proportional to the dose and predictable from single-dose pharmacokinetic data. Accumulation of zafirlukast in the plasma following twice-daily dosing is approximately 45%.
- The pharmacokinetic parameters of zafirlukast 20 mg administered as a single dose to 36 male volunteers are shown with the table below.
- Gender:
- The pharmacokinetics of zafirlukast are similar in males and females. Weight-adjusted apparent oral clearance does not differ due to gender.
- Race:
- No differences in the pharmacokinetics of zafirlukast due to race have been observed.
- Elderly:
- The apparent oral clearance of zafirlukast decreases with age. In patients above 65 years of age, there is an approximately 2-3 fold greater Cmax and AUC compared to young adult patients.
- Children:
- Following administration of a single 20 mg dose of zafirlukast to 20 boys and girls between 7 and 11 years of age, and in a second study, to 29 boys and girls between 5 and 6 years of age, the following pharmacokinetic parameters were obtained:
- Weight unadjusted apparent clearance was 11.4 L/h (42%) in the 7-11 year old children and 9.2 L/h (37%) in the 5-6 year old children, which resulted in greater systemic drug exposures than that obtained in adults for an identical dose. To maintain similar exposure levels in children compared to adults, a dose of 10 mg twice daily is recommended in children 5-11 years of age.
- Zafirlukast disposition was unchanged after multiple dosing (20 mg twice daily) in children and the degree of accumulation in plasma was similar to that observed in adults.
- Hepatic Insufficiency: In a study of patients with hepatic impairment (biopsy-proven cirrhosis), there was a reduced clearance of zafirlukast resulting in a 50-60% greater Cmax and AUC compared to normal subjects.
- Renal Insufficiency: Based on a cross-study comparison, there are no apparent differences in the pharmacokinetics of zafirlukast between renally-impaired patients and normal subjects.
- Drug-Drug Interactions: The following drug interaction studies have been conducted with zafirlukast (see PRECAUTIONS, DRUG INTERACTIONS).
- Coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin (a substrate of CYP2C9) resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time increased by approximately 35%. The pharmacokinetics of zafirlukast were unaffected by coadministration with warfarin.
- Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma concentrations of zafirlukast by approximately 30%, but no effect on plasma theophylline concentrations was observed.
- Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline.
- Coadministration of zafirlukast dosed at 40 mg twice daily in a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, resulted in no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.
- Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma concentrations of zafirlukast by approximately 45%.
- Coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state in 11 asthmatic patients resulted in decreased mean plasma concentrations of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
- Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased
- plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this
- interaction is unknown. Zafirlukast exposure is likely to be increased by other moderate and strong
- CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor,
- caused no change in plasma levels of zafirlukast.
## Nonclinical Toxicology
- In two-year carcinogenicity studies, zafirlukast was administered at dietary doses of 10, 100, and 300 mg/kg to mice and 40, 400, and 2000 mg/kg to rats. Male mice at an oral dose of 300 mg/kg/day (approximately 30 times the maximum recommended daily oral dose in adults and in children on a mg/m2 basis) showed an increased incidence of hepatocellular adenomas; female mice at this dose showed a greater incidence of whole body histocytic sarcomas. Male and female rats at an oral dose of 2000 mg/kg/day (resulting in approximately 160 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma area-under the curve values) of zafirlukast showed an increased incidence of urinary bladder transitional cell papillomas. Zafirlukast was not tumorigenic at oral doses up to 100 mg/kg (approximately 10 times the maximum recommended daily oral dose in adults and in children on a mg/m2 basis) in mice and at oral doses up to 400 mg/kg (resulting in approximately 140 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma AUC values) in rats. The clinical significance of these findings for the long-term use of Zafirlukast is unknown.
- Zafirlukast showed no evidence of mutagenic potential in the reverse microbial assay, in 2 forward point mutation (CHO-HGPRT and mouse lymphoma) assays or in two assays for chromosomal aberrations (the in vitro human peripheral blood lymphocyte clastogenic assay and the in vivo rat bone marrow micronucleus assay).
- No evidence of impairment of fertility and reproduction was seen in male and female rats treated with zafirlukast at oral doses up to 2000 mg/kg (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m2 basis).
# Clinical Studies
- Three U.S. double-blind, randomized, placebo-controlled, 13-week clinical trials in 1380 adults and children 12 years of age and older with mild-to-moderate asthma demonstrated that Zafirlukast improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta2-agonist use, FEV1, and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline beta2-agonist requirement of approximately 4-5 puffs of albuterol per day. The results of the largest of the trials are shown in the table below.
- In a second and smaller study, the effect of Zafirlukast on most efficacy parameters was comparable to the active control (inhaled cromolyn sodium 1600 mcg four times per day) and superior to placebo at end point for decreasing rescue beta2-agonist use (figure below).
- In these trials, improvement in asthma symptoms occurred within one week of initiating treatment with Zafirlukast. The role of Zafirlukast in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as-needed, inhaled beta2-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.
# How Supplied
## Storage
- Store at controlled room temperature, 20-25°C (68-77°F).
- Protect from light and moisture.
- Dispense in the original air-tight container.
# Images
## Drug Images
## Package and Label Display Panel
NDC 0310-0401-60
60 tablets
Zafirlukast®
ZAFIRLUKAST
10 mg tablets
Rx only
DISPENSE IN THE ORIGINAL
AIRTIGHT CONTAINER.
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: IPR Pharmaceuticals, Inc.
Canóvanas, PR 00729
Product of UK
AstraZeneca
NDC 0310-0402-60
60 tablets
Zafirlukast®
ZAFIRLUKAST
20 mg tablets
Rx only
DISPENSE IN THE ORIGINAL
AIRTIGHT CONTAINER.
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: IPR Pharmaceuticals, Inc.
Canóvanas, PR 00729
Product of UK
AstraZeneca
# Patient Counseling Information
- Patients should be told that a rare side effect of Zafirlukast is hepatic dysfunction, and to contact their physician immediately if they experience symptoms of hepatic dysfunction (eg. right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia). Liver failure resulting in liver transplantation and death has occurred in patients taking zafirlukast (see WARNINGS, HEPATOTOXICITY and ADVERSE REACTIONS).
- Zafirlukast is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. Zafirlukast is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients receiving Zafirlukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Patients should be instructed to notify their physician if neuropsychiatric events occur while using Zafirlukast (see PRECAUTIONS, NEUROPSYCHIATRIC EVENTS). Women who are breast-feeding should be instructed not to take Zafirlukast (see PRECAUTIONS, NURSING MOTHERS). Alternative antiasthma medication should be considered in such patients.
- The bioavailability of Zafirlukast may be decreased when taken with food. Patients should be instructed to take Zafirlukast at least 1 hour before or 2 hours after meals.
# Precautions with Alcohol
- Alcohol-Zafirlukast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Accolate®
# Look-Alike Drug Names
There is limited information regarding Zafirlukast Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Zafirlukast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Overview
Zafirlukast is a anti-Inflammatory , leukotriene pathway inhibitor that is FDA approved for the prophylaxis of and chronic treatment of asthma. Common adverse reactions include headache, nausea, diarrhea, abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
### Dosing Information
- Because food can reduce the bioavailability of zafirlukast, Zafirlukast should be taken at least 1 hour before or 2 hours after meals.
- The recommended dose of Zafirlukast in adults and children 12 years and older is 20 mg twice daily.
- Based on cross-study comparisons, the clearance of zafirlukast is reduced in elderly patients (65 years of age and older), such that Cmax and AUC are approximately twice those of younger adults. In clinical trials, a dose of 20 mg twice daily was not associated with an increase in the overall incidence of adverse events or withdrawals because of adverse events in elderly patients.
- Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis (see Contraindications). The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that the Cmax and AUC are approximately 50 - 60% greater than those of normal adults. Zafirlukast has not been evaluated in patients with hepatitis or in long-term studies of patients with cirrhosis.
- Dosage adjustment is not required for patients with renal impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zafirlukast in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zafirlukast in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.
### Dosing Information
- The recommended dose of Zafirlukast in children 5 through 11 years of age is 10 mg twice daily.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zafirlukast in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zafirlukast in pediatric patients.
# Contraindications
- Zafirlukast is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients.
- Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis.
# Warnings
- Cases of life-threatening hepatic failure have been reported in patients treated with Zafirlukast. Cases of liver injury without other attributable cause have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of Zafirlukast (40 mg/day). In most, but not all post-marketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping Zafirlukast. In rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. In extremely rare post-marketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations.
- Physicians may consider the value of liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery.
- Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia) and to contact their physician immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.
- If liver dysfunction is suspected based upon clinical signs or symptoms (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver), Zafirlukast should be discontinued.
- Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, Zafirlukast therapy should not be resumed. Patients in whom Zafirlukast was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to Zafirlukast (see PRECAUTIONS, INFORMATION FOR PATIENTS and ADVERSE REACTIONS).
- Zafirlukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with Zafirlukast can be continued during acute exacerbations of asthma.
- Coadministration of zafirlukast with warfarin results in a clinically significant increase in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and Zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly.
### PRECAUTIONS
- In rare cases, patients with asthma on Zafirlukast may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that Zafirlukast may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see ADVERSE REACTIONS).
- Neuropsychiatric events have been reported in adult, adolescent and pediatric patients taking Zafirlukast. Post-marketing reports with Zafirlukast include insomnia and depression. The clinical details of some post-marketing reports involving Zafirlukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Zafirlukast if such events occur.
# Adverse Reactions
## Clinical Trials Experience
- The safety database for Zafirlukast consists of more than 4000 healthy volunteers and patients who received Zafirlukast, of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received Zafirlukast for 1 year or longer. The majority of the patients were 18 years of age or older; however, 222 patients between the age of 12 and 18 years received Zafirlukast.
- A comparison of adverse events reported by ≥1% of zafirlukast-treated patients, and at rates numerically greater than in placebo-treated patients, is shown for all trials in the table below.
- The frequency of less common adverse events was comparable between Zafirlukast and placebo.
- Rarely, elevations of one or more liver enzymes have occurred in patients receiving Zafirlukast in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of Zafirlukast (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all postmarketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping Zafirlukast. In rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death (see WARNINGS, HEPATOTOXICITY and PRECAUTIONS, INFORMATION FOR PATIENTS).
- In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. A similar finding was not observed in other age groups studied. These infections were mostly mild or moderate in intensity and predominantly affected the respiratory tract. Infections occurred equally in both sexes, were dose-proportional to total milligrams of zafirlukast exposure, and were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown.
- In rare cases, patients with asthma on Zafirlukast may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that Zafirlukast may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see PRECAUTIONS, EOSINOPHILIC CONDITIONS).
- Neuropsychiatric adverse events, including insomnia and depression, have been reported in association with Zafirlukast therapy (see PRECAUTIONS, NEUROPSYCHIATRIC EVENTS). Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have also been reported in association with Zafirlukast therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with Zafirlukast therapy.
- Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Zafirlukast to an existing theophylline regimen have been reported. The mechanism of the interaction between Zafirlukast and theophylline in these patients is unknown and not predicted by available in vitro metabolism data and the results of two clinical drug interaction studies.
- Zafirlukast has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with Zafirlukast 10 mg twice daily or higher for at least 6 months, and 113 of them were treated for one year or longer in clinical trials. The safety profile of Zafirlukast 10 mg twice daily-versus placebo in the 4- and 6-week double-blind trials was generally similar to that observed in the adult clinical trials with Zafirlukast 20 mg twice daily.
- In pediatric patients receiving Zafirlukast in multi-dose clinical trials, the following events occurred with a frequency of ≥ 2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: headache (4.5 vs. 4.2%) and abdominal pain (2.8 vs. 2.3%).
- The post-marketing experience in this age group is similar to that seen in adults, including hepatic dysfunction, which may lead to liver failure.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zafirlukast in the drug label.
# Drug Interactions
- In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+ 63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and Zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see WARNINGS, CONCOMITANT WARFARIN ADMINISTRATION). No formal drug-drug interaction studies with Zafirlukast and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme (eg, tolbutamide, phenytoin, carbamazepine) have been conducted; however, care should be exercised when Zafirlukast is coadministered with these drugs.
- In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state resulted in decreased mean plasma levels of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
- Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline.
- Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed.
- Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Zafirlukast to an existing theophylline regimen have been reported. The mechanism of the interaction between Zafirlukast and theophylline in these patients is unknown (see ADVERSE REACTIONS).
- Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%.
- In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.
- Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increasedplasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this interaction is unknown. Zafirlukast exposure is likely to be increased by other moderate and strong CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast.
- No other formal drug-drug interaction studies between Zafirlukast and marketed drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As Zafirlukast is known to be an inhibitor of CYP3A4 in vitro, it is reasonable to employ appropriate clinical monitoring when these drugs are coadministered with Zafirlukast.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- No teratogenicity was observed at oral doses up to 1600 mg/kg/day in mice (approximately 160 times the maximum recommended daily oral dose in adults on a mg/m2 basis), up to 2000 mg/kg/day in rats (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m2 basis) and up to 2000 mg/kg/day in cynomolgus monkeys (which resulted in approximately 20 times the exposure to drug plus metabolites compared to that from the maximum recommended daily oral dose in adults based on comparison of the AUC values). At an oral dose of 2000 mg/kg/day in rats, maternal toxicity and deaths were seen with increased incidence of early fetal resorption. Spontaneous abortions occurred in cynomolgus monkeys at the maternally toxic oral dose of 2000 mg/kg/day. There are no adequate and well-controlled trials in pregnant women. Because animal reproductive studies are not always predictive of human response, Zafirlukast should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zafirlukast in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zafirlukast during labor and delivery.
### Nursing Mothers
- Zafirlukast is excreted in breast milk. Following repeated 40 mg twice-a-day dosing in healthy women, average steady-state concentrations of zafirlukast in breast milk were 50 ng/mL compared to 255 ng/mL in plasma. Because of the potential for tumorigenicity shown for zafirlukast in mouse and rat studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects of zafirlukast, Zafirlukast should not be administered to mothers who are breast-feeding.
### Pediatric Use
- The safety of Zafirlukast at doses of 10 mg twice daily has been demonstrated in 205 pediatric patients 5 through 11 years of age in placebo-controlled trials lasting up to six weeks and with 179 patients in this age range participating in 52 weeks of treatment in an open-label extension.
- The effectiveness of Zafirlukast for the prophylaxis and chronic treatment of asthma in pediatric patients 5 through 11 years of age is based on an extrapolation of the demonstrated efficacy of Zafirlukast in adults with asthma and the likelihood that the disease course, and pathophysiology and the drug’s effect are substantially similar between the two populations. The recommended dose for the patients 5 through 11 years of age is based upon a cross-study comparison of the pharmacokinetics of zafirlukast in adults and pediatric subjects, and on the safety profile of zafirlukast in both adult and pediatric patients at doses equal to or higher than the recommended dose.
- The safety and effectiveness of zafirlukast for pediatric patients less than 5 years of age has not been established. The effect of Zafirlukast on growth in children has not been determined.
### Geriatic Use
- Based on cross-study comparison, the clearance of zafirlukast is reduced in patients 65 years of age and older such that Cmax and AUC are approximately 2- to 3-fold greater than those of younger patients (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY).
- A total of 8094 patients were exposed to zafirlukast in North American and European short-term placebo-controlled clinical trials. Of these, 243 patients were elderly (age 65 years and older). No overall difference in adverse events was seen in the elderly patients, except for an increase in the frequency of infections among zafirlukast-treated elderly patients compared to placebo-treated elderly patients (7.0% vs. 2.9%). The infections were not severe, occurred mostly in the lower respiratory tract, and did not necessitate withdrawal of therapy.
- An open-label, uncontrolled, 4-week trial of 3759 asthma patients compared the safety and efficacy of Zafirlukast 20 mg given twice daily in three patient age groups, adolescents (12-17 years), adults (18-65 years), and elderly (greater than 65 years). A higher percentage of elderly patients (n=384) reported adverse events when compared to adults and adolescents. These elderly patients showed less improvement in efficacy measures. In the elderly patients, adverse events occurring in greater than 1% of the population included headache (4.7%), diarrhea and nausea (1.8%), and pharyngitis (1.3%). The elderly reported the lowest percentage of infections of all three age groups in this study.
### Gender
There is no FDA guidance on the use of Zafirlukast with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zafirlukast with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zafirlukast in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zafirlukast in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zafirlukast in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zafirlukast in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Zafirlukast in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Zafirlukast in the drug label.
# Overdosage
- No deaths occurred at oral zafirlukast doses of 2000 mg/kg in mice (approximately 210 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis), 2000 mg/kg in rats (approximately 420 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis), and 500 mg/kg in dogs (approximately 350 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis).
- Overdosage with Zafirlukast has been reported in four patients surviving reported doses as high as 200 mg. The predominant symptoms reported following Zafirlukast overdose were rash and upset stomach. There were no acute toxic effects in humans that could be consistently ascribed to the administration of Zafirlukast. It is reasonable to employ the usual supportive measures in the event of an overdose; eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
# Pharmacology
## Mechanism of Action
- Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects.
- In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early- and late-phase response and the nonspecific hyperresponsiveness.
- In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.
## Structure
- Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. The molecular weight of zafirlukast is 575.7 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Zafirlukast in the drug label.
## Pharmacokinetics
- Zafirlukast is rapidly absorbed following oral administration. Peak plasma concentrations are generally achieved 3 hours after oral administration. The absolute bioavailability of zafirlukast is unknown. In two separate studies, one using a high fat and the other a high protein meal, administration of zafirlukast with food reduced the mean bioavailability by approximately 40%.
- Zafirlukast is more than 99% bound to plasma proteins, predominantly albumin. The degree of binding was independent of concentration in the clinically relevant range. The apparent steady-state volume of distribution (Vss/F) is approximately 70 L, suggesting moderate distribution into tissues. Studies in rats using radiolabeled zafirlukast indicate minimal distribution across the blood-brain barrier.
- Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9 (CYP2C9) pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved total plasma concentrations.
- The apparent oral clearance (CL/f) of zafirlukast is approximately 20 L/h. Studies in the rat and dog suggest that biliary excretion is the primary route of excretion. Following oral administration of radiolabeled zafirlukast to volunteers, urinary excretion accounts for approximately 10% of the dose and the remainder is excreted in feces. Zafirlukast is not detected in urine.
- In the pivotal bioequivalence study, the mean terminal half-life of zafirlukast is approximately 10 hours in both normal adult subjects and patients with asthma. In other studies, the mean plasma half-life of zafirlukast ranged from approximately 8 to 16 hours in both normal subjects and patients with asthma. The pharmacokinetics of zafirlukast are approximately linear over the range from 5 mg to 80 mg. Steady-state plasma concentrations of zafirlukast are proportional to the dose and predictable from single-dose pharmacokinetic data. Accumulation of zafirlukast in the plasma following twice-daily dosing is approximately 45%.
- The pharmacokinetic parameters of zafirlukast 20 mg administered as a single dose to 36 male volunteers are shown with the table below.
- Gender:
- The pharmacokinetics of zafirlukast are similar in males and females. Weight-adjusted apparent oral clearance does not differ due to gender.
- Race:
- No differences in the pharmacokinetics of zafirlukast due to race have been observed.
- Elderly:
- The apparent oral clearance of zafirlukast decreases with age. In patients above 65 years of age, there is an approximately 2-3 fold greater Cmax and AUC compared to young adult patients.
- Children:
- Following administration of a single 20 mg dose of zafirlukast to 20 boys and girls between 7 and 11 years of age, and in a second study, to 29 boys and girls between 5 and 6 years of age, the following pharmacokinetic parameters were obtained:
- Weight unadjusted apparent clearance was 11.4 L/h (42%) in the 7-11 year old children and 9.2 L/h (37%) in the 5-6 year old children, which resulted in greater systemic drug exposures than that obtained in adults for an identical dose. To maintain similar exposure levels in children compared to adults, a dose of 10 mg twice daily is recommended in children 5-11 years of age.
- Zafirlukast disposition was unchanged after multiple dosing (20 mg twice daily) in children and the degree of accumulation in plasma was similar to that observed in adults.
- Hepatic Insufficiency: In a study of patients with hepatic impairment (biopsy-proven cirrhosis), there was a reduced clearance of zafirlukast resulting in a 50-60% greater Cmax and AUC compared to normal subjects.
- Renal Insufficiency: Based on a cross-study comparison, there are no apparent differences in the pharmacokinetics of zafirlukast between renally-impaired patients and normal subjects.
- Drug-Drug Interactions: The following drug interaction studies have been conducted with zafirlukast (see PRECAUTIONS, DRUG INTERACTIONS).
- Coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin (a substrate of CYP2C9) resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time increased by approximately 35%. The pharmacokinetics of zafirlukast were unaffected by coadministration with warfarin.
- Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma concentrations of zafirlukast by approximately 30%, but no effect on plasma theophylline concentrations was observed.
- Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline.
- Coadministration of zafirlukast dosed at 40 mg twice daily in a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, resulted in no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.
- Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma concentrations of zafirlukast by approximately 45%.
- Coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state in 11 asthmatic patients resulted in decreased mean plasma concentrations of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
- Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased
- plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this
- interaction is unknown. Zafirlukast exposure is likely to be increased by other moderate and strong
- CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor,
- caused no change in plasma levels of zafirlukast.
## Nonclinical Toxicology
- In two-year carcinogenicity studies, zafirlukast was administered at dietary doses of 10, 100, and 300 mg/kg to mice and 40, 400, and 2000 mg/kg to rats. Male mice at an oral dose of 300 mg/kg/day (approximately 30 times the maximum recommended daily oral dose in adults and in children on a mg/m2 basis) showed an increased incidence of hepatocellular adenomas; female mice at this dose showed a greater incidence of whole body histocytic sarcomas. Male and female rats at an oral dose of 2000 mg/kg/day (resulting in approximately 160 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma area-under the curve [AUC] values) of zafirlukast showed an increased incidence of urinary bladder transitional cell papillomas. Zafirlukast was not tumorigenic at oral doses up to 100 mg/kg (approximately 10 times the maximum recommended daily oral dose in adults and in children on a mg/m2 basis) in mice and at oral doses up to 400 mg/kg (resulting in approximately 140 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma AUC values) in rats. The clinical significance of these findings for the long-term use of Zafirlukast is unknown.
- Zafirlukast showed no evidence of mutagenic potential in the reverse microbial assay, in 2 forward point mutation (CHO-HGPRT and mouse lymphoma) assays or in two assays for chromosomal aberrations (the in vitro human peripheral blood lymphocyte clastogenic assay and the in vivo rat bone marrow micronucleus assay).
- No evidence of impairment of fertility and reproduction was seen in male and female rats treated with zafirlukast at oral doses up to 2000 mg/kg (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m2 basis).
# Clinical Studies
- Three U.S. double-blind, randomized, placebo-controlled, 13-week clinical trials in 1380 adults and children 12 years of age and older with mild-to-moderate asthma demonstrated that Zafirlukast improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta2-agonist use, FEV1, and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline beta2-agonist requirement of approximately 4-5 puffs of albuterol per day. The results of the largest of the trials are shown in the table below.
- In a second and smaller study, the effect of Zafirlukast on most efficacy parameters was comparable to the active control (inhaled cromolyn sodium 1600 mcg four times per day) and superior to placebo at end point for decreasing rescue beta2-agonist use (figure below).
- In these trials, improvement in asthma symptoms occurred within one week of initiating treatment with Zafirlukast. The role of Zafirlukast in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as-needed, inhaled beta2-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.
# How Supplied
## Storage
- Store at controlled room temperature, 20-25°C (68-77°F).
- Protect from light and moisture.
- Dispense in the original air-tight container.
# Images
## Drug Images
## Package and Label Display Panel
NDC 0310-0401-60
60 tablets
Zafirlukast®
ZAFIRLUKAST
10 mg tablets
Rx only
DISPENSE IN THE ORIGINAL
AIRTIGHT CONTAINER.
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: IPR Pharmaceuticals, Inc.
Canóvanas, PR 00729
Product of UK
AstraZeneca
NDC 0310-0402-60
60 tablets
Zafirlukast®
ZAFIRLUKAST
20 mg tablets
Rx only
DISPENSE IN THE ORIGINAL
AIRTIGHT CONTAINER.
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: IPR Pharmaceuticals, Inc.
Canóvanas, PR 00729
Product of UK
AstraZeneca
# Patient Counseling Information
- Patients should be told that a rare side effect of Zafirlukast is hepatic dysfunction, and to contact their physician immediately if they experience symptoms of hepatic dysfunction (eg. right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia). Liver failure resulting in liver transplantation and death has occurred in patients taking zafirlukast (see WARNINGS, HEPATOTOXICITY and ADVERSE REACTIONS).
- Zafirlukast is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. Zafirlukast is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients receiving Zafirlukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Patients should be instructed to notify their physician if neuropsychiatric events occur while using Zafirlukast (see PRECAUTIONS, NEUROPSYCHIATRIC EVENTS). Women who are breast-feeding should be instructed not to take Zafirlukast (see PRECAUTIONS, NURSING MOTHERS). Alternative antiasthma medication should be considered in such patients.
- The bioavailability of Zafirlukast may be decreased when taken with food. Patients should be instructed to take Zafirlukast at least 1 hour before or 2 hours after meals.
# Precautions with Alcohol
- Alcohol-Zafirlukast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Accolate®
# Look-Alike Drug Names
There is limited information regarding Zafirlukast Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Accolate | |
84a525711297c77765adea4cb6e703ead07fb6f6 | wikidoc | Aceclofenac | Aceclofenac
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Aceclofenac is a Non Steroidal Anti-inflamatory Drug (NSAID) that is FDA approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and periarthritis of scapulohumerous, lumbago, ischiadynia, pain caused by nonaticular rheutism. Common adverse reactions include dyspepsia, abdominal pain, nausea, rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose is 200 mg daily, taken as one dose (every 24 hours). However, the dose and dose frequency of Aceclofenac can be modified under the supervison of physician or pharmacist.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aceclofenac in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aceclofenac in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The dosage and indication is not established yet for children with less than 6 years old.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aceclofenac in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aceclofenac in pediatric patients.
# Contraindications
Aceclofenac is contraindicated in patients with:
- Patients with allergy to these drugs or other analogues (diclofenac).
- Patients with asthma.
- Like NSAIDS, acetylsalicylic acid and other drugs which inhibit prostagladin-synthesis may precipitate attacks of asthma, acute rhinitis or urticaria.
- Patients with active peptic ulcer.
# Warnings
- Patients with symptoms indicative of gastro-intestinal disorders, with a history of gastric ulceration. Patients with severe hepatic impairment or cardiac or renal impairment. Patients under the medication of diuretics. Patients in recovery after surgical treatment.
# Adverse Reactions
## Clinical Trials Experience
- The majority of side effects observed have been reversible and of a minor nature and include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness. To report suspected adverse reactions, call 1-800-FDA-1088.
## Postmarketing Experience
There is limited information regarding Aceclofenac Postmarketing Experience in the drug label.
# Drug Interactions
- There has been no drug interactions reported, but close monitoring of patients on combination with lithium and digoxin, oral anti diabetic agents, anticoagulants, diuretics, and other analgesics.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Since there is no information on the safe use of Aceclofenac during pregnancy and lactation, the use of Aclofenac should therefore be avoided in pregnancy and lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aceclofenac in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aceclofenac during labor and delivery.
### Nursing Mothers
- Since there is no information on the safe use of Aceclofenac during pregnancy and lactation, the use of Aceclofenac should therefore be avoided in pregnancy and lactation.
### Pediatric Use
- The dosage and indication is not established yet for children with less than 6 years old.
### Geriatic Use
There is no FDA guidance on the use of Aceclofenac in geriatric settings.
### Gender
There is no FDA guidance on the use of Aceclofenac with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aceclofenac with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Aceclofenac in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Aceclofenac in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aceclofenac in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aceclofenac in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Aceclofenac Administration in the drug label.
### Monitoring
There is limited information regarding Aceclofenac Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Aceclofenac and IV administrations.
# Overdosage
- There are no human data available on the consequences of Aceclofenac overdosage. If overdosage is observed, therapeutic measures should be taken according to symptoms; supportive and symptomatic treatment should be given for complications such as hypotension, gastrointestinal irritation, respiratory depression, and convulsions.
# Pharmacology
## Mechanism of Action
There is limited information regarding Aceclofenac Mechanism of Action in the drug label.
## Structure
## Pharmacodynamics
There is limited information regarding Aceclofenac Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Aceclofenac Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Aceclofenac Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Aceclofenac Clinical Studies in the drug label.
# How Supplied
- 10 Blister Packs with 10 Tablets in each Blister Pack
## Storage
- Preserve in tight containers. Store at room temperature not exceeding 30oC. Three (3) years from manufacturing date. Do not exceed the expiry date for use printed on the box.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Aceclofenac Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Aceclofenac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Acent
- Acenal
- Acelofan
- Acelom
# Look-Alike Drug Names
There is limited information regarding Aceclofenac Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Aceclofenac
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Aceclofenac is a Non Steroidal Anti-inflamatory Drug (NSAID) that is FDA approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and periarthritis of scapulohumerous, lumbago, ischiadynia, pain caused by nonaticular rheutism. Common adverse reactions include dyspepsia, abdominal pain, nausea, rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose is 200 mg daily, taken as one dose (every 24 hours). However, the dose and dose frequency of Aceclofenac can be modified under the supervison of physician or pharmacist.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aceclofenac in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aceclofenac in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The dosage and indication is not established yet for children with less than 6 years old.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aceclofenac in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aceclofenac in pediatric patients.
# Contraindications
Aceclofenac is contraindicated in patients with:
- Patients with allergy to these drugs or other analogues (diclofenac).
- Patients with asthma.
- Like NSAIDS, acetylsalicylic acid and other drugs which inhibit prostagladin-synthesis may precipitate attacks of asthma, acute rhinitis or urticaria.
- Patients with active peptic ulcer.
# Warnings
- Patients with symptoms indicative of gastro-intestinal disorders, with a history of gastric ulceration. Patients with severe hepatic impairment or cardiac or renal impairment. Patients under the medication of diuretics. Patients in recovery after surgical treatment.
# Adverse Reactions
## Clinical Trials Experience
- The majority of side effects observed have been reversible and of a minor nature and include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness. To report suspected adverse reactions, call 1-800-FDA-1088.
## Postmarketing Experience
There is limited information regarding Aceclofenac Postmarketing Experience in the drug label.
# Drug Interactions
- There has been no drug interactions reported, but close monitoring of patients on combination with lithium and digoxin, oral anti diabetic agents, anticoagulants, diuretics, and other analgesics.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Since there is no information on the safe use of Aceclofenac during pregnancy and lactation, the use of Aclofenac should therefore be avoided in pregnancy and lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aceclofenac in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aceclofenac during labor and delivery.
### Nursing Mothers
- Since there is no information on the safe use of Aceclofenac during pregnancy and lactation, the use of Aceclofenac should therefore be avoided in pregnancy and lactation.
### Pediatric Use
- The dosage and indication is not established yet for children with less than 6 years old.
### Geriatic Use
There is no FDA guidance on the use of Aceclofenac in geriatric settings.
### Gender
There is no FDA guidance on the use of Aceclofenac with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aceclofenac with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Aceclofenac in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Aceclofenac in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aceclofenac in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aceclofenac in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Aceclofenac Administration in the drug label.
### Monitoring
There is limited information regarding Aceclofenac Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Aceclofenac and IV administrations.
# Overdosage
- There are no human data available on the consequences of Aceclofenac overdosage. If overdosage is observed, therapeutic measures should be taken according to symptoms; supportive and symptomatic treatment should be given for complications such as hypotension, gastrointestinal irritation, respiratory depression, and convulsions.
# Pharmacology
## Mechanism of Action
There is limited information regarding Aceclofenac Mechanism of Action in the drug label.
## Structure
## Pharmacodynamics
There is limited information regarding Aceclofenac Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Aceclofenac Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Aceclofenac Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Aceclofenac Clinical Studies in the drug label.
# How Supplied
- 10 Blister Packs with 10 Tablets in each Blister Pack
## Storage
- Preserve in tight containers. Store at room temperature not exceeding 30oC. Three (3) years from manufacturing date. Do not exceed the expiry date for use printed on the box.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Aceclofenac Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Aceclofenac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Acent
- Acenal
- Acelofan
- Acelom
# Look-Alike Drug Names
There is limited information regarding Aceclofenac Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aceclofenac | |
e87371b3899d0a292f64c52e9df4539a00d714fc | wikidoc | Perindopril | Perindopril
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Dosing Information
- Use in Uncomplicated Hypertensive Patients:
- Initial dosage: 4 mg PO qd
- Maximun dosage: 16 mg/day PO
- Usually maintaining dosage: 4 mg-8 mg or 2 mg-4 mg PO bid
- Use in Elderly Patients
- Recommended initial dosage: 4 mg PO qd or 2 mg PO bid
- limited dosage: 8 mg/day (Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration)
## Stable Coronary Artery Disease
Dosing information
- Initial dosage: 4 mg PO qd for 2 weeks
- Maintainance dosage: 8 mg PO qd
- For seniors (age ≥ 70):
- Initial dosage for the 1st week: 2 mg PO qd
- Dosage for the 2nd week: 4 mg PO qd
- Maintaining dosage if tolerated: 8 mg PO qd
## Dose Adjustment in Renal Impairment and Dialysis
Dosing information
- Initial dosage: 2 mg/day
- Maximum dosage: 8 mg/day
Dosing Information
- 2 mg/day or 4 mg/day
## Prophylaxis treatment of Cerebrovascular accident
Dosing information
- 4 mg/day
## Duchenne muscular dystrophy
Dosing information
- 2-4 mg/day
## Myocardial infarction
Dosing information
- 4 mg/day
## Prophylaxis treatment of Paroxysmal atrial fibrillation
Dosing information
- 2 mg
- Do not co-administer aliskiren with ACEON in patients with diabetes.
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ACEON) may be subject to a variety of adverse events, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.
- Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors, including ACEON (0.1% of patients treated with ACEON in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue ACEON treatment immediately and observe until the swelling disappears. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.
- Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Hypotension
- ACEON can cause symptomatic hypotension. ACEON has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.
- Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting.
- ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.
- In patients at risk of excessive hypotension, ACEON therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of ACEON and/or diuretic is increased.
- If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. ACEON treatment can usually be continued following restoration of volume and blood pressure.
Neutropenia/Agranulocytosis
- ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.
Fetal Toxicity
- Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected discontinue ACEON as soon as possible.
Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving ACEON.
- In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ACEON, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor. In such patients, renal function should be monitored during the first few weeks of therapy.
- Some ACEON-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.
Hyperkalemia
- Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including ACEON. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes.
- Serum potassium should be monitored periodically in patients receiving ACEON.
Cough
- Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.
Hepatic Failure
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Surgery/Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, ACEON may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.
## Clinical Trials Experience
The following adverse reactions are discussed elsewhere in labeling:
- Anaphylactoid reactions, including angioedema
- Hypotension
- Neutropenia and agranulocytosis
- Impaired renal function
- Hyperkalemia
- Cough
Hypertension
- ACEON has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 ACEON-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEON® (perindopril erbumine) for at least one year.
- In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with ACEON and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness.
- Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with ACEON and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on ACEON was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).
- Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.
Stable Coronary Artery Disease
- Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension.
# Clinical Laboratory Test Findings
- Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with ACEON, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials.
- Liver Function Tests: Elevations in ALT (1.6% ACEON versus 0.9% placebo) and AST (0.5% ACEON versus 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.
- Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of ACEON, for at least two hours and until blood pressure has stabilized for another hour.
- The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.
Potassium Supplements and Potassium-Sparing Diuretics
- ACEON may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
Lithium
- Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.
Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including ACEON.
Digoxin
- A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.
Gentamicin
- Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including perindopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving perindopril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS)
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on ACEON and other agents that affect the RAS.
- Do not co-administer aliskiren with ACEON in patients with diabetes. Avoid use of aliskiren with ACEON in patients with renal impairment (GFR <60 ml/min).
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ACEON as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ACEON, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ACEON for hypotension, oliguria, and hyperkalemia.
Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.
Safety and effectiveness of ACEON in pediatric patients have not been established.
- Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.
- Experience with ACEON in elderly patients at daily doses exceeding 8 mg is limited.
- Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.
- Use in Elderly Patients: The recommended initial daily dosage of ACEON for the elderly is 4 mg daily, given in one or two divided doses. Experience with ACEON is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration.
- Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of ACEON. Consider reducing the dose of diuretic prior to starting ACEON.
- Stable Coronary Artery Disease
- In patients with stable coronary artery disease, ACEON should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), ACEON should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.
- Dose Adjustment in Renal Impairment and Dialysis
- Perindoprilat elimination is decreased in renally impaired patients. ACEON is not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.
- Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support.
- Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of perindopril overdose.
- No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of perindopril and its metabolites. Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.
- Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of perindopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat perindopril overdose by infusion of normal saline solution.
- ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ACEON remains to be elucidated.
- While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.
- Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform.
- Perindopril is the free acid form of perindopril erbumine, is a pro-drug and - metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.
- ACEON is available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril erbumine, each tablet contains the following inactive ingredients: colloidal silica (hydrophobic), lactose, magnesium stearate and microcrystalline cellulose. The 4 mg and 8 mg tablets also contain iron oxide.
With 4 mg, 8 mg and 16 mg doses of ACEON, Cmax and AUC of perindopril and perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.
Distribution: Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.
Metabolism and Elimination: Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.
Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.
The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of ACEON. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2 fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.
Elderly: Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat .
Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.
Renal Impairment: With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.
In a limited number of patients studied, perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min.
Hepatic Impairment: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.
Carcinogenicity: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.
Mutagenesis: No genotoxic potential was detected for ACEON, perindoprilat and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests and Chinese hamster bone marrow assay.
Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of ACEON during the period of spermatogenesis in males or oogenesis and gestation in females.
- In placebo-controlled studies of perindopril monotherapy (2 mg to 16 mg once daily) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood pressure. The 8 mg and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. In these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally slightly superior, but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of perindopril, the trough mean systolic and diastolic blood pressure effects were about 75 to 100% of peak effects.
- Perindopril's effects on blood pressure were similar when given alone or on a background of 25 mg hydrochlorothiazide In general, the effect of perindopril occurred promptly, with effects increasing slightly over several weeks.
- Formal interaction studies of ACEON® (perindopril erbumine) have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering ACEON with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system.
- In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients.
- The effectiveness of ACEON was not influenced by sex and it was less effective in black patients than in nonblack patients. In elderly patients (greater than or equal to 60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.
## Stable Coronary Artery Disease
- The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.
- The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).
Keep out of the reach of children.
- For further information, please call our medical communications department toll-free 1-800-718-9884.
Tell patients to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.
- ↑ Patel A, ADVANCE Collaborative Group. MacMahon S, Chalmers J, Neal B, Woodward M et al. (2007) Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370 (9590):829-40. DOI:10.1016/S0140-6736(07)61303-8 PMID: 17765963
- ↑ Chapman N, Huxley R, Anderson C, Bousser MG, Chalmers J, Colman S et al. (2004) Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke 35 (1):116-21. DOI:10.1161/01.STR.0000106480.76217.6F PMID: 14671247
- ↑ Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A et al. (2007) Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years' follow-up. Am Heart J 154 (3):596-602. DOI:10.1016/j.ahj.2007.05.014 PMID: 17719312
- ↑ Tuininga YS, Wiesfeld AC, van Veldhuisen DJ, van Gelder IC, Crijns HJ (2000) Electrophysiological changes of angiotensin-converting enzyme inhibition after myocardial infarction. J Card Fail 6 (2):77-9. PMID: 10908079
- ↑ Yin Y, Dalal D, Liu Z, Wu J, Liu D, Lan X et al. (2006) Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation. Eur Heart J 27 (15):1841-6. DOI:10.1093/eurheartj/ehl135 PMID: 16825288 | Perindopril
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Dosing Information
- Use in Uncomplicated Hypertensive Patients:
- Initial dosage: 4 mg PO qd
- Maximun dosage: 16 mg/day PO
- Usually maintaining dosage: 4 mg-8 mg or 2 mg-4 mg PO bid
- Use in Elderly Patients
- Recommended initial dosage: 4 mg PO qd or 2 mg PO bid
- limited dosage: 8 mg/day (Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration)
## Stable Coronary Artery Disease
Dosing information
- Initial dosage: 4 mg PO qd for 2 weeks
- Maintainance dosage: 8 mg PO qd
- For seniors (age ≥ 70):
- Initial dosage for the 1st week: 2 mg PO qd
- Dosage for the 2nd week: 4 mg PO qd
- Maintaining dosage if tolerated: 8 mg PO qd
## Dose Adjustment in Renal Impairment and Dialysis
Dosing information
- Initial dosage: 2 mg/day
- Maximum dosage: 8 mg/day
Dosing Information
- 2 mg/day or 4 mg/day[1]
## Prophylaxis treatment of Cerebrovascular accident
Dosing information
- 4 mg/day[2]
## Duchenne muscular dystrophy
Dosing information
- 2-4 mg/day[3]
## Myocardial infarction
Dosing information
- 4 mg/day[4]
## Prophylaxis treatment of Paroxysmal atrial fibrillation
Dosing information
- 2 mg[5]
- Do not co-administer aliskiren with ACEON in patients with diabetes.
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ACEON) may be subject to a variety of adverse events, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.
- Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors, including ACEON (0.1% of patients treated with ACEON in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue ACEON treatment immediately and observe until the swelling disappears. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.
- Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Hypotension
- ACEON can cause symptomatic hypotension. ACEON has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.
- Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting.
- ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.
- In patients at risk of excessive hypotension, ACEON therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of ACEON and/or diuretic is increased.
- If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. ACEON treatment can usually be continued following restoration of volume and blood pressure.
Neutropenia/Agranulocytosis
- ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.
Fetal Toxicity
- Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected discontinue ACEON as soon as possible.
Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving ACEON.
- In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ACEON, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor. In such patients, renal function should be monitored during the first few weeks of therapy.
- Some ACEON-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.
Hyperkalemia
- Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including ACEON. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes.
- Serum potassium should be monitored periodically in patients receiving ACEON.
Cough
- Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.
Hepatic Failure
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Surgery/Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, ACEON may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.
## Clinical Trials Experience
The following adverse reactions are discussed elsewhere in labeling:
- Anaphylactoid reactions, including angioedema
- Hypotension
- Neutropenia and agranulocytosis
- Impaired renal function
- Hyperkalemia
- Cough
Hypertension
- ACEON has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 ACEON-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEON® (perindopril erbumine) for at least one year.
- In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with ACEON and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness.
- Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with ACEON and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on ACEON was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).
- Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.
Stable Coronary Artery Disease
- Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension.
# Clinical Laboratory Test Findings
- Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with ACEON, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials.
- Liver Function Tests: Elevations in ALT (1.6% ACEON versus 0.9% placebo) and AST (0.5% ACEON versus 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.
- Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of ACEON, for at least two hours and until blood pressure has stabilized for another hour.
- The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.
Potassium Supplements and Potassium-Sparing Diuretics
- ACEON may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
Lithium
- Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.
Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including ACEON.
Digoxin
- A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.
Gentamicin
- Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including perindopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving perindopril and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS)
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on ACEON and other agents that affect the RAS.
- Do not co-administer aliskiren with ACEON in patients with diabetes. Avoid use of aliskiren with ACEON in patients with renal impairment (GFR <60 ml/min).
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ACEON as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ACEON, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ACEON for hypotension, oliguria, and hyperkalemia.
Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.
Safety and effectiveness of ACEON in pediatric patients have not been established.
- Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.
- Experience with ACEON in elderly patients at daily doses exceeding 8 mg is limited.
- Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.
- Use in Elderly Patients: The recommended initial daily dosage of ACEON for the elderly is 4 mg daily, given in one or two divided doses. Experience with ACEON is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration.
- Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of ACEON. Consider reducing the dose of diuretic prior to starting ACEON.
- Stable Coronary Artery Disease
- In patients with stable coronary artery disease, ACEON should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), ACEON should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.
- Dose Adjustment in Renal Impairment and Dialysis
- Perindoprilat elimination is decreased in renally impaired patients. ACEON is not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.
- Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support.
- Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of perindopril overdose.
- No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of perindopril and its metabolites. Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.
- Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of perindopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat perindopril overdose by infusion of normal saline solution.
- ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ACEON remains to be elucidated.
- While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.
- Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform.
- Perindopril is the free acid form of perindopril erbumine, is a pro-drug and * metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.
- ACEON is available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril erbumine, each tablet contains the following inactive ingredients: colloidal silica (hydrophobic), lactose, magnesium stearate and microcrystalline cellulose. The 4 mg and 8 mg tablets also contain iron oxide.
With 4 mg, 8 mg and 16 mg doses of ACEON, Cmax and AUC of perindopril and perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.
Distribution: Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.
Metabolism and Elimination: Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.
Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.
The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of ACEON. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2 fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.
Elderly: Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat .
Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.
Renal Impairment: With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.
In a limited number of patients studied, perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min.
Hepatic Impairment: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.
Carcinogenicity: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.
Mutagenesis: No genotoxic potential was detected for ACEON, perindoprilat and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests and Chinese hamster bone marrow assay.
Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of ACEON during the period of spermatogenesis in males or oogenesis and gestation in females.
- In placebo-controlled studies of perindopril monotherapy (2 mg to 16 mg once daily) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood pressure. The 8 mg and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. In these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally slightly superior, but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of perindopril, the trough mean systolic and diastolic blood pressure effects were about 75 to 100% of peak effects.
- Perindopril's effects on blood pressure were similar when given alone or on a background of 25 mg hydrochlorothiazide In general, the effect of perindopril occurred promptly, with effects increasing slightly over several weeks.
- Formal interaction studies of ACEON® (perindopril erbumine) have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering ACEON with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system.
- In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients.
- The effectiveness of ACEON was not influenced by sex and it was less effective in black patients than in nonblack patients. In elderly patients (greater than or equal to 60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.
## Stable Coronary Artery Disease
- The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.
- The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).
Keep out of the reach of children.
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Tell patients to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.
- ↑ Patel A, ADVANCE Collaborative Group. MacMahon S, Chalmers J, Neal B, Woodward M et al. (2007) Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370 (9590):829-40. DOI:10.1016/S0140-6736(07)61303-8 PMID: 17765963
- ↑ Chapman N, Huxley R, Anderson C, Bousser MG, Chalmers J, Colman S et al. (2004) Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke 35 (1):116-21. DOI:10.1161/01.STR.0000106480.76217.6F PMID: 14671247
- ↑ Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A et al. (2007) Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years' follow-up. Am Heart J 154 (3):596-602. DOI:10.1016/j.ahj.2007.05.014 PMID: 17719312
- ↑ Tuininga YS, Wiesfeld AC, van Veldhuisen DJ, van Gelder IC, Crijns HJ (2000) Electrophysiological changes of angiotensin-converting enzyme inhibition after myocardial infarction. J Card Fail 6 (2):77-9. PMID: 10908079
- ↑ Yin Y, Dalal D, Liu Z, Wu J, Liu D, Lan X et al. (2006) Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation. Eur Heart J 27 (15):1841-6. DOI:10.1093/eurheartj/ehl135 PMID: 16825288 | https://www.wikidoc.org/index.php/Aceon | |
c77e2b2aa6b647dd4cff55d33ee099fe8823e00c | wikidoc | Acer rubrum | Acer rubrum
Acer rubrum (Red Maple, also known as Swamp or Soft Maple), is one of the most common and widespread deciduous trees of eastern North America. It ranges from the Lake of the Woods on the border between Ontario and Minnesota, east to Newfoundland, south to near Miami, Florida, and southwest to east Texas. Many of its features, especially its leaves, are quite variable in form. At maturity it often attains a height of around 25 metres (82 feet). It is aptly named as its flowers, petioles, twigs and seeds are all red to varying degrees. Among these features, however, it is most well known for its brilliant deep scarlet foliage in autumn.
Over most of its range, red maple is adaptable to a very wide range of site conditions, perhaps more so than any other tree in eastern North America. It can be found growing in swamps, on poor dry soils, and most anywhere in between. Elevation is also not a limiting factor in its range, as it grows well from sea level to about 900 m (3,000 feet). Due to its attractive fall foliage and pleasing form, it is often used as a shade tree for landscapes. It is used commercially on a small scale for maple syrup production as well as for its medium to high quality lumber. It is also the State Tree of Rhode Island.
# Description
Though A. rubrum is generally easy to identify, it is highly variable in morphological characteristics. It is a medium to large sized tree, reaching heights of 18 to 27 metres (60 to 90 feet) and exceptionally over 35 metres (115 feet). The diameter can range from 46 to 76 cm (18 to 30 inches), depending on the growing conditions. In forests, the bark will remain free of branches until some distance up the tree. Individuals grown in the open are shorter and thicker with a more rounded crown. Generally speaking, however, the crown is irregularly ovoid with ascending whip-like curved shoots. The bark is a pale grey and smooth when the individual is young. As the tree grows the bark becomes darker and cracks into slightly raised long plates. The largest known living red maple is located near Armada, Michigan, at a height of 38.1 metres (125 feet) and a bole circumference, at breast height, of 4.95 metres (16.25 feet).
The leaves of the red maple offer the easiest way to distinguish it from its relatives. As with all maples, they are deciduous and arranged oppositely on the twig. They are typically 5-10 cm (2-4 inches) long and wide with 3-5 palmate lobes with a serrated margin. The sinuses are typically narrow, but the leaves can exhibit considerable variation. When 5 lobes are present, the three at the terminal end are larger than the other two near the base. In contrast, the leaves of the related silver maple, A. saccharinum, are much more deeply lobed, more sharply toothed and characteristically have 5 lobes. The upper side of A. rubrum's leaf is light green and the underside is whitish and can be either glaucous or hairy. The leaf stalks are usually red and are up to 10 cm (4 inches) long. Furthermore, the leaves turn a brilliant red in autumn.
The twigs of the red maple are reddish in colour and somewhat shiny with small lenticels. Dwarf shoots are present on many branches. The buds are usually blunt and greenish to reddish in coulour, generally with several loose scales. The lateral buds are slightly stalked, and in addition there may be collateral buds present as well. The buds form in fall and winter and are often visible from a distance due to their reddish tint. The leaf scars on the twig are V-shaped and contain 3 bundle scars.
The flowers are generally unisexual, with male and female flowers appearing in separate sessile clusters, though they are sometimes also bisexual. They appear in spring from April to May, usually coming before the leaves. The tree itself is considered polygamo-diecious, meaning some individuals are male, some female, and some monoecious. The flowers are red with 5 small petals and a 5-lobed calyx borne in hanging clusters, usually at the twig tips. They are lineal to oblong in shape and are pubescent. The pistillate flowers have one pistil formed from two fused carpels with a glabrous superior ovary and two long styles that protrude beyond the perianth. The staminate flowers contain between 4 and 12 stamens, often with 8.
The fruit is a 15 to 25 milimeter (.5 to .75 inch) long double samara with somewhat divergent wings at an angle of 50 to 60 degrees. They are borne on long slender stems and are variable in colour from light brown to reddish. They ripen from April through early June, before even the leaf development is altogether complete. After they reach maturity, the seeds are dispersed for a 1 to 2 week period from April through July.
# Distribution and habitat
A. rubrum is one of the most abundant and widespread trees in eastern North America. It can be found from the south of Newfoundland, Nova Scotia and southern Quebec to the south west of Ontario, extreme southeastern Manitoba and northern Minnesota; south to Wisconsin, Illinois, Missouri, eastern Oklahoma, and eastern Texas in its western range; and east to Florida. It has the largest continuous range along the North American Atlantic Coast of any tree that occurs in Florida. In total it ranges 2575 km (1,600 miles) from north to south. The species is native to all regions of the United States east of the 95th meridian, with only three exceptions, namely the Prairie Peninsula of the Midwest, the coastal prairie in southern Louisiana and southeastern Texas, and the swamp prairie of the Florida Everglades. The most interesting of these exceptions is its absence in the Prairie Peninsula. Here the red maple is not present in the bottom land forests of the Grain Belt, despite the fact it is common in similar habitats and species associations both to the north and south of this area.
The tree's range ends where the -40°C (-40°F) mean minimum isotherm begins, namely in southeastern Canada. On the other hand, the western range is limited by the much drier climate of the Great Plains. Nonetheless, it has the widest tolerance to climatic conditions of all the North American species of maple. As above, the absence of red maple in the Prairie Peninsula is probably not related to rainfall or other climatic conditions, since it grows healthily in other locations with comparable or even less annual precipitation.
A. rubrum does very well in a wide range of soil types, with varying textures, moisture, pH, and elevation, probably more so than any other forest tree in North America. It grows on glaciated as well as nonglaciated soils derived from the following rocks: granite, gneiss, schist, sandstone, shale, slate, conglomerate, quartzite, and limestone. Chlorosis can occur on very alkaline soils, though otherwise its pH tolerance is quite high. As concerns levels of moisture, the red maple grows everywhere from dry ridges and southwest facing slopes to peat bogs and swamps. It occurs commonly in rather extreme moisture conditions, both very wet and quite dry. While many types of tree prefer a south or north facing aspect, the red maple does not appear to have a preference. Its ideal conditions are in moderately well-drained, moist sites at low or intermediate elevations. However, it is nonetheless common in mountainous areas on relatively dry ridges, as well as on both the south and west sides of upper slopes. Furthermore, it is common in swampy areas, along the banks of slow moving streams, as well as on poorly drained flats and depressions. In northern Michigan and New England, the tree is found on the tops of ridges, sandy or rocky upland and otherwise dry soils, as well as in nearly pure stands on moist soils and the edges of swaps. In the far south of its range, it is almost exclusively associated with swamps.
Interestingly, it is thought that the pre-European forest of eastern North America contained far fewer red maples than at present. Most diversity surveys conducted in eastern forests prior to their large scale exploitation showed the red maple representing under 5% of all tree species and it was furthermore mostly confined to poorly drained areas. The density of the tree in many of these areas has increased 6 to 7 fold and this trend seems to be continuing. A series of disturbances to the oak and pine forests since European arrival, such as the suppression of forest fires and global warming, are most likely responsible for this phenomenon. Concern has been expressed, as the ongoing spread of the red maple is changing the nature of eastern forests by reducing the number of oaks and pines that would otherwise dominate.
# Ecology
Red maple seldom lives longer than 150 years, making it short to medium lived. It reaches maturity in 70 to 80 years. Its ability to thrive in a large number of habitats is largely due to its ability to produce roots to suit its site from a young age. In wet locations, red maple seedlings produce short taproots with long and developed lateral roots, while on dry sites, they develop long taproots with significantly shorter laterals. The roots are primarily horizontal, however, forming in the upper 25 cm (10 in) of the ground. Mature trees have woody roots up to 25 meters (80 ft) long. They are very tolerant of flooding, with one study showing that 60 days of flooding caused no leaf damage. At the same time, they are tolerant of drought due to their ability to stop growing under dry conditions by then producing a second growth flush when conditions later improve, even if growth has stopped for 2 weeks.
A. rubrum is one of the first plants to flower in spring. A crop of seeds is generally produced every year with a bumper crop often occurring every second year. A single tree between 5 and 20 cm (2 and 8 inches) in diameter can produce between 12,000 and 91,000 seeds in a season. A tree 30 cm (1 foot) in diameter was shown to produce nearly a million seeds.. Fertilization has also been shown to significantly increase the seed yield for up to two years after application. The seeds are epigeal and tend to germinate in early Summer soon after they are released, assuming a small amount of light, moisture, and sufficient temperatures are present. If the seeds are densely shaded, then germination commonly does not occur until the next Spring. Most seedlings do not survive in closed forest canopy situations. However, one to four year old seedling are common under dense canopy and though they eventually die if no light reaches them, they serve as a reservoir, waiting to fill any open area of the canopy above.
Red maple is able to increase its numbers significantly when associate trees are damaged by disease, cutting, or fire. One study found that 6 years after clearcutting a 3.4 hectare (8.5 acre) Oak-Hickory forest containing no red maples, the plot contained more than 2,200 red maple seedlings per hectare (900 per acre) taller than 1.4 m (4.5 feet). One of its associates, the black cherry (Prunus serotina), contains benzoic acid, which has been shown to be a potential allelopathic inhibitor of red maple growth. Red maple is one of the first species to start stem elongation. In one study, stem elongation was one-half completed in 1 week, after which growth slowed and was 90% completed within only 54 days. In good light and moisture conditions, the seedlings can grow 30 cm (1 ft) in their first year and up to 60 cm (2 ft) each year for the next few years making it a fast grower.
The red maple is a used as a food source by several forms of wildlife. Elk and white-tailed deer in particular use the current season's growth of red maple as an important source of winter food. Several Lepidoptera (butterflies and moths) utilize the leaves as food; see List of Lepidoptera that feed on maples.
Due to A. rubrum's very wide range, there is significant variation in hardiness, size, form, time of flushing, onset of dormancy, and other traits. Generally speaking, individuals from the north flush the earliest, have the most reddish Fall color, set their buds the earliest and take the least winter injury. Seedlings are tallest in the north-central and east-central part of the range. The fruits also vary geographically with northern individuals in areas with brief frost free periods producing fruits that are shorter and heavier than their southern counterparts. As a result of the variation there is much genetic potential for breeding programs with a goal of producing red maples for cultivation. This is especially useful for making urban cultivars that require resistance from verticillium wilt, air pollution, and drought.
Red maple frequently hybridizes with Silver Maple; the hybrid, known as Freeman's Maple Acer x freemanii, is intermediate between the parents.
## Toxicity
The leaves of red maple, especially when dead or wilted, are highly toxic to horses. The toxin is currently unknown, but it is believed to be an oxidant due to its destruction of red blood cells and thus causing the blood to be unable to properly transport oxygen, a condition otherwise known as acute hemolysis. The ingestion of 700 grams (1.5 pounds) of leaves is considered toxic and 1.4 kilograms (3 pounds) is lethal. Symptoms occur within one or two days after ingestion and can include depression, lethargy, increased rate and depth of breathing, increased heart rate, jaundice, dark brown urine, coma, and death. Treatment is limited and can include the use of methylene blue or mineral oil and activated carbon in order to stop further absorption of the toxin into the stomach. About 50% to 75% of affected horses die or are euthanized as a result.
# Cultivation
Red Maple is widely grown as an ornamental tree in parks and large gardens, except where soils are too alkaline or salty. In parts of the Pacific Northwest, it is one of the most common introduced trees. Its popularity in cultivation stems from its vigorous habit, its attractive and early red flowers, and most importantly, its flaming red fall foliage. The tree was introduced into the United Kingdom in 1656 and shortly thereafter entered cultivation. There it is frequently found in many parks and gardens, as well as occasionally in churchyards.
Red Maple is a good choice of a tree for urban areas when there is ample room for its root system. The red maple is excellent at withstanding harsh urban conditions, including tolerance of both dry and wet soils, and a higher tolerance of pollution than sugar maple. Like several other maples, its low root system can be invasive and it makes a poor choice for plantings in narrow strips between a sidewalk and a street. It attracts squirrels, who eat its buds in the early spring, although squirrels prefer the larger buds of the silver maple.
## Cultivars
Numerous cultivars have been selected, often for intensity of fall color, with 'October Glory' and 'Red Sunset' among the most popular. Toward its southern limit, 'Fireburst', 'Florida Flame', and 'Gulf Ember' are preferred. Many cultivars of Freeman's Maple are also grown widely. Below is a partial list of cultivars:
- 'Armstrong' - Columnar to fastigate in shape with silvery bark and modest orange to red fall foliage
- 'Autumn Blaze' - Rounded oval form with leaves that resemble the silver maple. The fall colour is orange red and persists longer than usual
- 'Autumn Flame' - A fast grower with exceptional bright red fall color developing early. The leaves are also smaller than the species.
- 'Autumn Radiance' - Dense oval crown with an orange-red fall colour
- 'Autumn Spire' - Broad columnar crown; red fall colour; very hardy
- 'Bowhall' - Conical to upright in form with a yellow-red fall colour
- 'Burgundy Bell' - Compact rounded uniform shape with long lasting, burgundy fall leaves
- 'Columnare' - An old cultivar growing to 20 metres (70 feet) with a narrow columnar to pyramidal form with dark green leaves turning orange and deep red in fall
- 'Gerling' - A compact, slow growing selection, this individual only reaches 10 metres (30 feet) and has orange-red fall foliage
- 'Northwood' - Branches are at a 45 degree angle to the trunk, forming a rounded oval crown. Though the foliage is deep green in summer, its orange-red fall colour is not as impressive as other cultivars.
- 'October Brilliance' - This selection is slow to leaf in spring, but has a tight crown and deep red fall colour
- 'October Glory' - Has a rounded oval crown with late developing intense red fall foliage. Along with 'Red Sunset', it is the most popular selection due to the dependable fall colour and vigorous growth.
- 'Red Sunset' - The other very popular choice, this selection does well in heat due to its drought tolerance and has an upright habit. It has very attractive orange-red fall colour and is also a rapid and vigorous grower.
- 'Scarlet Sentinel' - A columnar to oval selection with 5-lobed leaves resembling the silver maple. The fall colour is yellow-orange to orange-red and the tree is a fast grower.
- 'Schlesingeri' - A tree with a broad crown and early, long lasting fall colour that a deep red to reddish purple. Growth is also quite rapid.
- 'Shade King' - This fast growing cultivar has an upright-oval form with deep green summer leaves that turn red to orange in fall.
- 'V.J. Drake' - This selection is notable due to the fact that the edges of the leaves first turn a deep red before the colour progresses into the center.
# Other uses
In the lumber industry A. rubrum is considered a soft maple. The wood is close grained and as such it is similar to that of A. saccharum, but its texture is softer, less dense, and has a poorer figure and machining qualities. High grades of wood from the red maple can nonetheless be substituted for hard maple, particularly when it comes to making furniture. As a soft maple, the wood tends to shrink more during the drying process than with the hard maples.
Red maple is also used for the production of maple syrup, though the hard maples A. saccharum and A. nigrum, the black maple, are more commonly used. One study compared the sap and syrup from the Sugar Maple with those of the red maple, as well as those of the Silver Maple, boxelder (A. negundo), and Norway maple (A. platanoides), and all were found to be equal in sweetness, flavor, and quality. However, the buds of red maple and other soft maples emerge much earlier in the spring than the sugar maple, and after sprouting chemical makeup of the sap changes, imparting an undesirable flavor to the syrup. This being the case, red maple can only be tapped for syrup before the buds emerge, making the season very short. | Acer rubrum
Acer rubrum (Red Maple, also known as Swamp or Soft Maple), is one of the most common and widespread deciduous trees of eastern North America. It ranges from the Lake of the Woods on the border between Ontario and Minnesota, east to Newfoundland, south to near Miami, Florida, and southwest to east Texas. Many of its features, especially its leaves, are quite variable in form. At maturity it often attains a height of around 25 metres (82 feet). It is aptly named as its flowers, petioles, twigs and seeds are all red to varying degrees. Among these features, however, it is most well known for its brilliant deep scarlet foliage in autumn.
Over most of its range, red maple is adaptable to a very wide range of site conditions, perhaps more so than any other tree in eastern North America. It can be found growing in swamps, on poor dry soils, and most anywhere in between. Elevation is also not a limiting factor in its range, as it grows well from sea level to about 900 m (3,000 feet). Due to its attractive fall foliage and pleasing form, it is often used as a shade tree for landscapes. It is used commercially on a small scale for maple syrup production as well as for its medium to high quality lumber. It is also the State Tree of Rhode Island.
# Description
Though A. rubrum is generally easy to identify, it is highly variable in morphological characteristics. It is a medium to large sized tree, reaching heights of 18 to 27 metres (60 to 90 feet) and exceptionally over 35 metres (115 feet). The diameter can range from 46 to 76 cm (18 to 30 inches), depending on the growing conditions.[2] In forests, the bark will remain free of branches until some distance up the tree. Individuals grown in the open are shorter and thicker with a more rounded crown.[3] Generally speaking, however, the crown is irregularly ovoid with ascending whip-like curved shoots. The bark is a pale grey and smooth when the individual is young. As the tree grows the bark becomes darker and cracks into slightly raised long plates.[4] The largest known living red maple is located near Armada, Michigan, at a height of 38.1 metres (125 feet) and a bole circumference, at breast height, of 4.95 metres (16.25 feet).[2]
The leaves of the red maple offer the easiest way to distinguish it from its relatives. As with all maples, they are deciduous and arranged oppositely on the twig. They are typically 5-10 cm (2-4 inches) long and wide with 3-5 palmate lobes with a serrated margin. The sinuses are typically narrow, but the leaves can exhibit considerable variation.[3] When 5 lobes are present, the three at the terminal end are larger than the other two near the base. In contrast, the leaves of the related silver maple, A. saccharinum, are much more deeply lobed, more sharply toothed and characteristically have 5 lobes. The upper side of A. rubrum's leaf is light green and the underside is whitish and can be either glaucous or hairy. The leaf stalks are usually red and are up to 10 cm (4 inches) long. Furthermore, the leaves turn a brilliant red in autumn.
The twigs of the red maple are reddish in colour and somewhat shiny with small lenticels. Dwarf shoots are present on many branches. The buds are usually blunt and greenish to reddish in coulour, generally with several loose scales. The lateral buds are slightly stalked, and in addition there may be collateral buds present as well. The buds form in fall and winter and are often visible from a distance due to their reddish tint. The leaf scars on the twig are V-shaped and contain 3 bundle scars.[3]
The flowers are generally unisexual, with male and female flowers appearing in separate sessile clusters, though they are sometimes also bisexual. They appear in spring from April to May, usually coming before the leaves. The tree itself is considered polygamo-diecious, meaning some individuals are male, some female, and some monoecious.[2] The flowers are red with 5 small petals and a 5-lobed calyx borne in hanging clusters, usually at the twig tips. They are lineal to oblong in shape and are pubescent. The pistillate flowers have one pistil formed from two fused carpels with a glabrous superior ovary and two long styles that protrude beyond the perianth. The staminate flowers contain between 4 and 12 stamens, often with 8.[5]
The fruit is a 15 to 25 milimeter (.5 to .75 inch) long double samara with somewhat divergent wings at an angle of 50 to 60 degrees. They are borne on long slender stems and are variable in colour from light brown to reddish.[3] They ripen from April through early June, before even the leaf development is altogether complete. After they reach maturity, the seeds are dispersed for a 1 to 2 week period from April through July.[2]
# Distribution and habitat
A. rubrum is one of the most abundant and widespread trees in eastern North America. It can be found from the south of Newfoundland, Nova Scotia and southern Quebec to the south west of Ontario, extreme southeastern Manitoba and northern Minnesota; south to Wisconsin, Illinois, Missouri, eastern Oklahoma, and eastern Texas in its western range; and east to Florida. It has the largest continuous range along the North American Atlantic Coast of any tree that occurs in Florida. In total it ranges 2575 km (1,600 miles) from north to south. The species is native to all regions of the United States east of the 95th meridian, with only three exceptions, namely the Prairie Peninsula of the Midwest, the coastal prairie in southern Louisiana and southeastern Texas, and the swamp prairie of the Florida Everglades. The most interesting of these exceptions is its absence in the Prairie Peninsula. Here the red maple is not present in the bottom land forests of the Grain Belt, despite the fact it is common in similar habitats and species associations both to the north and south of this area.[2]
The tree's range ends where the -40°C (-40°F) mean minimum isotherm begins, namely in southeastern Canada. On the other hand, the western range is limited by the much drier climate of the Great Plains. Nonetheless, it has the widest tolerance to climatic conditions of all the North American species of maple. As above, the absence of red maple in the Prairie Peninsula is probably not related to rainfall or other climatic conditions, since it grows healthily in other locations with comparable or even less annual precipitation.[2]
A. rubrum does very well in a wide range of soil types, with varying textures, moisture, pH, and elevation, probably more so than any other forest tree in North America. It grows on glaciated as well as nonglaciated soils derived from the following rocks: granite, gneiss, schist, sandstone, shale, slate, conglomerate, quartzite, and limestone. Chlorosis can occur on very alkaline soils, though otherwise its pH tolerance is quite high. As concerns levels of moisture, the red maple grows everywhere from dry ridges and southwest facing slopes to peat bogs and swamps. It occurs commonly in rather extreme moisture conditions, both very wet and quite dry. While many types of tree prefer a south or north facing aspect, the red maple does not appear to have a preference. Its ideal conditions are in moderately well-drained, moist sites at low or intermediate elevations. However, it is nonetheless common in mountainous areas on relatively dry ridges, as well as on both the south and west sides of upper slopes. Furthermore, it is common in swampy areas, along the banks of slow moving streams, as well as on poorly drained flats and depressions. In northern Michigan and New England, the tree is found on the tops of ridges, sandy or rocky upland and otherwise dry soils, as well as in nearly pure stands on moist soils and the edges of swaps. In the far south of its range, it is almost exclusively associated with swamps.[2]
Interestingly, it is thought that the pre-European forest of eastern North America contained far fewer red maples than at present. Most diversity surveys conducted in eastern forests prior to their large scale exploitation showed the red maple representing under 5% of all tree species and it was furthermore mostly confined to poorly drained areas. The density of the tree in many of these areas has increased 6 to 7 fold and this trend seems to be continuing. A series of disturbances to the oak and pine forests since European arrival, such as the suppression of forest fires and global warming, are most likely responsible for this phenomenon. Concern has been expressed, as the ongoing spread of the red maple is changing the nature of eastern forests by reducing the number of oaks and pines that would otherwise dominate.[6]
# Ecology
Red maple seldom lives longer than 150 years, making it short to medium lived. It reaches maturity in 70 to 80 years. Its ability to thrive in a large number of habitats is largely due to its ability to produce roots to suit its site from a young age. In wet locations, red maple seedlings produce short taproots with long and developed lateral roots, while on dry sites, they develop long taproots with significantly shorter laterals. The roots are primarily horizontal, however, forming in the upper 25 cm (10 in) of the ground. Mature trees have woody roots up to 25 meters (80 ft) long. They are very tolerant of flooding, with one study showing that 60 days of flooding caused no leaf damage. At the same time, they are tolerant of drought due to their ability to stop growing under dry conditions by then producing a second growth flush when conditions later improve, even if growth has stopped for 2 weeks. [2]
A. rubrum is one of the first plants to flower in spring. A crop of seeds is generally produced every year with a bumper crop often occurring every second year. A single tree between 5 and 20 cm (2 and 8 inches) in diameter can produce between 12,000 and 91,000 seeds in a season. A tree 30 cm (1 foot) in diameter was shown to produce nearly a million seeds.[2]. Fertilization has also been shown to significantly increase the seed yield for up to two years after application. The seeds are epigeal and tend to germinate in early Summer soon after they are released, assuming a small amount of light, moisture, and sufficient temperatures are present. If the seeds are densely shaded, then germination commonly does not occur until the next Spring. Most seedlings do not survive in closed forest canopy situations. However, one to four year old seedling are common under dense canopy and though they eventually die if no light reaches them, they serve as a reservoir, waiting to fill any open area of the canopy above.
Red maple is able to increase its numbers significantly when associate trees are damaged by disease, cutting, or fire. One study found that 6 years after clearcutting a 3.4 hectare (8.5 acre) Oak-Hickory forest containing no red maples, the plot contained more than 2,200 red maple seedlings per hectare (900 per acre) taller than 1.4 m (4.5 feet).[2] One of its associates, the black cherry (Prunus serotina), contains benzoic acid, which has been shown to be a potential allelopathic inhibitor of red maple growth. Red maple is one of the first species to start stem elongation. In one study, stem elongation was one-half completed in 1 week, after which growth slowed and was 90% completed within only 54 days. In good light and moisture conditions, the seedlings can grow 30 cm (1 ft) in their first year and up to 60 cm (2 ft) each year for the next few years making it a fast grower.[2]
The red maple is a used as a food source by several forms of wildlife. Elk and white-tailed deer in particular use the current season's growth of red maple as an important source of winter food. Several Lepidoptera (butterflies and moths) utilize the leaves as food; see List of Lepidoptera that feed on maples.
Due to A. rubrum's very wide range, there is significant variation in hardiness, size, form, time of flushing, onset of dormancy, and other traits. Generally speaking, individuals from the north flush the earliest, have the most reddish Fall color, set their buds the earliest and take the least winter injury. Seedlings are tallest in the north-central and east-central part of the range. The fruits also vary geographically with northern individuals in areas with brief frost free periods producing fruits that are shorter and heavier than their southern counterparts. As a result of the variation there is much genetic potential for breeding programs with a goal of producing red maples for cultivation. This is especially useful for making urban cultivars that require resistance from verticillium wilt, air pollution, and drought.[2]
Red maple frequently hybridizes with Silver Maple; the hybrid, known as Freeman's Maple Acer x freemanii, is intermediate between the parents.
## Toxicity
The leaves of red maple, especially when dead or wilted, are highly toxic to horses. The toxin is currently unknown, but it is believed to be an oxidant due to its destruction of red blood cells and thus causing the blood to be unable to properly transport oxygen, a condition otherwise known as acute hemolysis. The ingestion of 700 grams (1.5 pounds) of leaves is considered toxic and 1.4 kilograms (3 pounds) is lethal. Symptoms occur within one or two days after ingestion and can include depression, lethargy, increased rate and depth of breathing, increased heart rate, jaundice, dark brown urine, coma, and death. Treatment is limited and can include the use of methylene blue or mineral oil and activated carbon in order to stop further absorption of the toxin into the stomach. About 50% to 75% of affected horses die or are euthanized as a result.[7]
# Cultivation
Red Maple is widely grown as an ornamental tree in parks and large gardens, except where soils are too alkaline or salty. In parts of the Pacific Northwest, it is one of the most common introduced trees. Its popularity in cultivation stems from its vigorous habit, its attractive and early red flowers, and most importantly, its flaming red fall foliage. The tree was introduced into the United Kingdom in 1656 and shortly thereafter entered cultivation. There it is frequently found in many parks and gardens, as well as occasionally in churchyards.[4]
Red Maple is a good choice of a tree for urban areas when there is ample room for its root system. The red maple is excellent at withstanding harsh urban conditions, including tolerance of both dry and wet soils, and a higher tolerance of pollution than sugar maple. Like several other maples, its low root system can be invasive and it makes a poor choice for plantings in narrow strips between a sidewalk and a street. It attracts squirrels, who eat its buds in the early spring, although squirrels prefer the larger buds of the silver maple.[8]
## Cultivars
Numerous cultivars have been selected, often for intensity of fall color, with 'October Glory' and 'Red Sunset' among the most popular. Toward its southern limit, 'Fireburst', 'Florida Flame', and 'Gulf Ember' are preferred. Many cultivars of Freeman's Maple are also grown widely. Below is a partial list of cultivars[9][10]:
- 'Armstrong' - Columnar to fastigate in shape with silvery bark and modest orange to red fall foliage
- 'Autumn Blaze' - Rounded oval form with leaves that resemble the silver maple. The fall colour is orange red and persists longer than usual
- 'Autumn Flame' - A fast grower with exceptional bright red fall color developing early. The leaves are also smaller than the species.
- 'Autumn Radiance' - Dense oval crown with an orange-red fall colour
- 'Autumn Spire' - Broad columnar crown; red fall colour; very hardy
- 'Bowhall' - Conical to upright in form with a yellow-red fall colour
- 'Burgundy Bell' - Compact rounded uniform shape with long lasting, burgundy fall leaves
- 'Columnare' - An old cultivar growing to 20 metres (70 feet) with a narrow columnar to pyramidal form with dark green leaves turning orange and deep red in fall
- 'Gerling' - A compact, slow growing selection, this individual only reaches 10 metres (30 feet) and has orange-red fall foliage
- 'Northwood' - Branches are at a 45 degree angle to the trunk, forming a rounded oval crown. Though the foliage is deep green in summer, its orange-red fall colour is not as impressive as other cultivars.
- 'October Brilliance' - This selection is slow to leaf in spring, but has a tight crown and deep red fall colour
- 'October Glory' - Has a rounded oval crown with late developing intense red fall foliage. Along with 'Red Sunset', it is the most popular selection due to the dependable fall colour and vigorous growth.
- 'Red Sunset' - The other very popular choice, this selection does well in heat due to its drought tolerance and has an upright habit. It has very attractive orange-red fall colour and is also a rapid and vigorous grower.
- 'Scarlet Sentinel' - A columnar to oval selection with 5-lobed leaves resembling the silver maple. The fall colour is yellow-orange to orange-red and the tree is a fast grower.
- 'Schlesingeri' - A tree with a broad crown and early, long lasting fall colour that a deep red to reddish purple. Growth is also quite rapid.
- 'Shade King' - This fast growing cultivar has an upright-oval form with deep green summer leaves that turn red to orange in fall.
- 'V.J. Drake' - This selection is notable due to the fact that the edges of the leaves first turn a deep red before the colour progresses into the center.
# Other uses
In the lumber industry A. rubrum is considered a soft maple. The wood is close grained and as such it is similar to that of A. saccharum, but its texture is softer, less dense, and has a poorer figure and machining qualities. High grades of wood from the red maple can nonetheless be substituted for hard maple, particularly when it comes to making furniture. As a soft maple, the wood tends to shrink more during the drying process than with the hard maples.
Red maple is also used for the production of maple syrup, though the hard maples A. saccharum and A. nigrum, the black maple, are more commonly used. One study compared the sap and syrup from the Sugar Maple with those of the red maple, as well as those of the Silver Maple, boxelder (A. negundo), and Norway maple (A. platanoides), and all were found to be equal in sweetness, flavor, and quality. However, the buds of red maple and other soft maples emerge much earlier in the spring than the sugar maple, and after sprouting chemical makeup of the sap changes, imparting an undesirable flavor to the syrup. This being the case, red maple can only be tapped for syrup before the buds emerge, making the season very short.[2] | https://www.wikidoc.org/index.php/Acer_rubrum | |
98757cfcc73a96edc48a286982b9bd98dceaef97 | wikidoc | Acetic acid | Acetic acid
Acetic acid, also known as ethanoic acid, is an organic chemical compound, giving vinegar its sour taste and pungent smell. Its structural formula is represented as CH3COOH. Pure, water-free acetic acid (glacial acetic acid) is a colourless liquid that attracts water from the environment (hygroscopy), and freezes below 16.7 °C (62 °F) to a colourless crystalline solid. Acetic acid is corrosive, and its vapour causes irritation to the eyes, a dry and burning nose, sore throat and congestion to the lungs. It is a weak acid because at standard temperature and pressure the dissociated acid exists in equilibrium with the undissociated form in aqueous solutions, in contrast to strong acids, which are fully dissociated.
Acetic acid is one of the simplest carboxylic acids (the second-simplest, next to formic acid). It is an important chemical reagent and industrial chemical that is used in the production of polyethylene terephthalate mainly used in soft drink bottles; cellulose acetate, mainly for photographic film; and polyvinyl acetate for wood glue, as well as synthetic fibres and fabrics. In households diluted acetic acid is often used in descaling agents. In the food industry acetic acid is used under the food additive code E260 as an acidity regulator.
The global demand of acetic acid is around 6.5 million tonnes per year (Mt/a), of which approximately 1.5 Mt/a is met by recycling; the remainder is manufactured from petrochemical feedstocks or from biological sources.
# Nomenclature
The trivial name acetic acid is the most commonly used and officially preferred name by the IUPAC. This name derives from acetum, the Latin word for vinegar,
and is related to the word acid itself.
The synonym ethanoic acid is a systematic name that is used in introductions to chemical nomenclature.
Glacial acetic acid is a trivial name for water-free acetic acid. Similar to the German name Eisessig (literally, ice-vinegar), the name comes from the ice-like crystals that form slightly below room temperature at 16.7 °C (about 62 °F).
The most common and official abbreviation for acetic acid is AcOH or HOAc where Ac stands for the acetyl group CH3−C(=O)−;. In the context of acid-base reactions the abbreviation HAc is often used where Ac instead stands for the acetate anion (CH3COO−), although this use is regarded by many as misleading. In either case, the Ac is not to be confused with the abbreviation for the chemical element actinium.
Acetic acid has the empirical formula CH2O and the molecular formula C2H4O2 or HC2H3O2 (to emphasize the role of the 'active' hydrogen in forming the salt sodium acetate). To better reflect its structure, acetic acid is often written as CH3-CO2-H, CH3COOH, CH3CO2H, or HOCOCH3. The ion resulting from loss of H+ from acetic acid is the acetate anion. The name acetate can also refer to a salt containing this anion, or an ester of acetic acid.
# History
Vinegar was known, early in civilization, as the natural result of air exposure of beer and wine, as acetic acid-producing bacteria are present throughout the world.
The use of acetic acid in alchemy extends into the third century BC, when the Greek philosopher Theophrastos described how vinegar acted on metals to produce pigments useful in art, including white lead (lead carbonate) and verdigris, a green mixture of copper salts including copper(II) acetate. Ancient Romans boiled soured wine in lead pots to produce a highly sweet syrup called sapa. Sapa was rich in lead acetate, a sweet substance also called sugar of lead or sugar of Saturn, which contributed to lead poisoning among the Roman aristocracy.
In the 8th century, the Muslim alchemist Jabir Ibn Hayyan (Geber) was the first to concentrate acetic acid from vinegar through distillation. In the Renaissance, glacial acetic acid was prepared through the dry distillation of metal acetates. The 16th century German alchemist Andreas Libavius described such a procedure, and he compared the glacial acetic acid produced by this means to vinegar. The presence of water in vinegar has such a profound effect on acetic acid's properties that for centuries chemists believed that glacial acetic acid and the acid found in vinegar were two different substances. The French chemist Pierre Adet proved them to be identical.
In 1847 the German chemist Hermann Kolbe synthesized acetic acid from inorganic materials for the first time. This reaction sequence consisted of chlorination of carbon disulfide to carbon tetrachloride, followed by pyrolysis to tetrachloroethylene and aqueous chlorination to trichloroacetic acid, and concluded with electrolytic reduction to acetic acid.
By 1910 most glacial acetic acid was obtained from the "pyroligneous liquor" from distillation of wood. The acetic acid was isolated from this by treatment with milk of lime, and the resultant calcium acetate was then acidified with sulfuric acid to recover acetic acid. At this time Germany was producing 10,000 tons of glacial acetic acid, around 30% of which was used for the manufacture of indigo dye.
# Chemical properties
The hydrogen (H) atom in the carboxyl group (−COOH) in carboxylic acids such as acetic acid can be given off as an H+ ion (proton), giving them their acidic character. Acetic acid is a weak, effectively monoprotic acid in aqueous solution, with a pKa value of 4.8. Its conjugate base is acetate (CH3COO−). A 1.0 M solution (about the concentration of domestic vinegar) has a pH of 2.4, indicating that merely 0.4% of the acetic acid molecules are dissociated.
The crystal structure of acetic acid shows that the molecules pair up into dimers connected by hydrogen bonds. The dimers can also be detected in the vapour at 120 °C. They also occur in the liquid phase in dilute solutions in non-hydrogen-bonding solvents, and a certain extent in pure acetic acid, but are disrupted by hydrogen-bonding solvents. The dissociation enthalpy of the dimer is estimated at 65.0–66.0 kJ/mol, and the dissociation entropy at 154–157 J mol–1 K–1. This dimerization behaviour is shared by other lower carboxylic acids.
Liquid acetic acid is a hydrophilic (polar) protic solvent, similar to ethanol and water. With a moderate dielectric constant of 6.2, it can dissolve not only polar compounds such as inorganic salts and sugars, but also non-polar compounds such as oils and elements such as sulfur and iodine. It readily mixes with other polar and non-polar solvents such as water, chloroform, and hexane. This dissolving property and miscibility of acetic acid makes it a widely used industrial chemical.
## Chemical reactions
Acetic acid is corrosive to metals including iron, magnesium, and zinc, forming hydrogen gas and metal salts called acetates. Aluminium, when exposed to oxygen, forms a thin layer of aluminium oxide on its surface which is relatively resistant, so that aluminium tanks can be used to transport acetic acid. Metal acetates can also be prepared from acetic acid and an appropriate base, as in the popular "baking soda + vinegar" reaction. With the notable exception of chromium(II) acetate, almost all acetates are soluble in water.
Acetic acid undergoes the typical chemical reactions of a carboxylic acid, such producing water and a metal ethanoate when reacting with alkalis, producing a metal ethanoate when reacted with a metal, and producing a metal ethanoate, water and carbon dioxide when reacting with carbonates and hydrogencarbonates. Most notable of all its reactions is the formation of ethanol by reduction, and formation of derivatives such as acetyl chloride via nucleophilic acyl substitution. Other substitution derivatives include acetic anhydride; this anhydride is produced by loss of water from two molecules of acetic acid. Esters of acetic acid can likewise be formed via Fischer esterification, and amides can also be formed. When heated above 440 °C, acetic acid decomposes to produce carbon dioxide and methane, or to produce ketene and water.
Acetic acid can be detected by its characteristic smell. A colour reaction for salts of acetic acid is iron(III) chloride solution, which results in a deeply red colour that disappears after acidification. Acetates when heated with arsenic trioxide form cacodyl oxide, which can be detected by its malodorous vapours.
## Biochemistry
The acetyl group, derived from acetic acid, is fundamental to the biochemistry of virtually all forms of life. When bound to coenzyme A it is central to the metabolism of carbohydrates and fats. However, the concentration of free acetic acid in cells is kept at a low level to avoid disrupting the control of the pH of the cell contents. Unlike longer-chain carboxylic acids (the fatty acids), acetic acid does not occur in natural triglycerides. However, the artificial triglyceride triacetin (glycerin triacetate) is a common food additive, and is found in cosmetics and topical medicines.
Acetic acid is produced and excreted by certain bacteria, notably the Acetobacter genus and Clostridium acetobutylicum. These bacteria are found universally in foodstuffs, water, and soil, and acetic acid is produced naturally as fruits and other foods spoil. Acetic acid is also a component of the vaginal lubrication of humans and other primates, where it appears to serve as a mild antibacterial agent.
# Production
Acetic acid is produced both synthetically and by bacterial fermentation. Today, the biological route accounts for only about 10% of world production, but it remains important for vinegar production, as the world food purity laws stipulate that vinegar used in foods must be of biological origin. About 75% of acetic acid made for use in the chemical industry is made by methanol carbonylation, explained below. Alternative methods account for the rest.
Total worldwide production of virgin acetic acid is estimated at 5 Mt/a (million tonnes per year), approximately half of which is produced in the United States. European production stands at approximately 1 Mt/a and is declining, and 0.7 Mt/a is produced in Japan. Another 1.5 Mt are recycled each year, bringing the total world market to 6.5 Mt/a. The two biggest producers of virgin acetic acid are Celanese and BP Chemicals. Other major producers include Millennium Chemicals, Sterling Chemicals, Samsung, Eastman, and Svensk Etanolkemi.
## Methanol carbonylation
Most virgin acetic acid is produced by methanol carbonylation. In this process, methanol and carbon monoxide react to produce acetic acid according to the chemical equation:
The process involves iodomethane as an intermediate, and occurs in three steps. A catalyst, usually a metal complex, is needed for the carbonylation (step 2).
By altering the process conditions, acetic anhydride may also be produced on the same plant. Because both methanol and carbon monoxide are commodity raw materials, methanol carbonylation long appeared to be an attractive method for acetic acid production. Henry Drefyus at British Celanese developed a methanol carbonylation pilot plant as early as 1925. However, a lack of practical materials that could contain the corrosive reaction mixture at the high pressures needed (200 atm or more) discouraged commercialization of these routes. The first commercial methanol carbonylation process, which used a cobalt catalyst, was developed by German chemical company BASF in 1963. In 1968, a rhodium-based catalyst (cis−−) was discovered that could operate efficiently at lower pressure with almost no by-products. The first plant using this catalyst was built by US chemical company Monsanto in 1970, and rhodium-catalysed methanol carbonylation became the dominant method of acetic acid production (see Monsanto process). In the late 1990s, the chemicals company BP Chemicals commercialized the Cativa catalyst (−), which is promoted by ruthenium. This iridium-catalysed process is greener and more efficient and has largely supplanted the Monsanto process, often in the same production plants.
## Acetaldehyde oxidation
Prior to the commercialization of the Monsanto process, most acetic acid was produced by oxidation of acetaldehyde. This remains the second most important manufacturing method, although it is uncompetitive with methanol carbonylation. The acetaldehyde may be produced via oxidation of butane or light naphtha, or by hydration of ethylene.
When butane or light naphtha is heated with air in the presence of various metal ions, including those of manganese, cobalt and chromium; peroxides form and then decompose to produce acetic acid according to the chemical equation
Typically, the reaction is run at a combination of temperature and pressure designed to be as hot as possible while still keeping the butane a liquid. Typical reaction conditions are 150 °C and 55 atm. Side products may also form, including butanone, ethyl acetate, formic acid, and propionic acid. These side products are also commercially valuable, and the reaction conditions may be altered to produce more of them if this is economically useful. However, the separation of acetic acid from these by-products adds to the cost of the process.
Under similar conditions and using similar catalysts as are used for butane oxidation, acetaldehyde can be oxidized by the oxygen in air to produce acetic acid
Using modern catalysts, this reaction can have an acetic acid yield greater than 95%. The major side products are ethyl acetate, formic acid, and formaldehyde, all of which have lower boiling points than acetic acid and are readily separated by distillation.
## Ethylene oxidation
Acetaldehyde may be prepared from ethylene via the Wacker process, and then oxidized as above. More recently a cheaper single-stage conversion of ethylene to acetic acid was commercialized by chemical company Showa Denko, which opened an ethylene oxidation plant in Ōita, Japan, in 1997. The process is catalysed by a palladium metal catalyst supported on a heteropoly acid such as tungstosilicic acid. It is thought to be competitive with methanol carbonylation for smaller plants (100–250 kt/a), depending on the local price of ethylene.
## Oxidative fermentation
For most of human history, acetic acid, in the form of vinegar, has been made by acetic acid bacteria of the genus Acetobacter. Given sufficient oxygen, these bacteria can produce vinegar from a variety of alcoholic foodstuffs. Commonly used feeds include apple cider, wine, and fermented grain, malt, rice, or potato mashes. The overall chemical reaction facilitated by these bacteria is:
A dilute alcohol solution inoculated with Acetobacter and kept in a warm, airy place will become vinegar over the course of a few months. Industrial vinegar-making methods accelerate this process by improving the supply of oxygen to the bacteria.
The first batches of vinegar produced by fermentation probably followed errors in the winemaking process. If must is fermented at too high a temperature, acetobacter will overwhelm the yeast naturally occurring on the grapes. As the demand for vinegar for culinary, medical, and sanitary purposes increased, vintners quickly learned to use other organic materials to produce vinegar in the hot summer months before the grapes were ripe and ready for processing into wine. This method was slow, however, and not always successful, as the vintners did not understand the process.
One of the first modern commercial processes was the "fast method" or "German method", first practised in Germany in 1823. In this process, fermentation takes place in a tower packed with wood shavings or charcoal. The alcohol-containing feed is trickled into the top of the tower, and fresh air supplied from the bottom by either natural or forced convection. The improved air supply in this process cut the time to prepare vinegar from months to weeks.
Most vinegar today is made in submerged tank culture, first described in 1949 by Otto Hromatka and Heinrich Ebner. In this method, alcohol is fermented to vinegar in a continuously stirred tank, and oxygen is supplied by bubbling air through the solution. Using modern applications of this method, vinegar of 15% acetic acid can be prepared in only 24 hours in batch process, even 20% in 60 h fed-batch process.
## Anaerobic fermentation
Species of anaerobic bacteria, including members of the genus Clostridium, can convert sugars to acetic acid directly, without using ethanol as an intermediate. The overall chemical reaction conducted by these bacteria may be represented as:
More interestingly from the point of view of an industrial chemist, these acetogenic bacteria can produce acetic acid from one-carbon compounds, including methanol, carbon monoxide, or a mixture of carbon dioxide and hydrogen:
This ability of Clostridium to utilize sugars directly, or to produce acetic acid from less costly inputs, means that these bacteria could potentially produce acetic acid more efficiently than ethanol-oxidizers like Acetobacter. However, Clostridium bacteria are less acid-tolerant than Acetobacter. Even the most acid-tolerant Clostridium strains can produce vinegar of only a few per cent acetic acid, compared to Acetobacter strains that can produce vinegar of up to 20% acetic acid. At present, it remains more cost-effective to produce vinegar using Acetobacter than to produce it using Clostridium and then concentrating it. As a result, although acetogenic bacteria have been known since 1940, their industrial use remains confined to a few niche applications.
# Applications
Acetic acid is a chemical reagent for the production of chemical compounds. The largest single use of acetic acid is in the production of vinyl acetate monomer, closely followed by acetic anhydride and ester production. The volume of acetic acid used in vinegar is comparatively small.
## Vinyl acetate monomer
The major use of acetic acid is for the production of vinyl acetate monomer (VAM). This application consumes approximately 40% to 45% of the world's production of acetic acid. The reaction is of ethylene and acetic acid with oxygen over a palladium catalyst.
Vinyl acetate can be polymerized to polyvinyl acetate or to other polymers, which are applied in paints and adhesives.
## Ester production
The major esters of acetic acid are commonly used solvents for inks, paints and coatings. The esters include ethyl acetate, n-butyl acetate, isobutyl acetate, and propyl acetate. They are typically produced by catalysed reaction from acetic acid and the corresponding alcohol.
: H3C-COOH + HO-R → H3C-CO-O-R + H2O, where R = a general alkyl group
Most acetate esters, however, are produced from acetaldehyde using the Tishchenko reaction. Additionally, ether acetates are used as solvents for nitrocellulose, acrylic lacquers, varnish removers and wood stains. First glycol monoethers are produced from ethylene oxide or propylene oxide with alcohol, which are then esterified with acetic acid. The three major products are ethylene glycol monoethyl ether acetate (EEA), ethylene glycol monobutyl ether acetate (EBA), and propylene glycol monomethyl ether acetate (PMA). This application consumes about 15% to 20% of worldwide acetic acid. Ether acetates, for example EEA, have been shown to be harmful to human reproduction.
## Acetic anhydride
The condensation product of two molecules of acetic acid is acetic anhydride. The worldwide production of acetic anhydride is a major application, and uses approximately 25% to 30% of the global production of acetic acid. Acetic anhydride may be produced directly by methanol carbonylation bypassing the acid, and Cativa plants can be adapted for anhydride production.
Acetic anhydride is a strong acetylation agent. As such, its major application is for cellulose acetate, a synthetic textile also used for photographic film. Acetic anhydride is also a reagent for the production of aspirin, heroin, and other compounds.
## Vinegar
In the form of vinegar, acetic acid solutions (typically 5% to 18% acetic acid, with the percentage usually calculated by mass) are used directly as a condiment, and also in the pickling of vegetables and other foodstuffs. Table vinegar tends to be more diluted (5% to 8% acetic acid), while commercial food pickling generally employs more concentrated solutions. The amount of acetic acid used as vinegar on a worldwide scale is not large, but historically, this is by far the oldest and most well-known application.
## Use as solvent
Glacial acetic acid is an excellent polar protic solvent, as noted above. It is frequently used as a solvent for recrystallization to purify organic compounds. Pure molten acetic acid is used as a solvent in the production of terephthalic acid (TPA), the raw material for polyethylene terephthalate (PET). Although currently accounting for 5%–10% of acetic acid use worldwide, this specific application is expected to grow significantly in the next decade, as PET production increases.
Acetic acid is often used as a solvent for reactions involving carbocations, such as Friedel-Crafts alkylation. For example, one stage in the commercial manufacture of synthetic camphor involves a Wagner-Meerwein rearrangement of camphene to isobornyl acetate; here acetic acid acts both as a solvent and as a nucleophile to trap the rearranged carbocation. Acetic acid is the solvent of choice when reducing an aryl nitro-group to an aniline using palladium-on-carbon.
Glacial acetic acid is used in analytical chemistry for the estimation of weakly alkaline substances such as organic amides. Glacial acetic acid is a much weaker base than water, so the amide behaves as a strong base in this medium. It then can be titrated using a solution in glacial acetic acid of a very strong acid, such as perchloric acid.
## Other applications
Dilute solutions of acetic acids are also used for their mild acidity. Examples in the household environment include the use in a stop bath during the development of photographic films, and in descaling agents to remove limescale from taps and kettles. The acidity is also used for treating the sting of the box jellyfish by disabling the stinging cells of the jellyfish, preventing serious injury or death if applied immediately, and for treating outer ear infections in people in preparations such as Vosol. Equivalently, acetic acid is used as a spray-on preservative for livestock silage, to discourage bacterial and fungal growth. Glacial acetic acid is also used as a wart and verruca remover.
Organic or inorganic salts are produced from acetic acid, including:
- Sodium acetate, used in the textile industry and as a food preservative (E262).
- Copper(II) acetate, used as a pigment and a fungicide.
- Aluminium acetate and iron(II) acetate—used as mordants for dyes.
- Palladium(II) acetate, used as a catalyst for organic coupling reactions such as the Heck reaction.
- Silver acetate, used as a pesticide.
Substituted acetic acids produced include:
- Monochloroacetic acid (MCA), dichloroacetic acid (considered a by-product), and trichloroacetic acid. MCA is used in the manufacture of indigo dye.
- Bromoacetic acid, which is esterified to produce the reagent ethyl bromoacetate.
- Trifluoroacetic acid, which is a common reagent in organic synthesis.
Amounts of acetic acid used in these other applications together (apart from TPA) account for another 5%–10% of acetic acid use worldwide. These applications are, however, not expected to grow as much as TPA production.
# Safety
Concentrated acetic acid is corrosive and must therefore be handled with appropriate care, since it can cause skin burns, permanent eye damage, and irritation to the mucous membranes. These burns or blisters may not appear until hours after exposure. Latex gloves offer no protection, so specially resistant gloves, such as those made of nitrile rubber, should be worn when handling the compound. Concentrated acetic acid can be ignited with difficulty in the laboratory. It becomes a flammable risk if the ambient temperature exceeds 39 °C (102 °F), and can form explosive mixtures with air above this temperature (explosive limits: 5.4%–16%).
The hazards of solutions of acetic acid depend on the concentration. The following table lists the EU classification of acetic acid solutions:
Solutions at more than 25% acetic acid are handled in a fume hood because of the pungent, corrosive vapour. Dilute acetic acid, in the form of vinegar, is harmless. However, ingestion of stronger solutions is dangerous to human and animal life. It can cause severe damage to the digestive system, and a potentially lethal change in the acidity of the blood.
Due to incompatibilities, it is recommended to keep acetic acid away from chromic acid, ethylene glycol, nitric acid, perchloric acid, permanganates, peroxides and hydroxyls. | Acetic acid
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Acetic acid, also known as ethanoic acid, is an organic chemical compound, giving vinegar its sour taste and pungent smell. Its structural formula is represented as CH3COOH. Pure, water-free acetic acid (glacial acetic acid) is a colourless liquid that attracts water from the environment (hygroscopy), and freezes below 16.7 °C (62 °F) to a colourless crystalline solid. Acetic acid is corrosive, and its vapour causes irritation to the eyes, a dry and burning nose, sore throat and congestion to the lungs. It is a weak acid because at standard temperature and pressure the dissociated acid exists in equilibrium with the undissociated form in aqueous solutions, in contrast to strong acids, which are fully dissociated.
Acetic acid is one of the simplest carboxylic acids (the second-simplest, next to formic acid). It is an important chemical reagent and industrial chemical that is used in the production of polyethylene terephthalate mainly used in soft drink bottles; cellulose acetate, mainly for photographic film; and polyvinyl acetate for wood glue, as well as synthetic fibres and fabrics. In households diluted acetic acid is often used in descaling agents. In the food industry acetic acid is used under the food additive code E260 as an acidity regulator.
The global demand of acetic acid is around 6.5 million tonnes per year (Mt/a), of which approximately 1.5 Mt/a is met by recycling; the remainder is manufactured from petrochemical feedstocks or from biological sources.
# Nomenclature
The trivial name acetic acid is the most commonly used and officially preferred name by the IUPAC. This name derives from acetum, the Latin word for vinegar,
and is related to the word acid itself.
The synonym ethanoic acid is a systematic name that is used in introductions to chemical nomenclature.
Glacial acetic acid is a trivial name for water-free acetic acid. Similar to the German name Eisessig (literally, ice-vinegar), the name comes from the ice-like crystals that form slightly below room temperature at 16.7 °C (about 62 °F).
The most common and official abbreviation for acetic acid is AcOH or HOAc where Ac stands for the acetyl group CH3−C(=O)−;. In the context of acid-base reactions the abbreviation HAc is often used where Ac instead stands for the acetate anion (CH3COO−), although this use is regarded by many as misleading. In either case, the Ac is not to be confused with the abbreviation for the chemical element actinium.
Acetic acid has the empirical formula CH2O and the molecular formula C2H4O2 or HC2H3O2 (to emphasize the role of the 'active' hydrogen in forming the salt sodium acetate).[1] To better reflect its structure, acetic acid is often written as CH3-CO2-H, CH3COOH, CH3CO2H, or HOCOCH3. The ion resulting from loss of H+ from acetic acid is the acetate anion. The name acetate can also refer to a salt containing this anion, or an ester of acetic acid.
# History
Vinegar was known, early in civilization, as the natural result of air exposure of beer and wine, as acetic acid-producing bacteria are present throughout the world.
The use of acetic acid in alchemy extends into the third century BC, when the Greek philosopher Theophrastos described how vinegar acted on metals to produce pigments useful in art, including white lead (lead carbonate) and verdigris, a green mixture of copper salts including copper(II) acetate. Ancient Romans boiled soured wine in lead pots to produce a highly sweet syrup called sapa. Sapa was rich in lead acetate, a sweet substance also called sugar of lead or sugar of Saturn, which contributed to lead poisoning among the Roman aristocracy.
In the 8th century, the Muslim alchemist Jabir Ibn Hayyan (Geber) was the first to concentrate acetic acid from vinegar through distillation. In the Renaissance, glacial acetic acid was prepared through the dry distillation of metal acetates. The 16th century German alchemist Andreas Libavius described such a procedure, and he compared the glacial acetic acid produced by this means to vinegar. The presence of water in vinegar has such a profound effect on acetic acid's properties that for centuries chemists believed that glacial acetic acid and the acid found in vinegar were two different substances. The French chemist Pierre Adet proved them to be identical.
In 1847 the German chemist Hermann Kolbe synthesized acetic acid from inorganic materials for the first time. This reaction sequence consisted of chlorination of carbon disulfide to carbon tetrachloride, followed by pyrolysis to tetrachloroethylene and aqueous chlorination to trichloroacetic acid, and concluded with electrolytic reduction to acetic acid.[2]
By 1910 most glacial acetic acid was obtained from the "pyroligneous liquor" from distillation of wood. The acetic acid was isolated from this by treatment with milk of lime, and the resultant calcium acetate was then acidified with sulfuric acid to recover acetic acid. At this time Germany was producing 10,000 tons of glacial acetic acid, around 30% of which was used for the manufacture of indigo dye.[3][4]
# Chemical properties
The hydrogen (H) atom in the carboxyl group (−COOH) in carboxylic acids such as acetic acid can be given off as an H+ ion (proton), giving them their acidic character. Acetic acid is a weak, effectively monoprotic acid in aqueous solution, with a pKa value of 4.8. Its conjugate base is acetate (CH3COO−). A 1.0 M solution (about the concentration of domestic vinegar) has a pH of 2.4, indicating that merely 0.4% of the acetic acid molecules are dissociated.
The crystal structure of acetic acid shows that the molecules pair up into dimers connected by hydrogen bonds.[5] The dimers can also be detected in the vapour at 120 °C. They also occur in the liquid phase in dilute solutions in non-hydrogen-bonding solvents, and a certain extent in pure acetic acid,[6] but are disrupted by hydrogen-bonding solvents. The dissociation enthalpy of the dimer is estimated at 65.0–66.0 kJ/mol, and the dissociation entropy at 154–157 J mol–1 K–1.[7] This dimerization behaviour is shared by other lower carboxylic acids.
Liquid acetic acid is a hydrophilic (polar) protic solvent, similar to ethanol and water. With a moderate dielectric constant of 6.2, it can dissolve not only polar compounds such as inorganic salts and sugars, but also non-polar compounds such as oils and elements such as sulfur and iodine. It readily mixes with other polar and non-polar solvents such as water, chloroform, and hexane. This dissolving property and miscibility of acetic acid makes it a widely used industrial chemical.
## Chemical reactions
Acetic acid is corrosive to metals including iron, magnesium, and zinc, forming hydrogen gas and metal salts called acetates. Aluminium, when exposed to oxygen, forms a thin layer of aluminium oxide on its surface which is relatively resistant, so that aluminium tanks can be used to transport acetic acid. Metal acetates can also be prepared from acetic acid and an appropriate base, as in the popular "baking soda + vinegar" reaction. With the notable exception of chromium(II) acetate, almost all acetates are soluble in water.
Acetic acid undergoes the typical chemical reactions of a carboxylic acid, such producing water and a metal ethanoate when reacting with alkalis, producing a metal ethanoate when reacted with a metal, and producing a metal ethanoate, water and carbon dioxide when reacting with carbonates and hydrogencarbonates. Most notable of all its reactions is the formation of ethanol by reduction, and formation of derivatives such as acetyl chloride via nucleophilic acyl substitution. Other substitution derivatives include acetic anhydride; this anhydride is produced by loss of water from two molecules of acetic acid. Esters of acetic acid can likewise be formed via Fischer esterification, and amides can also be formed. When heated above 440 °C, acetic acid decomposes to produce carbon dioxide and methane, or to produce ketene and water.
Acetic acid can be detected by its characteristic smell. A colour reaction for salts of acetic acid is iron(III) chloride solution, which results in a deeply red colour that disappears after acidification. Acetates when heated with arsenic trioxide form cacodyl oxide, which can be detected by its malodorous vapours.
## Biochemistry
The acetyl group, derived from acetic acid, is fundamental to the biochemistry of virtually all forms of life. When bound to coenzyme A it is central to the metabolism of carbohydrates and fats. However, the concentration of free acetic acid in cells is kept at a low level to avoid disrupting the control of the pH of the cell contents. Unlike longer-chain carboxylic acids (the fatty acids), acetic acid does not occur in natural triglycerides. However, the artificial triglyceride triacetin (glycerin triacetate) is a common food additive, and is found in cosmetics and topical medicines.
Acetic acid is produced and excreted by certain bacteria, notably the Acetobacter genus and Clostridium acetobutylicum. These bacteria are found universally in foodstuffs, water, and soil, and acetic acid is produced naturally as fruits and other foods spoil. Acetic acid is also a component of the vaginal lubrication of humans and other primates, where it appears to serve as a mild antibacterial agent.[8]
# Production
Acetic acid is produced both synthetically and by bacterial fermentation. Today, the biological route accounts for only about 10% of world production, but it remains important for vinegar production, as the world food purity laws stipulate that vinegar used in foods must be of biological origin. About 75% of acetic acid made for use in the chemical industry is made by methanol carbonylation, explained below. Alternative methods account for the rest.[9]
Total worldwide production of virgin acetic acid is estimated at 5 Mt/a (million tonnes per year), approximately half of which is produced in the United States. European production stands at approximately 1 Mt/a and is declining, and 0.7 Mt/a is produced in Japan. Another 1.5 Mt are recycled each year, bringing the total world market to 6.5 Mt/a.[10][11] The two biggest producers of virgin acetic acid are Celanese and BP Chemicals. Other major producers include Millennium Chemicals, Sterling Chemicals, Samsung, Eastman, and Svensk Etanolkemi.
## Methanol carbonylation
Most virgin acetic acid is produced by methanol carbonylation. In this process, methanol and carbon monoxide react to produce acetic acid according to the chemical equation:
The process involves iodomethane as an intermediate, and occurs in three steps. A catalyst, usually a metal complex, is needed for the carbonylation (step 2).
By altering the process conditions, acetic anhydride may also be produced on the same plant. Because both methanol and carbon monoxide are commodity raw materials, methanol carbonylation long appeared to be an attractive method for acetic acid production. Henry Drefyus at British Celanese developed a methanol carbonylation pilot plant as early as 1925.[12] However, a lack of practical materials that could contain the corrosive reaction mixture at the high pressures needed (200 atm or more) discouraged commercialization of these routes. The first commercial methanol carbonylation process, which used a cobalt catalyst, was developed by German chemical company BASF in 1963. In 1968, a rhodium-based catalyst (cis−[Rh(CO)2I2]−) was discovered that could operate efficiently at lower pressure with almost no by-products. The first plant using this catalyst was built by US chemical company Monsanto in 1970, and rhodium-catalysed methanol carbonylation became the dominant method of acetic acid production (see Monsanto process). In the late 1990s, the chemicals company BP Chemicals commercialized the Cativa catalyst ([Ir(CO)2I2]−), which is promoted by ruthenium. This iridium-catalysed process is greener and more efficient[13] and has largely supplanted the Monsanto process, often in the same production plants.
## Acetaldehyde oxidation
Prior to the commercialization of the Monsanto process, most acetic acid was produced by oxidation of acetaldehyde. This remains the second most important manufacturing method, although it is uncompetitive with methanol carbonylation. The acetaldehyde may be produced via oxidation of butane or light naphtha, or by hydration of ethylene.
When butane or light naphtha is heated with air in the presence of various metal ions, including those of manganese, cobalt and chromium; peroxides form and then decompose to produce acetic acid according to the chemical equation
Typically, the reaction is run at a combination of temperature and pressure designed to be as hot as possible while still keeping the butane a liquid. Typical reaction conditions are 150 °C and 55 atm. Side products may also form, including butanone, ethyl acetate, formic acid, and propionic acid. These side products are also commercially valuable, and the reaction conditions may be altered to produce more of them if this is economically useful. However, the separation of acetic acid from these by-products adds to the cost of the process.
Under similar conditions and using similar catalysts as are used for butane oxidation, acetaldehyde can be oxidized by the oxygen in air to produce acetic acid
Using modern catalysts, this reaction can have an acetic acid yield greater than 95%. The major side products are ethyl acetate, formic acid, and formaldehyde, all of which have lower boiling points than acetic acid and are readily separated by distillation.[14]
## Ethylene oxidation
Acetaldehyde may be prepared from ethylene via the Wacker process, and then oxidized as above. More recently a cheaper single-stage conversion of ethylene to acetic acid was commercialized by chemical company Showa Denko, which opened an ethylene oxidation plant in Ōita, Japan, in 1997.[15] The process is catalysed by a palladium metal catalyst supported on a heteropoly acid such as tungstosilicic acid. It is thought to be competitive with methanol carbonylation for smaller plants (100–250 kt/a), depending on the local price of ethylene.
## Oxidative fermentation
For most of human history, acetic acid, in the form of vinegar, has been made by acetic acid bacteria of the genus Acetobacter. Given sufficient oxygen, these bacteria can produce vinegar from a variety of alcoholic foodstuffs. Commonly used feeds include apple cider, wine, and fermented grain, malt, rice, or potato mashes. The overall chemical reaction facilitated by these bacteria is:
A dilute alcohol solution inoculated with Acetobacter and kept in a warm, airy place will become vinegar over the course of a few months. Industrial vinegar-making methods accelerate this process by improving the supply of oxygen to the bacteria.
The first batches of vinegar produced by fermentation probably followed errors in the winemaking process. If must is fermented at too high a temperature, acetobacter will overwhelm the yeast naturally occurring on the grapes. As the demand for vinegar for culinary, medical, and sanitary purposes increased, vintners quickly learned to use other organic materials to produce vinegar in the hot summer months before the grapes were ripe and ready for processing into wine. This method was slow, however, and not always successful, as the vintners did not understand the process.
One of the first modern commercial processes was the "fast method" or "German method", first practised in Germany in 1823. In this process, fermentation takes place in a tower packed with wood shavings or charcoal. The alcohol-containing feed is trickled into the top of the tower, and fresh air supplied from the bottom by either natural or forced convection. The improved air supply in this process cut the time to prepare vinegar from months to weeks.
Most vinegar today is made in submerged tank culture, first described in 1949 by Otto Hromatka and Heinrich Ebner. In this method, alcohol is fermented to vinegar in a continuously stirred tank, and oxygen is supplied by bubbling air through the solution. Using modern applications of this method, vinegar of 15% acetic acid can be prepared in only 24 hours in batch process, even 20% in 60 h fed-batch process.
## Anaerobic fermentation
Species of anaerobic bacteria, including members of the genus Clostridium, can convert sugars to acetic acid directly, without using ethanol as an intermediate. The overall chemical reaction conducted by these bacteria may be represented as:
More interestingly from the point of view of an industrial chemist, these acetogenic bacteria can produce acetic acid from one-carbon compounds, including methanol, carbon monoxide, or a mixture of carbon dioxide and hydrogen:
This ability of Clostridium to utilize sugars directly, or to produce acetic acid from less costly inputs, means that these bacteria could potentially produce acetic acid more efficiently than ethanol-oxidizers like Acetobacter. However, Clostridium bacteria are less acid-tolerant than Acetobacter. Even the most acid-tolerant Clostridium strains can produce vinegar of only a few per cent acetic acid, compared to Acetobacter strains that can produce vinegar of up to 20% acetic acid. At present, it remains more cost-effective to produce vinegar using Acetobacter than to produce it using Clostridium and then concentrating it. As a result, although acetogenic bacteria have been known since 1940, their industrial use remains confined to a few niche applications.
# Applications
Acetic acid is a chemical reagent for the production of chemical compounds. The largest single use of acetic acid is in the production of vinyl acetate monomer, closely followed by acetic anhydride and ester production. The volume of acetic acid used in vinegar is comparatively small.
## Vinyl acetate monomer
The major use of acetic acid is for the production of vinyl acetate monomer (VAM). This application consumes approximately 40% to 45% of the world's production of acetic acid. The reaction is of ethylene and acetic acid with oxygen over a palladium catalyst.
Vinyl acetate can be polymerized to polyvinyl acetate or to other polymers, which are applied in paints and adhesives.
## Ester production
The major esters of acetic acid are commonly used solvents for inks, paints and coatings. The esters include ethyl acetate, n-butyl acetate, isobutyl acetate, and propyl acetate. They are typically produced by catalysed reaction from acetic acid and the corresponding alcohol.
: H3C-COOH + HO-R → H3C-CO-O-R + H2O, where R = a general alkyl group
Most acetate esters, however, are produced from acetaldehyde using the Tishchenko reaction. Additionally, ether acetates are used as solvents for nitrocellulose, acrylic lacquers, varnish removers and wood stains. First glycol monoethers are produced from ethylene oxide or propylene oxide with alcohol, which are then esterified with acetic acid. The three major products are ethylene glycol monoethyl ether acetate (EEA), ethylene glycol monobutyl ether acetate (EBA), and propylene glycol monomethyl ether acetate (PMA). This application consumes about 15% to 20% of worldwide acetic acid. Ether acetates, for example EEA, have been shown to be harmful to human reproduction.
## Acetic anhydride
The condensation product of two molecules of acetic acid is acetic anhydride. The worldwide production of acetic anhydride is a major application, and uses approximately 25% to 30% of the global production of acetic acid. Acetic anhydride may be produced directly by methanol carbonylation bypassing the acid, and Cativa plants can be adapted for anhydride production.
Acetic anhydride is a strong acetylation agent. As such, its major application is for cellulose acetate, a synthetic textile also used for photographic film. Acetic anhydride is also a reagent for the production of aspirin, heroin, and other compounds.
## Vinegar
In the form of vinegar, acetic acid solutions (typically 5% to 18% acetic acid, with the percentage usually calculated by mass) are used directly as a condiment, and also in the pickling of vegetables and other foodstuffs. Table vinegar tends to be more diluted (5% to 8% acetic acid), while commercial food pickling generally employs more concentrated solutions. The amount of acetic acid used as vinegar on a worldwide scale is not large, but historically, this is by far the oldest and most well-known application.
## Use as solvent
Glacial acetic acid is an excellent polar protic solvent, as noted above. It is frequently used as a solvent for recrystallization to purify organic compounds. Pure molten acetic acid is used as a solvent in the production of terephthalic acid (TPA), the raw material for polyethylene terephthalate (PET). Although currently accounting for 5%–10% of acetic acid use worldwide, this specific application is expected to grow significantly in the next decade, as PET production increases.
Acetic acid is often used as a solvent for reactions involving carbocations, such as Friedel-Crafts alkylation. For example, one stage in the commercial manufacture of synthetic camphor involves a Wagner-Meerwein rearrangement of camphene to isobornyl acetate; here acetic acid acts both as a solvent and as a nucleophile to trap the rearranged carbocation. Acetic acid is the solvent of choice when reducing an aryl nitro-group to an aniline using palladium-on-carbon.
Glacial acetic acid is used in analytical chemistry for the estimation of weakly alkaline substances such as organic amides. Glacial acetic acid is a much weaker base than water, so the amide behaves as a strong base in this medium. It then can be titrated using a solution in glacial acetic acid of a very strong acid, such as perchloric acid.
## Other applications
Dilute solutions of acetic acids are also used for their mild acidity. Examples in the household environment include the use in a stop bath during the development of photographic films, and in descaling agents to remove limescale from taps and kettles. The acidity is also used for treating the sting of the box jellyfish by disabling the stinging cells of the jellyfish, preventing serious injury or death if applied immediately, and for treating outer ear infections in people in preparations such as Vosol. Equivalently, acetic acid is used as a spray-on preservative for livestock silage, to discourage bacterial and fungal growth. Glacial acetic acid is also used as a wart and verruca remover.
Organic or inorganic salts are produced from acetic acid, including:
- Sodium acetate, used in the textile industry and as a food preservative (E262).
- Copper(II) acetate, used as a pigment and a fungicide.
- Aluminium acetate and iron(II) acetate—used as mordants for dyes.
- Palladium(II) acetate, used as a catalyst for organic coupling reactions such as the Heck reaction.
- Silver acetate, used as a pesticide.
Substituted acetic acids produced include:
- Monochloroacetic acid (MCA), dichloroacetic acid (considered a by-product), and trichloroacetic acid. MCA is used in the manufacture of indigo dye.
- Bromoacetic acid, which is esterified to produce the reagent ethyl bromoacetate.
- Trifluoroacetic acid, which is a common reagent in organic synthesis.
Amounts of acetic acid used in these other applications together (apart from TPA) account for another 5%–10% of acetic acid use worldwide. These applications are, however, not expected to grow as much as TPA production.
# Safety
Concentrated acetic acid is corrosive and must therefore be handled with appropriate care, since it can cause skin burns, permanent eye damage, and irritation to the mucous membranes. These burns or blisters may not appear until hours after exposure. Latex gloves offer no protection, so specially resistant gloves, such as those made of nitrile rubber, should be worn when handling the compound. Concentrated acetic acid can be ignited with difficulty in the laboratory. It becomes a flammable risk if the ambient temperature exceeds 39 °C (102 °F), and can form explosive mixtures with air above this temperature (explosive limits: 5.4%–16%).
The hazards of solutions of acetic acid depend on the concentration. The following table lists the EU classification of acetic acid solutions:
Solutions at more than 25% acetic acid are handled in a fume hood because of the pungent, corrosive vapour. Dilute acetic acid, in the form of vinegar, is harmless. However, ingestion of stronger solutions is dangerous to human and animal life. It can cause severe damage to the digestive system, and a potentially lethal change in the acidity of the blood.
Due to incompatibilities, it is recommended to keep acetic acid away from chromic acid, ethylene glycol, nitric acid, perchloric acid, permanganates, peroxides and hydroxyls. | https://www.wikidoc.org/index.php/Acetic | |
a94688dcc632b231f7ba4d9d85513b4ba4f23c99 | wikidoc | Acidophilus | Acidophilus
Acidophilus is a general name for a group of probiotics, often added to milk or sold as a capsule, which contains one or more of the following bacteria which aid in digestion: -
- Lactobacillus acidophilus (A)
- Lactobacillus casei (C)
- Lactobacillus bulgaricus (L)
- Bifidobacterium bifidum (B)
- Streptococcus thermophilus
Only L. acidophilus is the true acidophilus strain, but many producers (mainly in the US) use it as a more generic name for mixtures of bacteria, one of which is L. acidophilus.
Acidophilus can be found in some quality yogurts and other traditional foods naturally.
See the individual bacteria and the link on probiotics for more detailed information. | Acidophilus
Acidophilus is a general name for a group of probiotics, often added to milk or sold as a capsule, which contains one or more of the following bacteria which aid in digestion: -
- Lactobacillus acidophilus (A)
- Lactobacillus casei (C)
- Lactobacillus bulgaricus (L)
- Bifidobacterium bifidum (B)
- Streptococcus thermophilus
Only L. acidophilus is the true acidophilus strain, but many producers (mainly in the US) use it as a more generic name for mixtures of bacteria, one of which is L. acidophilus.
Acidophilus can be found in some quality yogurts and other traditional foods naturally.[citation needed]
See the individual bacteria and the link on probiotics for more detailed information. | https://www.wikidoc.org/index.php/Acidophilus | |
115bd909f7634b0ae7589ab3d17745df0109b2a9 | wikidoc | Rabeprazole | Rabeprazole
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# Overview
Rabeprazole is a proton-pump inhibitor (PPI) that is FDA approved for the treatment of Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers, Helicobacter pylori Eradication, Pathological Hypersecretory Conditions including Zollinger-Ellison Syndrome. Common adverse reactions include abdominal pain, headache, diarrhoea, nausea, vomiting, flatulence, infection and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Healing of Erosive or Ulcerative GERD in Adults
- Rabeprazole is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole may be considered.
- Maintenance of Healing of Erosive or Ulcerative GERD in Adults
- Rabeprazole is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.
- Treatment of Symptomatic GERD in Adults
- Rabeprazole is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks.
- Healing of Duodenal Ulcers in Adults
- Rabeprazole is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.
- Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults
- Rabeprazole, in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
- In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted
- Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults
- Rabeprazole is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
- Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older
- Rabeprazole is indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.
- Healing of Erosive or Ulcerative GERD in Adults
- The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily for four to eight weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole may be considered.
- Maintenance of Healing of Erosive or Ulcerative GERD in Adults
- The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily. Controlled studies do not extend beyond 12 months.
- Treatment of Symptomatic GERD in Adults
- The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily for 4 weeks. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered.
- Healing of Duodenal Ulcers in Adults
The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily after the morning meal for a period up to four weeks. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.
- Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults
- Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults
- The dosage of Rabeprazole in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with Rabeprazole for up to one year.
- Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older
- The recommended oral dose for adolescents 12 years of age and older is one 20 mg Delayed-Release Tablet once daily for up to 8 weeks
- Elderly, Renal, and Hepatic Impaired Patients
- No dosage adjustment is necessary in elderly patients, in patients with renal disease, or in patients with mild to moderate hepatic impairment.
- Administration of rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.
- Delayed-Release Tablets: 20 mg
- Delayed-Release Capsules: 5 mg and 10 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rabeprazole in adult patients.
### Non–Guideline-Supported Use
- Gastric ulcer
- Helicobacter pylori gastrointestinal tract infection - Peptic ulcer disease, Quadruple therapy
- Indigestion
- Laryngopharyngeal reflux
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
- Rabeprazole is indicated for treatment of GERD in children 1 to 11 years of age for up to 12 weeks.
- Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
- The recommended dosage of Rabeprazole for pediatric patients 1 to 11 years of age by body weight is:
- Less than 15 kg: 5 mg once daily for up to 12 weeks with the option to increase to 10 mg if inadequate response.
- 15 kg or more: 10 mg once daily for up to 12 weeks
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rabeprazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rabeprazole in pediatric patients.
# Contraindications
- Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria
# Warnings
- Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
- Patients with healed GERD were treated for up to 40 months with rabeprazole and monitored with serial gastric biopsies. Patients without H. pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with H. pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum. Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable. Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable. At baseline, 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum. At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum. Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.
- Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
- Acute interstitial nephritis has been observed in patients taking PPIs including Rabeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Rabeprazole if acute interstitial nephritis develops.
- Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
- Published observational studies suggest that PPI therapy like Rabeprazole may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
- Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with ACIPHEX, refer to Warnings and Precautions sections of those package inserts.
- Several published observational studies in adults suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.
- Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
- For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
- Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients
# Adverse Reactions
## Clinical Trials Experience
### Clinical Studies Experience
- The data described below reflect exposure to Rabeprazole in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in adult patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers, and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male: 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian, and 5% other. Most patients received either 10 mg, 20 mg, or 40 mg/day of Rabeprazole.
- An analysis of adverse reactions appearing in ≥2% of Rabeprazole patients (n=1064), and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions:
- pain (3% vs. 1%)
- pharyngitis (3% vs. 2%)
- flatulence (3% vs. 1%)
- infection (2% vs. 1%)
- constipation (2% vs. 1%)
- Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to rabeprazole for 6 months while at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of Rabeprazole, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
- The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies.
- Other adverse reactions seen in controlled clinical trials, which do not meet the above criteria (≥2% of ACIPHEX-treated patients and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following:
- headache
- abdominal pain
- diarrhea
- dry mouth
- dizziness
- peripheral edema
- hepatic enzyme increase
- hepatitis
- hepatic encephalopathy
- myalgia
- arthralgia
- Combination Treatment with Amoxicillin and Clarithromycin
- In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.
- No clinically significant laboratory abnormalities particular to the drug combinations were observed.
- In a multicenter, open-label study of adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to ACIPHEX that occurred in ≥2% of 111 patients were:
- headache (9.9%)
- diarrhea (4.5%)
- nausea (4.5%)
- vomiting (3.6%)
- abdominal pain (3.6%)
- The related reported adverse reactions that occurred in ≥2% of patients were:
- headache (5.4%)
- nausea (1.8%)
- There were no adverse reactions reported in this study that were not previously observed in adults
- In a two-part, randomized, multicenter, double-blind, parallel-group study, 127 pediatric patients 1 to 11 years of age with endoscopically proven GERD received either 5 mg or 10 mg (<15 kg body weight) or 10 mg or 20 mg (≥15 kg body weight) rabeprazole. In this study, some patients were exposed to rabeprazole for 36 weeks. Adverse reactions that occurred in ≥5% of patients included:
- abdominal pain (5%)
- diarrhea (5%)
- headache (5%)
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Rabeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- sudden death
- coma
- hyperammonemia
- jaundice
- rhabdomyolysis
- disorientation
- delirium
- anaphylaxis
- angioedema
- bullous and other drug eruptions of the skin
- severe dermatologic reactions, including toxic epidermal necrolysis (some fatal)
- Stevens-Johnson syndrome
- erythema multiforme
- interstitial pneumonia
- interstitial nephritis
- TSH elevations
- bone fractures
- hypomagnesemia
- Clostridium difficile associated diarrhea
- agranulocytosis
- hemolytic anemia
- leukopenia
- pancytopenia
- thrombocytopenia
- Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.
# Drug Interactions
### Drugs Metabolized by CYP450
- Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.
### Warfarin
- There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
### Cyclosporine
- In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.
### Compounds Dependent on Gastric pH for Absorption
- Due to its effects on gastric acid secretion, rabeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with Rabeprazole.
- Concomitant treatment with rabeprazole (20 mg daily) and ketoconazole in healthy subjects decreased the bioavailability of ketoconazole by 30% and increased the AUC and Cmax for digoxin by 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
- Concomitant use of atazanavir and PPIs is not recommended. Co-administration of atazanavir with PPIs is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
- Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use ACIPHEX with caution in transplant patients receiving MMF.
### Drugs Metabolized by CYP2C19
In a clinical study in Japan evaluating rabeprazole in adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.
### Combined Administration with Clarithromycin
Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.
- Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs
### Methotrexate
- Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.
### Clopidogrel
- Concomitant administration of rabeprazole and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Rabeprazole.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies with Rabeprazole in pregnant women. No evidence of teratogenicity was seen in animal reproduction studies with rabeprazole at 13 and 8 times the human exposure at the recommended dose for GERD, in rats and rabbits, respectively. Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation. Because of these findings, Rabeprazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Embryo-fetal developmental studies have been performed in rats at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11.8 µghr/mL, about 13 times the human exposure at the recommended oral dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 µghr/mL, about 8 times the human exposure at the recommended oral dose for GERD) and have revealed no evidence of harm to the fetus due to rabeprazole.
- Administration of rabeprazole to rats in late gestation and during lactation at an oral dose of 400 mg/kg/day (about 195 times the human oral dose based on mg/m2) resulted in decreases in body weight gain of the pups.
- A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with a different PPI at about 3.4 to 57 times an oral human dose on a body surface area basis. Decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity were noted at doses of this PPI equal to or greater than 3.4 times an oral human dose on a body surface area basis. Physeal dysplasia in the femur was also observed in offspring after in utero and lactational exposure to the PPI at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis. Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when the PPI was administered at oral doses of 3.4 to 57 times an oral human dose on a body surface area basis. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rabeprazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rabeprazole during labor and delivery.
### Nursing Mothers
- It is not known if Rabeprazole is excreted in human milk; however, rabeprazole is present in rat milk. Because many drugs are excreted in milk, caution should be exercised when Rabeprazole is administered to a nursing woman.
### Pediatric Use
- In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD, were randomized and treated with either Rabeprazole 10 mg or Rabeprazole 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse event profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.
- The use of Rabeprazole for treatment of GERD in pediatric patients 1 to 11 years of age is supported by a randomized, multicenter, double-blind clinical trial which evaluated two dose levels of rabeprazole in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment. Dosing was determined by body weight: Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg and those weighing 15.0 kg or more received 10 or 20 mg of ACIPHEX Sprinkle daily. After 12 weeks of rabeprazole treatment, 81% of patients demonstrated esophageal mucosal healing on endoscopic assessment. In patients who had esophageal mucosal healing at 12 weeks and elected to continue for 24 more weeks of rabeprazole, 90% retained esophageal mucosal healing at 36 weeks. No prespecified formal hypothesis testing for evaluation of efficacy was conducted. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. There were no adverse reactions reported in this study that were not previously observed in adolescents or adults.
### Symptomatic GERD in Infants 1 to 11 Months of Age
- Studies conducted do not support the use of Rabeprazole for the treatment of GERD in pediatric patients younger than 1 year of age.
- In a randomized, multicenter, placebo-controlled withdrawal trial, infants 1 to 11 months of age with a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD, were treated up to 8 weeks in two treatment periods. In the first treatment period (open-label), 344 infants received 10 mg of Rabeprazole for up to 3 weeks. Infants with clinical response were then eligible to enter the second treatment period, which was double-blind and randomized. Two hundred sixty-eight infants were randomized to receive either placebo or 5 mg or 10 mg Rabeprazole.
- This study did not demonstrate efficacy based on assessment of frequency of regurgitation and weight-for-age Z-score. Adverse reactions that occurred in ≥5% of patients in any treatment group and with a higher rate than placebo included pyrexia (7%) and increased serum gastrin levels (5%). There were no adverse reactions reported in this study that were not previously observed in adolescents and adults.
### Neonates <1 Month and Preterm Infants <44 Weeks Corrected Gestational Age
- Use of Rabeprazole in neonates is strongly discouraged at this time for the treatment of GERD, based on the risk of prolonged acid suppression and lack of demonstrated safety and effectiveness in neonates.
- Based on population pharmacokinetic analysis, the median (range) for the apparent clearance (CL/F) was 1.05 L/h (0.0543-3.44 L/h) in neonates and 4.46 L/h (0.822-12.4 L/h) in patients 1 to 11 months of age following once daily administration of oral Rabeprazole.
### Geriatic Use
- Of the total number of subjects in clinical studies of Rabeprazole, 19% were 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
- Duodenal ulcer and erosive esophagitis healing rates in women are similar to those in men. Adverse reactions and laboratory test abnormalities in women occurred at rates similar to those in men.
### Race
There is no FDA guidance on the use of Rabeprazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rabeprazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rabeprazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rabeprazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rabeprazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### Monitoring
- Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
- For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
# IV Compatibility
There is limited information regarding IV Compatibility of Rabeprazole in the drug label.
# Overdosage
- Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. There has been no experience with large overdoses with rabeprazole. Seven reports of accidental overdosage with rabeprazole have been received. The maximum reported overdose was 80 mg. There were no clinical signs or symptoms associated with any reported overdose. Patients with Zollinger-Ellison syndrome have been treated with up to 120 mg rabeprazole QD. No specific antidote for rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
- Single oral doses of rabeprazole at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position, and convulsion in mice and rats and watery diarrhea, tremor, convulsion, and coma in dogs.
# Pharmacology
## Mechanism of Action
- Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.
- In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.
## Structure
- The active ingredient in ACIPHEX (rabeprazole sodium) Delayed-Release Tablets and in ACIPHEX Sprinkle (rabeprazole sodium) Delayed-Release Capsules is rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2--methyl]sulfinyl]-1H-benzimidazole sodium salt. It has an empirical formula of C18H20N3NaO3S and a molecular weight of 381.42. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural figure is:
## Pharmacodynamics
- The antisecretory effect begins within one hour after oral administration of 20 mg Rabeprazole. The median inhibitory effect of Rabeprazole on 24-hour gastric acidity is 88% of maximal after the first dose. Rabeprazole 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H+, K+ATPase.
- Compared to placebo, Rabeprazole, 10 mg, 20 mg, and 40 mg, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.
- After administration of 20 mg Rabeprazole Tablets once daily for eight days, the mean percent of time that gastric pH>3 or gastric pH>4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg Rabeprazole Tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:
- In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, Rabeprazole 20 mg and 40 mg Tablets per day decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that esophageal pH4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving Rabeprazole 20 mg and in 100% of subjects receiving Rabeprazole 40 mg. With Rabeprazole 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.
- In patients given daily doses of Rabeprazole for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease, the median fasting gastrin level increased in a dose-related manner. The group median values stayed within the normal range.
- In a group of subjects treated daily with ACIPHEX 20 mg tablets for 4 weeks, a doubling of mean serum gastrin concentrations was observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. In a study of CYP2C19 genotyped subjects in Japan, poor metabolizers developed statistically significantly higher serum gastrin concentrations than extensive metabolizers.
- Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells, which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females.
- In over 400 patients treated with Rabeprazole Tablets (10 or 20 mg/day) for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton-pump inhibitor. No patient developed the adenomatoid, dysplastic, or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.
- Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with Rabeprazole for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.
- In humans treated with Rabeprazole for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with Rabeprazole and ocular effects.
- The following in vitro data are available but the clinical significance is unknown.
- Rabeprazole sodium, amoxicillin, and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections.
- Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology,1 and minimum inhibitory concentrations (MICs) were determined.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
- larithromycin pretreatment resistance rate (MIC ≥1 μg/mL) to H. pylori was 9% (51/ 560) at baseline in all treatment groups combined. A total of >99% (558/560) of patients had H. pylori isolates, which were considered to be susceptible (MIC ≤0.25 μg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL.
- For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.
- Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.
## Pharmacokinetics
- Rabeprazole Delayed-Release Tablets and Delayed-Release granules in the capsule formulation are enteric-coated to allow rabeprazole sodium, which is acid labile, to pass through the stomach relatively intact.
- After oral administration of 20 mg Rabeprazole tablet, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2.0 to 5.0 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing.
- Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When Rabeprazole Tablets are administered with a high fat meal, Tmax is variable, which concomitant food intake may delay the absorption up to 4 hours or longer. However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus Rabeprazole Tablets may be taken without regard to timing of meals.
- After oral administration to healthy adults of 10 mg Rabeprazole granules sprinkled on applesauce under fasting condition, median time (Tmax) to peak plasma concentrations (Cmax) of rabeprazole was 2.5 hours and ranged 1.0 to 6.5 hours. The plasma half-life of rabeprazole ranges from 1 to 2 hours.
- In healthy adults, a concomitant high fat meal delayed the absorption of rabeprazole from ACIPHEX granules sprinkled on one Tablespoon of applesauce resulting in the median Tmax of 4.5 hours and decreased the Cmax, and AUClast on average by 55% and 33%, respectively. ACIPHEX granules should be taken before a meal.
- When 10 mg ACIPHEX granules administered under fasting conditions to healthy adults on one Tablespoon (15 mL) of applesauce, one Tablespoon (15 mL) of yogurt, or when mixed with a small amount (5 mL) of liquid infant formula, the type of soft food did not significantly affect Tmax, Cmax and AUC of rabeprazole.
- Rabeprazole is 96.3% bound to human plasma proteins.
- Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.
- Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid, its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.
- In 20 healthy elderly subjects administered 20 mg rabeprazole tablet once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration.
- The pharmacokinetics of rabeprazole was studied in pediatric patients with GERD aged up to 16 years in four separate clinical studies.
- The pharmacokinetics of rabeprazole was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received rabeprazole 20 mg tablets once daily for five or seven days. An approximate 40% increase in exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult volunteers.
- In patients with GERD 1 to 11 years of age, following once daily administration of rabeprazole granules at doses from 0.14 to 1 mg/kg, the median time to peak plasma concentration ranged 2-4 hours and the half-life was about 2.5 hour. No appreciable accumulation was noted following 5 days of dosing compared to exposure after a single dose.
- Based on population pharmacokinetic analysis, over the body weight range from 7 to 77.3 kg, the apparent rabeprazole clearance increased from 8.0 to 13.5 L/hr, an increase of 68.8%.
- The mean estimated total exposure, i.e., AUC after a 10 mg dose of ACIPHEX Sprinkle in patients with GERD 1 to 11 years of age, is comparable to a 10 mg dose of Rabeprazole Tablets in adolescents and adults.
- In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC0-∞ values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.
- In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.
- In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.
- In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.
- No information exists on rabeprazole disposition in patients with severe hepatic impairment. Please refer to the Dosage and Administration (2.7) for information on dosage adjustment in patients with hepatic impairment.
- Sixteen healthy volunteers genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg rabeprazole sodium, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and Cmax for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the rabeprazole AUC and Cmax increased by 11% and 34%, respectively, following combined administration. The AUC and Cmax for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns
- Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects, including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with Rabeprazole 20 mg (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when Rabeprazole was coadministered compared to administration of clopidogrel with placebo.
## Nonclinical Toxicology
- In a 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 μghr/mL, which is 1.6 times the human exposure (plasma AUC0-∞ = 0.88 μghr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week carcinogenicity study in p53+/- transgenic mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17 to 24 times the human exposure at the recommended dose for GERD. In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30, and 60 mg/kg/day and females with 5, 15, 30, 60, and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 μghr/mL, which is about 0.1 times the human exposure at the recommended dose for GERD. In male rats, no treatment related tumors were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 μghr/mL (0.2 times the human exposure at the recommended dose for GERD).
- Rabeprazole was positive in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward gene mutation test, and the mouse lymphoma cell (L5178Y/TK+/-) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Rabeprazole was negative in the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.
- Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 μghr/mL, about 10 times the human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats.
- Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25, or 150 mg/kg/day and dogs were dosed at 3, 10, or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.
- When juvenile animals were treated for 28 days with a different PPI at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed.
# Clinical Studies
- In a U.S. multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg or 40 mg ACIPHEX QD. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows:
- In addition, there was a statistically significant difference in favor of the Rabeprazole 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p≤0.026). All Rabeprazole groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p≤0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all Rabeprazole groups when compared to placebo at both Weeks 4 and 8 (p≤0.007).
- In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, Rabeprazole was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment:
- Rabeprazole 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). Rabeprazole 20 mg once daily was also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.
- The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S. multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of Rabeprazole QD or placebo. As demonstrated in the tables below, Rabeprazole was significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks:
- Two U.S. multicenter, double-blind, placebo-controlled studies were conducted in 316 adult patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.
- The percentage of heartburn free daytime and/or nighttime periods was greater with Rabeprazole 20 mg compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for Rabeprazole 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.
- In addition, the combined analysis of these two studies showed ACIPHEX 20 mg significantly improved other GERD-associated symptoms (regurgitation, belching, and early satiety) by week 4 compared with placebo (all p values < 0.005).
- Rabeprazole 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).
- In a U.S. randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Rabeprazole QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:
- At Weeks 2 and 4, significantly more patients in the ACIPHEX 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the Rabeprazole 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both Rabeprazole groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both Rabeprazole groups compared to placebo at Weeks 2 and 4 (p<0.001).
- An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg Rabeprazole QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between Rabeprazole and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, Rabeprazole was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:
- Rabeprazole and omeprazole were comparable in providing complete resolution of symptoms.
- The U.S. multicenter study was a double-blind, parallel-group comparison of rabeprazole, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin, and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) and those who were symptomatic but without peptic ulcer disease , as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.
- Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with Rabeprazole at doses from 20 to 120 mg for up to 12 months. Rabeprazole produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Rabeprazole also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of Rabeprazole used to treat this small cohort of patients with gastric hypersecretion were well tolerated.
- In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or suspected or endoscopically proven GERD were randomized and treated with either Rabeprazole 10 mg or Rabeprazole 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy.
- The use of ACIPHEX Sprinkle in pediatric patients 1 to 11 years of age is supported by a two-part, multicenter, randomized, double-blind, parallel 2 dose arms clinical trial which was conducted in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment.
- Part 1 was 12 weeks in duration. Patients were randomized to one of two rabeprazole dose levels based on body weight. Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg rabeprazole, and those with body weight ≥15 kg received either 10 or 20 mg of rabeprazole. Part 2 was a 24-week double-blinded extension of Part 1 (on same dose assigned in Part 1). Endoscopic evaluations were performed at 12 weeks (Part 1) and 36 weeks (Part 2) to assess esophageal healing. No prespecified formal hypothesis testing was conducted.
- For Part 1, rates of endoscopic healing were calculated and are shown in Table 14.
- Of the 87 patients with healing in Part 1, 64 patients were enrolled into Part 2. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. Of the 52 patients with available data, healing was observed in 47 (90%) patients at 36 weeks.
# How Supplied
- Rabeprazole 20 mg is supplied as delayed-release light yellow enteric-coated tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side.
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) . Protect from moisture.
- ACIPHEX Sprinkle (5 mg) is supplied as transparent blue and opaque white capsules containing enteric coated granules. Identification and strength (ACX 5mg) are imprinted on the body of the capsule. An arrow (↑) imprint on the capsule cap indicates direction for opening a capsule.
- Bottles of 30 (NDC 13551-205-01)
- ACIPHEX Sprinkle (10 mg) is supplied as transparent yellow and opaque white capsules containing enteric coated granules. Identification and strength (ACX 10mg) are imprinted on the body of the capsule. An arrow (↑) imprint on the capsule cap indicates direction for opening a capsule.
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### How to Take Rabeprazole
- Patients should be cautioned that Rabeprazole Delayed-Release Tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Rabeprazole can be taken with or without food.
- Rabeprazole Sprinkle Delayed-Release Capsules should be opened and the granule contents sprinkled on a small amount of soft food (e.g., apple sauce, fruit, or vegetable based baby food, or yogurt) or empty contents into a small amount of liquid (e.g., infant formula, apple juice, or pediatric electrolyte solution). Food or liquid should be at or below room temperature. The whole dose should be taken within 15 minutes of being sprinkled. The granules should not be chewed or crushed. The dose should be taken 30 minutes before a meal. Do not store mixture for future use.
- Advise patient to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea
# Precautions with Alcohol
- Alcohol-Rabeprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aciphex
# Look-Alike Drug Names
There is limited information regarding Rabeprazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rabeprazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Rabeprazole is a proton-pump inhibitor (PPI) that is FDA approved for the treatment of Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers, Helicobacter pylori Eradication, Pathological Hypersecretory Conditions including Zollinger-Ellison Syndrome. Common adverse reactions include abdominal pain, headache, diarrhoea, nausea, vomiting, flatulence, infection and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Healing of Erosive or Ulcerative GERD in Adults
- Rabeprazole is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole may be considered.
- Maintenance of Healing of Erosive or Ulcerative GERD in Adults
- Rabeprazole is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.
- Treatment of Symptomatic GERD in Adults
- Rabeprazole is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks.
- Healing of Duodenal Ulcers in Adults
- Rabeprazole is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.
- Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults
- Rabeprazole, in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
- In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted
- Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults
- Rabeprazole is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
- Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older
- Rabeprazole is indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.
- Healing of Erosive or Ulcerative GERD in Adults
- The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily for four to eight weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole may be considered.
- Maintenance of Healing of Erosive or Ulcerative GERD in Adults
- The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily. Controlled studies do not extend beyond 12 months.
- Treatment of Symptomatic GERD in Adults
- The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily for 4 weeks. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered.
- Healing of Duodenal Ulcers in Adults
The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily after the morning meal for a period up to four weeks. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.
- Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults
-
- Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults
- The dosage of Rabeprazole in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with Rabeprazole for up to one year.
- Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older
- The recommended oral dose for adolescents 12 years of age and older is one 20 mg Delayed-Release Tablet once daily for up to 8 weeks
- Elderly, Renal, and Hepatic Impaired Patients
- No dosage adjustment is necessary in elderly patients, in patients with renal disease, or in patients with mild to moderate hepatic impairment.
- Administration of rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.
- Delayed-Release Tablets: 20 mg
- Delayed-Release Capsules: 5 mg and 10 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rabeprazole in adult patients.
### Non–Guideline-Supported Use
- Gastric ulcer[1]
- Helicobacter pylori gastrointestinal tract infection - Peptic ulcer disease, Quadruple therapy[2]
- Indigestion[3]
- Laryngopharyngeal reflux[4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
- Rabeprazole is indicated for treatment of GERD in children 1 to 11 years of age for up to 12 weeks.
- Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
- The recommended dosage of Rabeprazole for pediatric patients 1 to 11 years of age by body weight is:
- Less than 15 kg: 5 mg once daily for up to 12 weeks with the option to increase to 10 mg if inadequate response.
- 15 kg or more: 10 mg once daily for up to 12 weeks
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rabeprazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rabeprazole in pediatric patients.
# Contraindications
- Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria
# Warnings
- Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
- Patients with healed GERD were treated for up to 40 months with rabeprazole and monitored with serial gastric biopsies. Patients without H. pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with H. pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum. Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable. Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable. At baseline, 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum. At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum. Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.
- Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
- Acute interstitial nephritis has been observed in patients taking PPIs including Rabeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Rabeprazole if acute interstitial nephritis develops.
- Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
- Published observational studies suggest that PPI therapy like Rabeprazole may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
- Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with ACIPHEX, refer to Warnings and Precautions sections of those package inserts.
- Several published observational studies in adults suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines.
- Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
- For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
- Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients
# Adverse Reactions
## Clinical Trials Experience
### Clinical Studies Experience
- The data described below reflect exposure to Rabeprazole in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in adult patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers, and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male: 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian, and 5% other. Most patients received either 10 mg, 20 mg, or 40 mg/day of Rabeprazole.
- An analysis of adverse reactions appearing in ≥2% of Rabeprazole patients (n=1064), and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions:
- pain (3% vs. 1%)
- pharyngitis (3% vs. 2%)
- flatulence (3% vs. 1%)
- infection (2% vs. 1%)
- constipation (2% vs. 1%)
- Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to rabeprazole for 6 months while at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of Rabeprazole, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
- The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies.
- Other adverse reactions seen in controlled clinical trials, which do not meet the above criteria (≥2% of ACIPHEX-treated patients and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following:
- headache
- abdominal pain
- diarrhea
- dry mouth
- dizziness
- peripheral edema
- hepatic enzyme increase
- hepatitis
- hepatic encephalopathy
- myalgia
- arthralgia
- Combination Treatment with Amoxicillin and Clarithromycin
- In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.
- No clinically significant laboratory abnormalities particular to the drug combinations were observed.
- In a multicenter, open-label study of adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to ACIPHEX that occurred in ≥2% of 111 patients were:
- headache (9.9%)
- diarrhea (4.5%)
- nausea (4.5%)
- vomiting (3.6%)
- abdominal pain (3.6%)
- The related reported adverse reactions that occurred in ≥2% of patients were:
- headache (5.4%)
- nausea (1.8%)
- There were no adverse reactions reported in this study that were not previously observed in adults
- In a two-part, randomized, multicenter, double-blind, parallel-group study, 127 pediatric patients 1 to 11 years of age with endoscopically proven GERD received either 5 mg or 10 mg (<15 kg body weight) or 10 mg or 20 mg (≥15 kg body weight) rabeprazole. In this study, some patients were exposed to rabeprazole for 36 weeks. Adverse reactions that occurred in ≥5% of patients included:
- abdominal pain (5%)
- diarrhea (5%)
- headache (5%)
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Rabeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- sudden death
- coma
- hyperammonemia
- jaundice
- rhabdomyolysis
- disorientation
- delirium
- anaphylaxis
- angioedema
- bullous and other drug eruptions of the skin
- severe dermatologic reactions, including toxic epidermal necrolysis (some fatal)
- Stevens-Johnson syndrome
- erythema multiforme
- interstitial pneumonia
- interstitial nephritis
- TSH elevations
- bone fractures
- hypomagnesemia
- Clostridium difficile associated diarrhea
- agranulocytosis
- hemolytic anemia
- leukopenia
- pancytopenia
- thrombocytopenia
- Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.
# Drug Interactions
### Drugs Metabolized by CYP450
- Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.
### Warfarin
- There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
### Cyclosporine
- In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.
### Compounds Dependent on Gastric pH for Absorption
- Due to its effects on gastric acid secretion, rabeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with Rabeprazole.
- Concomitant treatment with rabeprazole (20 mg daily) and ketoconazole in healthy subjects decreased the bioavailability of ketoconazole by 30% and increased the AUC and Cmax for digoxin by 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
- Concomitant use of atazanavir and PPIs is not recommended. Co-administration of atazanavir with PPIs is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
- Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use ACIPHEX with caution in transplant patients receiving MMF.
### Drugs Metabolized by CYP2C19
In a clinical study in Japan evaluating rabeprazole in adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.
### Combined Administration with Clarithromycin
Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.
- Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs
### Methotrexate
- Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.
### Clopidogrel
- Concomitant administration of rabeprazole and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Rabeprazole.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies with Rabeprazole in pregnant women. No evidence of teratogenicity was seen in animal reproduction studies with rabeprazole at 13 and 8 times the human exposure at the recommended dose for GERD, in rats and rabbits, respectively. Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation. Because of these findings, Rabeprazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Embryo-fetal developmental studies have been performed in rats at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11.8 µg•hr/mL, about 13 times the human exposure at the recommended oral dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 µg•hr/mL, about 8 times the human exposure at the recommended oral dose for GERD) and have revealed no evidence of harm to the fetus due to rabeprazole.
- Administration of rabeprazole to rats in late gestation and during lactation at an oral dose of 400 mg/kg/day (about 195 times the human oral dose based on mg/m2) resulted in decreases in body weight gain of the pups.
- A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with a different PPI at about 3.4 to 57 times an oral human dose on a body surface area basis. Decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity were noted at doses of this PPI equal to or greater than 3.4 times an oral human dose on a body surface area basis. Physeal dysplasia in the femur was also observed in offspring after in utero and lactational exposure to the PPI at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis. Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when the PPI was administered at oral doses of 3.4 to 57 times an oral human dose on a body surface area basis. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rabeprazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rabeprazole during labor and delivery.
### Nursing Mothers
- It is not known if Rabeprazole is excreted in human milk; however, rabeprazole is present in rat milk. Because many drugs are excreted in milk, caution should be exercised when Rabeprazole is administered to a nursing woman.
### Pediatric Use
- In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD, were randomized and treated with either Rabeprazole 10 mg or Rabeprazole 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse event profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.
- The use of Rabeprazole for treatment of GERD in pediatric patients 1 to 11 years of age is supported by a randomized, multicenter, double-blind clinical trial which evaluated two dose levels of rabeprazole in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment. Dosing was determined by body weight: Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg and those weighing 15.0 kg or more received 10 or 20 mg of ACIPHEX Sprinkle daily. After 12 weeks of rabeprazole treatment, 81% of patients demonstrated esophageal mucosal healing on endoscopic assessment. In patients who had esophageal mucosal healing at 12 weeks and elected to continue for 24 more weeks of rabeprazole, 90% retained esophageal mucosal healing at 36 weeks. No prespecified formal hypothesis testing for evaluation of efficacy was conducted. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. There were no adverse reactions reported in this study that were not previously observed in adolescents or adults.
### Symptomatic GERD in Infants 1 to 11 Months of Age
- Studies conducted do not support the use of Rabeprazole for the treatment of GERD in pediatric patients younger than 1 year of age.
- In a randomized, multicenter, placebo-controlled withdrawal trial, infants 1 to 11 months of age with a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD, were treated up to 8 weeks in two treatment periods. In the first treatment period (open-label), 344 infants received 10 mg of Rabeprazole for up to 3 weeks. Infants with clinical response were then eligible to enter the second treatment period, which was double-blind and randomized. Two hundred sixty-eight infants were randomized to receive either placebo or 5 mg or 10 mg Rabeprazole.
- This study did not demonstrate efficacy based on assessment of frequency of regurgitation and weight-for-age Z-score. Adverse reactions that occurred in ≥5% of patients in any treatment group and with a higher rate than placebo included pyrexia (7%) and increased serum gastrin levels (5%). There were no adverse reactions reported in this study that were not previously observed in adolescents and adults.
### Neonates <1 Month and Preterm Infants <44 Weeks Corrected Gestational Age
- Use of Rabeprazole in neonates is strongly discouraged at this time for the treatment of GERD, based on the risk of prolonged acid suppression and lack of demonstrated safety and effectiveness in neonates.
- Based on population pharmacokinetic analysis, the median (range) for the apparent clearance (CL/F) was 1.05 L/h (0.0543-3.44 L/h) in neonates and 4.46 L/h (0.822-12.4 L/h) in patients 1 to 11 months of age following once daily administration of oral Rabeprazole.
### Geriatic Use
- Of the total number of subjects in clinical studies of Rabeprazole, 19% were 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
- Duodenal ulcer and erosive esophagitis healing rates in women are similar to those in men. Adverse reactions and laboratory test abnormalities in women occurred at rates similar to those in men.
### Race
There is no FDA guidance on the use of Rabeprazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rabeprazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rabeprazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rabeprazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rabeprazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
-
### Monitoring
- Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
- For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
# IV Compatibility
There is limited information regarding IV Compatibility of Rabeprazole in the drug label.
# Overdosage
- Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. There has been no experience with large overdoses with rabeprazole. Seven reports of accidental overdosage with rabeprazole have been received. The maximum reported overdose was 80 mg. There were no clinical signs or symptoms associated with any reported overdose. Patients with Zollinger-Ellison syndrome have been treated with up to 120 mg rabeprazole QD. No specific antidote for rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
- Single oral doses of rabeprazole at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position, and convulsion in mice and rats and watery diarrhea, tremor, convulsion, and coma in dogs.
# Pharmacology
## Mechanism of Action
- Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.
- In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.
## Structure
- The active ingredient in ACIPHEX (rabeprazole sodium) Delayed-Release Tablets and in ACIPHEX Sprinkle (rabeprazole sodium) Delayed-Release Capsules is rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2-[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium salt. It has an empirical formula of C18H20N3NaO3S and a molecular weight of 381.42. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural figure is:
## Pharmacodynamics
- The antisecretory effect begins within one hour after oral administration of 20 mg Rabeprazole. The median inhibitory effect of Rabeprazole on 24-hour gastric acidity is 88% of maximal after the first dose. Rabeprazole 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H+, K+ATPase.
- Compared to placebo, Rabeprazole, 10 mg, 20 mg, and 40 mg, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.
- After administration of 20 mg Rabeprazole Tablets once daily for eight days, the mean percent of time that gastric pH>3 or gastric pH>4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg Rabeprazole Tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:
- In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, Rabeprazole 20 mg and 40 mg Tablets per day decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that esophageal pH<4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH>4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving Rabeprazole 20 mg and in 100% of subjects receiving Rabeprazole 40 mg. With Rabeprazole 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.
- In patients given daily doses of Rabeprazole for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease, the median fasting gastrin level increased in a dose-related manner. The group median values stayed within the normal range.
- In a group of subjects treated daily with ACIPHEX 20 mg tablets for 4 weeks, a doubling of mean serum gastrin concentrations was observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. In a study of CYP2C19 genotyped subjects in Japan, poor metabolizers developed statistically significantly higher serum gastrin concentrations than extensive metabolizers.
- Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells, which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females.
- In over 400 patients treated with Rabeprazole Tablets (10 or 20 mg/day) for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton-pump inhibitor. No patient developed the adenomatoid, dysplastic, or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.
- Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with Rabeprazole for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.
- In humans treated with Rabeprazole for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with Rabeprazole and ocular effects.
- The following in vitro data are available but the clinical significance is unknown.
- Rabeprazole sodium, amoxicillin, and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections.
- Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology,1 and minimum inhibitory concentrations (MICs) were determined.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
- larithromycin pretreatment resistance rate (MIC ≥1 μg/mL) to H. pylori was 9% (51/ 560) at baseline in all treatment groups combined. A total of >99% (558/560) of patients had H. pylori isolates, which were considered to be susceptible (MIC ≤0.25 μg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL.
- For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.
- Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.
## Pharmacokinetics
- Rabeprazole Delayed-Release Tablets and Delayed-Release granules in the capsule formulation are enteric-coated to allow rabeprazole sodium, which is acid labile, to pass through the stomach relatively intact.
- After oral administration of 20 mg Rabeprazole tablet, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2.0 to 5.0 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing.
- Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When Rabeprazole Tablets are administered with a high fat meal, Tmax is variable, which concomitant food intake may delay the absorption up to 4 hours or longer. However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus Rabeprazole Tablets may be taken without regard to timing of meals.
- After oral administration to healthy adults of 10 mg Rabeprazole granules sprinkled on applesauce under fasting condition, median time (Tmax) to peak plasma concentrations (Cmax) of rabeprazole was 2.5 hours and ranged 1.0 to 6.5 hours. The plasma half-life of rabeprazole ranges from 1 to 2 hours.
- In healthy adults, a concomitant high fat meal delayed the absorption of rabeprazole from ACIPHEX granules sprinkled on one Tablespoon of applesauce resulting in the median Tmax of 4.5 hours and decreased the Cmax, and AUClast on average by 55% and 33%, respectively. ACIPHEX granules should be taken before a meal.
- When 10 mg ACIPHEX granules administered under fasting conditions to healthy adults on one Tablespoon (15 mL) of applesauce, one Tablespoon (15 mL) of yogurt, or when mixed with a small amount (5 mL) of liquid infant formula, the type of soft food did not significantly affect Tmax, Cmax and AUC of rabeprazole.
- Rabeprazole is 96.3% bound to human plasma proteins.
- Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.
- Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid, its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.
- In 20 healthy elderly subjects administered 20 mg rabeprazole tablet once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration.
- The pharmacokinetics of rabeprazole was studied in pediatric patients with GERD aged up to 16 years in four separate clinical studies.
- The pharmacokinetics of rabeprazole was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received rabeprazole 20 mg tablets once daily for five or seven days. An approximate 40% increase in exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult volunteers.
- In patients with GERD 1 to 11 years of age, following once daily administration of rabeprazole granules at doses from 0.14 to 1 mg/kg, the median time to peak plasma concentration ranged 2-4 hours and the half-life was about 2.5 hour. No appreciable accumulation was noted following 5 days of dosing compared to exposure after a single dose.
- Based on population pharmacokinetic analysis, over the body weight range from 7 to 77.3 kg, the apparent rabeprazole clearance increased from 8.0 to 13.5 L/hr, an increase of 68.8%.
- The mean estimated total exposure, i.e., AUC after a 10 mg dose of ACIPHEX Sprinkle in patients with GERD 1 to 11 years of age, is comparable to a 10 mg dose of Rabeprazole Tablets in adolescents and adults.
- In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC0-∞ values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.
- In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.
- In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.
- In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.
- No information exists on rabeprazole disposition in patients with severe hepatic impairment. Please refer to the Dosage and Administration (2.7) for information on dosage adjustment in patients with hepatic impairment.
- Sixteen healthy volunteers genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg rabeprazole sodium, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and Cmax for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the rabeprazole AUC and Cmax increased by 11% and 34%, respectively, following combined administration. The AUC and Cmax for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns
- Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects, including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with Rabeprazole 20 mg (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when Rabeprazole was coadministered compared to administration of clopidogrel with placebo.
## Nonclinical Toxicology
- In a 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 μg•hr/mL, which is 1.6 times the human exposure (plasma AUC0-∞ = 0.88 μg•hr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week carcinogenicity study in p53+/- transgenic mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17 to 24 times the human exposure at the recommended dose for GERD. In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30, and 60 mg/kg/day and females with 5, 15, 30, 60, and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 μg•hr/mL, which is about 0.1 times the human exposure at the recommended dose for GERD. In male rats, no treatment related tumors were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 μg•hr/mL (0.2 times the human exposure at the recommended dose for GERD).
- Rabeprazole was positive in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward gene mutation test, and the mouse lymphoma cell (L5178Y/TK+/-) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Rabeprazole was negative in the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.
- Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 μg•hr/mL, about 10 times the human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats.
- Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25, or 150 mg/kg/day and dogs were dosed at 3, 10, or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.
- When juvenile animals were treated for 28 days with a different PPI at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed.
# Clinical Studies
- In a U.S. multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg or 40 mg ACIPHEX QD. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows:
- In addition, there was a statistically significant difference in favor of the Rabeprazole 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p≤0.026). All Rabeprazole groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p≤0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all Rabeprazole groups when compared to placebo at both Weeks 4 and 8 (p≤0.007).
- In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, Rabeprazole was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment:
- Rabeprazole 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). Rabeprazole 20 mg once daily was also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.
- The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S. multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of Rabeprazole QD or placebo. As demonstrated in the tables below, Rabeprazole was significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks:
- Two U.S. multicenter, double-blind, placebo-controlled studies were conducted in 316 adult patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.
- The percentage of heartburn free daytime and/or nighttime periods was greater with Rabeprazole 20 mg compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for Rabeprazole 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.
- In addition, the combined analysis of these two studies showed ACIPHEX 20 mg significantly improved other GERD-associated symptoms (regurgitation, belching, and early satiety) by week 4 compared with placebo (all p values < 0.005).
- Rabeprazole 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).
- In a U.S. randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Rabeprazole QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:
- At Weeks 2 and 4, significantly more patients in the ACIPHEX 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the Rabeprazole 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both Rabeprazole groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both Rabeprazole groups compared to placebo at Weeks 2 and 4 (p<0.001).
- An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg Rabeprazole QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between Rabeprazole and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, Rabeprazole was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:
- Rabeprazole and omeprazole were comparable in providing complete resolution of symptoms.
- The U.S. multicenter study was a double-blind, parallel-group comparison of rabeprazole, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin, and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.
- Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with Rabeprazole at doses from 20 to 120 mg for up to 12 months. Rabeprazole produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Rabeprazole also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of Rabeprazole used to treat this small cohort of patients with gastric hypersecretion were well tolerated.
- In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or suspected or endoscopically proven GERD were randomized and treated with either Rabeprazole 10 mg or Rabeprazole 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy.
- The use of ACIPHEX Sprinkle in pediatric patients 1 to 11 years of age is supported by a two-part, multicenter, randomized, double-blind, parallel 2 dose arms clinical trial which was conducted in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment.
- Part 1 was 12 weeks in duration. Patients were randomized to one of two rabeprazole dose levels based on body weight. Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg rabeprazole, and those with body weight ≥15 kg received either 10 or 20 mg of rabeprazole. Part 2 was a 24-week double-blinded extension of Part 1 (on same dose assigned in Part 1). Endoscopic evaluations were performed at 12 weeks (Part 1) and 36 weeks (Part 2) to assess esophageal healing. No prespecified formal hypothesis testing was conducted.
- For Part 1, rates of endoscopic healing were calculated and are shown in Table 14.
- Of the 87 patients with healing in Part 1, 64 patients were enrolled into Part 2. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. Of the 52 patients with available data, healing was observed in 47 (90%) patients at 36 weeks.
# How Supplied
- Rabeprazole 20 mg is supplied as delayed-release light yellow enteric-coated tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side.
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture.
- ACIPHEX Sprinkle (5 mg) is supplied as transparent blue and opaque white capsules containing enteric coated granules. Identification and strength (ACX 5mg) are imprinted on the body of the capsule. An arrow (↑) imprint on the capsule cap indicates direction for opening a capsule.
- Bottles of 30 (NDC 13551-205-01)
- ACIPHEX Sprinkle (10 mg) is supplied as transparent yellow and opaque white capsules containing enteric coated granules. Identification and strength (ACX 10mg) are imprinted on the body of the capsule. An arrow (↑) imprint on the capsule cap indicates direction for opening a capsule.
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### How to Take Rabeprazole
- Patients should be cautioned that Rabeprazole Delayed-Release Tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Rabeprazole can be taken with or without food.
- Rabeprazole Sprinkle Delayed-Release Capsules should be opened and the granule contents sprinkled on a small amount of soft food (e.g., apple sauce, fruit, or vegetable based baby food, or yogurt) or empty contents into a small amount of liquid (e.g., infant formula, apple juice, or pediatric electrolyte solution). Food or liquid should be at or below room temperature. The whole dose should be taken within 15 minutes of being sprinkled. The granules should not be chewed or crushed. The dose should be taken 30 minutes before a meal. Do not store mixture for future use.
- Advise patient to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea
# Precautions with Alcohol
- Alcohol-Rabeprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aciphex[5]
# Look-Alike Drug Names
There is limited information regarding Rabeprazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aciphex | |
fe2361b99eaed908310a83b57a2fba5ddabb308e | wikidoc | Acriflavine | Acriflavine
Acriflavine is a topical antiseptic. It has the form of an orange or brown powder. It may be harmful in the eyes or if inhaled. It is a dye and it stains the skin and may irritate. Commercial preparations are often mixtures with proflavine. It is known under a variety of names.
Acriflavine was developed in 1912 by Paul Ehrlich, a German medical researcher and was used during the First World War against sleeping sickness. It is derived from acridine. The hydrochloride form is more irritating than the base form.
Acriflavine is also used as treatment for external fungal infections of aquarium fish. | Acriflavine
Acriflavine is a topical antiseptic. It has the form of an orange or brown powder. It may be harmful in the eyes or if inhaled. It is a dye and it stains the skin and may irritate. Commercial preparations are often mixtures with proflavine. It is known under a variety of names.
Acriflavine was developed in 1912 by Paul Ehrlich, a German medical researcher and was used during the First World War against sleeping sickness. It is derived from acridine. The hydrochloride form is more irritating than the base form.
Acriflavine is also used as treatment for external fungal infections of aquarium fish. | https://www.wikidoc.org/index.php/Acriflavine | |
6a2824fdf083a70e870360f5753cfc89713d0479 | wikidoc | Acrivastine | Acrivastine
# Overview
Acrivastine is a medication used for the treatment of allergies and hay fever. It is a second-generation H1-receptor antagonist antihistamine (like its base molecule triprolidine) and works by blocking Histamine H1 receptors.
This non-sedating antihistamine is sold under the brand name Benadryl Allergy Relief in the United Kingdom by McNeil Laboratories, not to be confused with Benadryl Once a Day, which is cetirizine and is also sold by McNeil in the UK. It is available as an over-the-counter medication in the UK, also offered with pseudoephedrine under the Benadryl brand
In the U.S., acrivastine is the active ingredient in the Semprex brand. Semprex-D is also acrivastine-based, but contains a decongestant, pseudoephedrine. Semprex-D is marketed in the U.S. by Actient Pharmaceuticals.
# Comparisons with other popular antihistamines
Unlike cetirizine or loratadine, the standard dosage of which is one tablet every day, a single acrivastine tablet may be taken up to three times a day. Not to be taken by over 65's, pregnant women or people with compromised liver or kidney function.
# Pill Images | Acrivastine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Acrivastine is a medication used for the treatment of allergies and hay fever. It is a second-generation H1-receptor antagonist antihistamine (like its base molecule triprolidine) and works by blocking Histamine H1 receptors.
This non-sedating[verification needed] antihistamine is sold under the brand name Benadryl Allergy Relief in the United Kingdom by McNeil Laboratories, not to be confused with Benadryl Once a Day, which is cetirizine and is also sold by McNeil in the UK. It is available as an over-the-counter medication in the UK, also offered with pseudoephedrine under the Benadryl brand
In the U.S., acrivastine is the active ingredient in the Semprex brand. Semprex-D is also acrivastine-based, but contains a decongestant, pseudoephedrine. Semprex-D is marketed in the U.S. by Actient Pharmaceuticals.[1]
# Comparisons with other popular antihistamines
Unlike cetirizine or loratadine, the standard dosage of which is one tablet every day, a single acrivastine tablet may be taken up to three times a day.[2] Not to be taken by over 65's, pregnant women or people with compromised liver or kidney function.
# Pill Images | https://www.wikidoc.org/index.php/Acrivastine | |
ea5428ee044ab18ff6e237ffa358ced9859ab5cc | wikidoc | Acrochordon | Acrochordon
Synonyms and keywords:: Skin tag; pedunculated papilloma; fibroepithelial polyp.
# Overview
An acrochordon (a.k.a. skin tag, pedunculated papilloma or fibroepithelial polyp) is a small benign tumor that forms primarily in areas where the skin forms creases, such as the neck, armpits and groin. They may also occur on the face, usually on the eyelids. Though larger have been seen, they usually range in size from grain of rice to that of a golf ball. The surface of acrochorda may be smooth or irregular in appearance. They are often raised from the surface of the skin on a fleshy stalk called a peduncle. Microscopically, an acrochordon consists of a fibrovascular core, sometimes also with fat cells, covered by an unremarkable epidermis. Since they also contain nerve cells, acrochorda cannot be painlessly removed without anesthesia (usually local).
Skin tags are harmless, although they are sometimes irritated by clothing or jewelery and can interfere with shaving and other routine grooming. Why and how skin tags form is not entirely known, but there are correlations with age and obesity. Some also state that individuals with high stress levels tend to attain more acrochorda then other individuals. However, none of that has been scientifically proven. They are more common in people with diabetes mellitus and in pregnant women. Acrochorda have been reported to have an incidence of 46% in the general population. A genetic component (causation) is thought to exist. Rarely, they can be associated with the Birt-Hogg-Dubé syndrome and Polycystic Ovary Syndrome.
# Treatment
- Cauterization: with an electrolysis instrument
- Cryosurgery (freezing)
- Ligation: cutting off blood supply
- Excision: with a scalpel, or other surgical instrument
Each of these treatments is considered minor surgery, typically performed by a physician in the office. In some jurisdictions, an aesthetician is permitted to remove them with electrology. Since removal of skin tags is considered cosmetic, the procedure may not be covered by health care systems and medical insurance.
# Physical examination
## Gallery
- Acrochordon. Adapted from [
- Acrochordon. Adapted from [
- Acrochordon. Adapted from [ | Acrochordon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords:: Skin tag; pedunculated papilloma; fibroepithelial polyp.
# Overview
An acrochordon (a.k.a. skin tag, pedunculated papilloma or fibroepithelial polyp) is a small benign tumor that forms primarily in areas where the skin forms creases, such as the neck, armpits and groin. They may also occur on the face, usually on the eyelids. Though larger have been seen, they usually range in size from grain of rice to that of a golf ball. The surface of acrochorda may be smooth or irregular in appearance. They are often raised from the surface of the skin on a fleshy stalk called a peduncle. Microscopically, an acrochordon consists of a fibrovascular core, sometimes also with fat cells, covered by an unremarkable epidermis. Since they also contain nerve cells, acrochorda cannot be painlessly removed without anesthesia (usually local).
Skin tags are harmless, although they are sometimes irritated by clothing or jewelery and can interfere with shaving and other routine grooming. Why and how skin tags form is not entirely known, but there are correlations with age and obesity. Some also state that individuals with high stress levels tend to attain more acrochorda then other individuals. However, none of that has been scientifically proven. They are more common in people with diabetes mellitus and in pregnant women. Acrochorda have been reported to have an incidence of 46% in the general population[3]. A genetic component (causation) is thought to exist. Rarely, they can be associated with the Birt-Hogg-Dubé syndrome and Polycystic Ovary Syndrome.
# Treatment
- Cauterization: with an electrolysis instrument
- Cryosurgery (freezing)
- Ligation: cutting off blood supply
- Excision: with a scalpel, or other surgical instrument
Each of these treatments is considered minor surgery, typically performed by a physician in the office. In some jurisdictions, an aesthetician is permitted to remove them with electrology. Since removal of skin tags is considered cosmetic, the procedure may not be covered by health care systems and medical insurance.
# Physical examination
## Gallery
- Acrochordon. Adapted from [http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=10
- Acrochordon. Adapted from [http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=10
- Acrochordon. Adapted from [http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=10
# External links
- Skin Tags Acrochordon
- Skin tags:Information for patients on Wikisurgery
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Acrochordon | |
c1a7272afc0a56c310c0550f205f0448555f419b | wikidoc | Acrospiroma | Acrospiroma
Synonyms and keywords:: Nodular hidradenoma, poroma.
# Overview
Acrospiroma (sometimes alternatively described as poroma) is a term used to refer to a benign adnexal tumor of the apical sweat gland (akral "peripheral" + spiroma "epithelial tumor of sweat gland"). Some authoritative sources use this term as a synonym for poroma, and others use it as a broader designation that includes poroma and hidradenoma. Under the general umbrella of sweat gland tumors derived from the apical portion of the secretory duct, there are several sub-types that are distinct by subtle histologic differences and slightly different clinical presentations. Specific types include:
- poromas
- hidroacanthoma simplex
- dermal duct tumor
- hidradenomas (nodular and clear cell sub-types)
Generally, these tumors can be of either eccrine or apocrine or even mixed-type sweat gland origin. Acrospiroma/poromas were traditionally thought to display purely eccrine differentiation, but it is now accepted that these tumors can be variable. Thus, it is more specific to classify any single tumor as a eccrine/apocrine sub-type of acrospiroma. This is in contrast to sub-types that have shown to be more purely eccrine differentiation, such as dermal duct tumors, hidroacanthoma simplex, or eccrine poromas.
Acrospiromas are by definition benign, with malignant transformation very rare. Surgical excision is usually curative and local recurrences are rare, although malignant tumors may metastasize.
# Physical Examination
## Gallery
### Head
- url = >
- url = >
- url = > | Acrospiroma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords:: Nodular hidradenoma, poroma.
# Overview
Acrospiroma (sometimes alternatively described as poroma) is a term used to refer to a benign adnexal tumor of the apical sweat gland (akral "peripheral" + spiroma "epithelial tumor of sweat gland").[1] Some authoritative sources use this term as a synonym for poroma,[2] and others use it as a broader designation that includes poroma and hidradenoma.[3] Under the general umbrella of sweat gland tumors derived from the apical portion of the secretory duct, there are several sub-types that are distinct by subtle histologic differences and slightly different clinical presentations. Specific types include:
- poromas
- hidroacanthoma simplex
- dermal duct tumor
- hidradenomas (nodular and clear cell sub-types)
Generally, these tumors can be of either eccrine or apocrine or even mixed-type sweat gland origin. Acrospiroma/poromas were traditionally thought to display purely eccrine differentiation, but it is now accepted that these tumors can be variable. Thus, it is more specific to classify any single tumor as a eccrine/apocrine sub-type of acrospiroma. This is in contrast to sub-types that have shown to be more purely eccrine differentiation, such as dermal duct tumors, hidroacanthoma simplex, or eccrine poromas.[4][5]
Acrospiromas are by definition benign, with malignant transformation very rare.[6] Surgical excision is usually curative and local recurrences are rare, although malignant tumors may metastasize.[4]
# Physical Examination
## Gallery
### Head
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=188>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=188>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=188> | https://www.wikidoc.org/index.php/Acrospiroma | |
e0d709c2bae6adc840321302c7db30b162509e0f | wikidoc | Actinomycin | Actinomycin
Actinomycin is any of a class of polypeptide antibiotics isolated from soil bacteria of the genus Streptomyces.
# Mechanism
Actinomycin-D is primarily used as an investigative tool in cell biology to inhibit transcription. It does this by binding DNA at the transcription initiation complex and preventing elongation by RNA polymerase.
As it can bind DNA duplexes, it can also interfere with DNA replication, although other chemicals such as hydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.
# Clinical use
## As chemotherapy
Actinomycin-D is marketed under the trade name Dactinomycin. Actinomycin-D is one of the older chemotherapy drugs which has been used in therapy for many years.
It is a clear, yellow liquid which is administered intravenously and most commonly used in treatment of a variety of cancers, including:
- gestational trophoblastic neoplasia
- Wilms' tumor
- rhabdomyosarcoma
## As an antibiotic
It was the first antibiotic shown to have anti-cancer activity, but is not normally used as such, as it is highly toxic, causing damage to genetic material.
It was the first antibiotic ever isolated by Selman Waksman.
# Research use
Actinomycin-D and its fluorescent derivative, 7-amino-actinomycin D, are used as stains in microscopy and flow cytometry applications. The affinity of these stains compounds for GC-rich regions of DNA strands makes them excellent markers for DNA.
7-amino-actinomycin D (7aad) is used as a DNA stain .7aad binds to single stranded DNA. Therefore it is a useful tool in determining apoptosis and distinguishing between dead cells and live ones. (Source) | Actinomycin
Actinomycin is any of a class of polypeptide antibiotics isolated from soil bacteria of the genus Streptomyces.
# Mechanism
Actinomycin-D is primarily used as an investigative tool in cell biology to inhibit transcription. It does this by binding DNA at the transcription initiation complex and preventing elongation by RNA polymerase.[1]
As it can bind DNA duplexes, it can also interfere with DNA replication, although other chemicals such as hydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.
# Clinical use
## As chemotherapy
Actinomycin-D is marketed under the trade name Dactinomycin. Actinomycin-D is one of the older chemotherapy drugs which has been used in therapy for many years.
It is a clear, yellow liquid which is administered intravenously and most commonly used in treatment of a variety of cancers, including:
- gestational trophoblastic neoplasia[2]
- Wilms' tumor[3]
- rhabdomyosarcoma [4]
## As an antibiotic
It was the first antibiotic shown to have anti-cancer activity, but is not normally used as such, as it is highly toxic, causing damage to genetic material.
It was the first antibiotic ever isolated by Selman Waksman.
# Research use
Actinomycin-D and its fluorescent derivative, 7-amino-actinomycin D, are used as stains in microscopy and flow cytometry applications. The affinity of these stains compounds for GC-rich regions of DNA strands makes them excellent markers for DNA.
7-amino-actinomycin D (7aad) is used as a DNA stain .7aad binds to single stranded DNA. Therefore it is a useful tool in determining apoptosis and distinguishing between dead cells and live ones. (Source) | https://www.wikidoc.org/index.php/Actinomycin | |
7d837c8573941d1f92a702de11047b9cc441d6e3 | wikidoc | Risedronate | Risedronate
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Risedronate is a bisphosphonate that is FDA approved for the treatment of postmenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis and paget’s disease. Common adverse reactions include rash，abdominal pain， constipation，diarrhea，indigestion，nausea，backache，urinary tract infectious disease and influenza-like illness..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Postmenopausal Osteoporosis
- Recommended regimen is:
- 5 mg PO qd
- 35 mg PO once-a-week
- 75 mg PO taken on two consecutive days for a total of two tablets each month
- 150 mg PO taken once-a-month
### Prevention of Postmenopausal Osteoporosis
- Recommended regimen is:
- 5 mg PO qd
- 35 mg PO taken once-a-week
- Alternatively, 75 mg PO taken on two consecutive days for a total of two tablets each month may be considered
- Alternatively, 150 mg PO, taken once-a-month may be considered
### Treatment to Increase Bone Mass in Men with Osteoporosis
- Recommended regimen is:
- 35 mg PO once-a-week
### Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
- Recommended regimen is:
- 5 mg PO qd
### Treatment of Paget’s Disease
- Recommended treatment regimen: 30 mg PO qd for 2 months.
- Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Risedronate in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Risedronate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Actonel is not indicated for use in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Risedronate in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Risedronate in pediatric patients.
# Contraindications
- Actonel is contraindicated in patients with the following conditions:
- Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
- Inability to stand or sit upright for at least 30 minutes
- Hypocalcemia
- Known hypersensitivity to Actonel or any of its excipients. Angioedema, generalized rash and bullous skin reactions, some severe, have been reported.
# Warnings
### Drug Products with the Same Active Ingredient
- Actonel contains the same active ingredient found in Atelvia®. A patient being treated with Atelvia should not receive Actonel.
### Upper Gastrointestinal Adverse Reactions
- Actonel, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Actonel is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
- Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Actonel and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
- The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with Actonel should be used under appropriate supervision.
- There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
### Mineral Metabolism
- Hypocalcemia has been reported in patients taking Actonel. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting Actonel therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated.
### Jaw Osteonecrosis
- Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including Actonel. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
- For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
- Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
### Musculoskeletal Pain
- In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.
### Atypical Subtrochanteric and Diaphyseal Femoral Fractures
- Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
- Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (for example, prednisone) at the time of fracture.
- Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
### Renal Impairment
- Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
### Glucocorticoid-Induced Osteoporosis
- Before initiating Actonel treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.
### Laboratory Test Interactions
- Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Actonel have not been performed.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### Treatment of Postmenopausal Osteoporosis
Daily Dosing
- The safety of Actonel 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to Actonel 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.
- The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the Actonel 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Actonel 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the Actonel 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality.
- Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and Actonel 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10.0% versus 10.8%), dyspepsia (10.6% versus 10.8%), and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the Actonel 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and Actonel 5 mg daily groups.
Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and Actonel 5 mg daily groups were: back pain (26.1% versus 28.0%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%).
- Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with Actonel 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and Actonel 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and Actonel 5 mg once daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with Actonel 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests.
- Endoscopic Findings: In the Actonel clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients between the placebo and treated groups . Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% Actonel).
Once-a-Week Dosing
- The safety of Actonel 35 mg once-a-week in the treatment of Postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing Actonel 5 mg daily and Actonel 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to ACTONEL 5 mg daily and 485 exposed to Actonel 35 mg once-a-week. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.
- The incidence of all-cause mortality was 0.4% in the Actonel 5 mg daily group and 1.0% in the Actonel 35 mg once-a-week group.The incidence of serious adverse events was 7.1% in the Actonel 5 mg daily group and 8.2% in the Actonel 35 mg once-a-week group.The percentage of patients who withdrew from the study due to adverse events was 11.9% in the Actonel 5 mg daily group and 11.5% in the Actonel 35 mg once-a-week group.The overall safety and tolerability profiles of the two dosing regimens were similar.
- Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the Actonel 5 mg daily group and the Actonel 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%).
- Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the Actonel 5 mg daily group and 14.2% of patients in the Actonel 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the Actonel 5 mg daily group and 6.2% of patients in the Actonel 35 mg once-a-week group.
- Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the Actonel 5 mg daily and Actonel 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%).
Monthly Dosing
Two Consecutive Days per Month
- The safety of Actonel 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to Actonel 5 mg daily and 616 were exposed to Actonel 75 mg two consecutive days per month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day.
- The incidence of all-cause mortality was 1.0% for the Actonel 5 mg daily group and 0.5% for the Actonel 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the Actonel 5 mg daily group and 14.4% in the Actonel 75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the Actonel 5 mg daily group and 13.0% in the Actonel 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar.
- Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on Actonel 5 mg daily and 7.6% of patients on Actonel 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0.0% of patients on Actonel 5 mg daily and 0.6% of patients on Actonel 75 mg two consecutive days per month.
- Gastrointestinal Adverse Events: The Actonel 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1.0% versus 0.2%) and diarrhea (1.0% versus 0.3%) compared to the Actonel 5 mg daily group. Most of these events occurred within a few days of dosing.
- Ocular Adverse Events: None of the patients treated with Actonel 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with Actonel 5 mg daily reported uveitis.
- Laboratory Test Findings: When Actonel 5 mg daily and Actonel 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the Actonel 5 mg daily group, Actonel 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3.0%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.
Once-a-Month
- The safety of Actonel 150 mg administered once-a-month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to Actonel 5 mg daily and 650 exposed to Actonel 150 mg once-a-month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 international units of vitamin D supplementation per day.
- The incidence of all-cause mortality was 0.5% for the Actonel 5 mg daily group and 0.0% for the Actonel 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the Actonel 5 mg daily group and 6.2% in the Actonel 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the Actonel 5 mg daily group and 8.6% in the Actonel 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar.
- Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the Actonel 5 mg daily group and 5.2% in the Actonel 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on Actonel 5 mg daily and 1.4% of patients on Actonel 150 mg once-a-month.
- Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with Actonel 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The Actonel 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0.0%) compared to the Actonel 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%).
- Ocular Adverse Events: None of the patients treated with Actonel 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with Actonel 5 mg daily reported iritis.
- Laboratory Test Findings: When Actonel 5 mg daily and Actonel 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the Actonel 5 mg daily regimen, Actonel 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.
### Prevention of Postmenopausal Osteoporosis
Daily Dosing
- The safety of Actonel 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and Actonel-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to Actonel 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to Actonel 5 mg. All women received 1000 mg of elemental calcium per day.
- In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the Actonel 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the Actonel 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the Actonel 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of Actonel 5 mg group.
- In the second trial, the incidence of all-cause mortality was 0.0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the Actonel 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the Actonel 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the Actonel 5 mg group.
Once-a-Week Dosing
- There were no deaths in a 1-year, double-blind, placebo-controlled study of Actonel 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on Actonel reported arthralgia (placebo 7.8%; Actonel 13.9%), myalgia (placebo 2.1%; Actonel 5.1%), and nausea (placebo 4.3%; Actonel 7.3%) than subjects on placebo.
### Treatment to Increase Bone Mass in Men with Osteoporosis
- In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo (N = 93) or Actonel 35 mg once-a-week (N = 191). The overall safety and tolerability profile of Actonel in men with osteoporosis was similar to the adverse events reported in the Actonel Postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; Actonel 35 mg 5%), nephrolithiasis (placebo 0%; Actonel 35 mg 3%), and arrhythmia (placebo 0%; Actonel 35 mg 2%).
### Treatment and Prevention of Glucocorticoid-Induced osteoporosis
- The safety of Actonel 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to Actonel 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day.
- The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the Actonel 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the Actonel 5 mg daily group. The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the Actonel 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the Actonel 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the Actonel 5 mg daily group.
### Treatment of Paget’s Disease
- Actonel has been studied in 392 patients with Paget’s Disease of bone. As in trials of Actonel for other indications, the adverse experiences reported in the Paget’s Disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race.
- The safety of Actonel was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years. The duration of the trial was 540 days, with 61 patients exposed to Actonel and 61 patients exposed to Didronel®. The adverse event profile was similar for Actonel and Didronel: 6.6% (4/61) of patients treated with Actonel 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months. Table 2 lists adverse events reported in greater than or equal to 5% of Actonel-treated patients in Phase 3 Paget's disease trials. Adverse events shown are considered to be possibly or probably causally related in at least one patient.
- Gastrointestinal Adverse Events: During the first year of the study (treatment and non treatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events. The incidence of diarrhea was 19.7% in the Actonel group and 14.8% in the Didronel group; none were serious or resulted in withdrawal.
- Ocular Adverse Events: Three patients who received Actonel 30 mg daily experienced acute iritis in 1 supportive study. All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during Actonel treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.
## Postmarketing Experience
- Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity Reactions
- Hypersensitivity and skin reactions have been reported rarely, including angioedema, generalized rash and bullous skin reactions, some severe.
Gastrointestinal Adverse Events
- Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported.
Musculoskeletal Pain
- Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely.
Eye Inflammation
- Reactions of eye inflammation including iritis and uveitis have been reported rarely.
Jaw Osteonecrosis
- Osteonecrosis of the jaw has been reported rarely.
Pulmonary
- Asthma exacerbations
# Drug Interactions
- No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450).
### Calcium Supplements/Antacids
- Co-administration of Actonel and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of Actonel.
### Hormone Replacement Therapy
- One study of about 500 early postmenopausal women has been conducted to date in which treatment with Actonel 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, Actonel may be used concomitantly with hormone replacement therapy.
### Aspirin/Nonsteroidal Anti-Inflammatory Drugs
- Of over 5700 patients enrolled in the Actonel Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in Actonel-treated patients (24.5%).
### H2 Blockers and Proton Pump Inhibitors (PPIs)
- Of over 5700 patients enrolled in the Actonel Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in Actonel-treated patients.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category C: There are no adequate and well-controlled studies of Actonel in pregnant women. Actonel should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
- Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.
- In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of Actonel is unclear.
- No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.
- Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.
- Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Risedronate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Risedronate during labor and delivery.
### Nursing Mothers
- Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether Actonel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Actonel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Actonel is not indicated for use in pediatric patients.
- The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In Actonel-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.
- The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).
### Geriatic Use
- Of the patients receiving Actonel in postmenopausal osteoporosis studies, 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget’s disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the maleosteoporosis trial, 28% of patients receiving Actonel were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for Actonel compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the Actonel trials, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Risedronate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Risedronate with respect to specific racial populations.
### Renal Impairment
- Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.
### Hepatic Impairment
- No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Risedronate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Risedronate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Risedronate contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind Actonel and reduce absorption of the drug.
- In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.
- Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m2).
# Pharmacology
## Mechanism of Action
- Actonel has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Actonel inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that Actonel treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.
## Structure
- Actonel (risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Actonel tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C7H10NO7P2Na 2.5 H2O. The chemical name of risedronate sodium is bis monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:
- Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.
## Pharmacodynamics
- Actonel treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Actonel to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of Actonel for the treatment of osteoporosis in postmenopausal women, Actonel 5 mg daily and Actonel 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the Actonel 5 mg daily and Actonel 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Actonel 5 mg daily or Actonel 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively. In a 1–year study comparing Actonel 5 mg daily versus Actonel 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively.
Osteoporosis in Men
- In a 2-year study of men with osteoporosis, treatment with Actonel 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; Actonel 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; Actonel 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; Actonel 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase.
Glucocorticoid-Induced Osteoporosis
- Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Actonel decreases bone resorption without directly inhibiting bone formation.
- In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, Actonel 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone-specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy.
Paget’s Disease
- Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
- In pagetic patients treated with Actonel 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption).
## Pharmacokinetics
Absorption
- Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (Tmax) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution.
Food Effect
- The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Actonel is effective when administered at least 30 minutes before breakfast.
Distribution
- The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.
Metabolism
- There is no evidence of systemic metabolism of risedronate.
Excretion
- In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting non renal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%).
Specific Populations
- Pediatric: Actonel is not indicated for use in pediatric patients.
- Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.
- Geriatric: Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.
- Race: Pharmacokinetic differences due to race have not been studied.
- Renal Impairment: Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.
- Hepatic Impairment: No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (less than 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.
- Drug Interactions: No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450)
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice.
Mutagenesis
- Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.
Impairment of Fertility
- In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time.
- Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.
### Animal Toxicology and/or Pharmacology
- Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the 5 mg/day human daily dose.
- In dogs treated with an oral dose approximately 5 times the human daily dose, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose.
- The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg. This indicates that Actonel administered at the therapeutic dose is unlikely to induce osteomalacia.
- Dosing multiples provided above are based on the recommended human dose of 5 mg/day and normalized using body surface area (mg/m2).
# Clinical Studies
### Treatment of Osteoporosis in Postmenopausal Women
- The fracture efficacy of Actonel 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Actonel 5 mg, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Actonel 5 mg, N = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low 25-hydroxyvitamin D3 levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 international units/day.
Effect on Vertebral Fractures
- Fractures of previously un deformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (that is, clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient’s first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Actonel 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 3). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.
Effect on Osteoporosis-Related Nonvertebral Fractures
- In VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related non vertebral fractures. Actonel 5 mg daily significantly reduced the incidence of non vertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies.
Effect on Bone Mineral Density
- The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that Actonel 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 4 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. In both VERT studies (VERT MN and VERT NA), Actonel 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points.
# How Supplied
- Actonel® is available as follows:
- 5 mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other.
- NDC 0430-0471-15 bottle of 30
- 30 mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other.
- NDC 0430-0470-15 bottle of 30
35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other.
NDC 0430-0472-03 dose pack of 4
NDC 0430-0472-07 dose pack of 12
75 mg film-coated, oval, pink tablets with RSN on 1 face and 75 mg on the other.
NDC 0430-0477-02 dose pack of 2
150 mg film-coated, oval, blue tablets with RSN on 1 face and 150 mg on the other.
NDC 0430-0478-01 dose pack of 1
NDC 0430-0478-02 dose pack of 3
## Storage
- Store at controlled room temperature 20° to 25° C (68° to 77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Risedronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Actonel
- Atelvia
# Look-Alike Drug Names
Actonel - Actos
# Drug Shortage Status
# Price | Risedronate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Risedronate is a bisphosphonate that is FDA approved for the treatment of postmenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis and paget’s disease. Common adverse reactions include rash，abdominal pain， constipation，diarrhea，indigestion，nausea，backache，urinary tract infectious disease and influenza-like illness..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Postmenopausal Osteoporosis
- Recommended regimen is:
- 5 mg PO qd
- 35 mg PO once-a-week
- 75 mg PO taken on two consecutive days for a total of two tablets each month
- 150 mg PO taken once-a-month
### Prevention of Postmenopausal Osteoporosis
- Recommended regimen is:
- 5 mg PO qd
- 35 mg PO taken once-a-week
- Alternatively, 75 mg PO taken on two consecutive days for a total of two tablets each month may be considered
- Alternatively, 150 mg PO, taken once-a-month may be considered
### Treatment to Increase Bone Mass in Men with Osteoporosis
- Recommended regimen is:
- 35 mg PO once-a-week
### Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
- Recommended regimen is:
- 5 mg PO qd
### Treatment of Paget’s Disease
- Recommended treatment regimen: 30 mg PO qd for 2 months.
- Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Risedronate in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Risedronate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Actonel is not indicated for use in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Risedronate in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Risedronate in pediatric patients.
# Contraindications
- Actonel is contraindicated in patients with the following conditions:
- Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
- Inability to stand or sit upright for at least 30 minutes
- Hypocalcemia
- Known hypersensitivity to Actonel or any of its excipients. Angioedema, generalized rash and bullous skin reactions, some severe, have been reported.
# Warnings
### Drug Products with the Same Active Ingredient
- Actonel contains the same active ingredient found in Atelvia®. A patient being treated with Atelvia should not receive Actonel.
### Upper Gastrointestinal Adverse Reactions
- Actonel, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Actonel is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
- Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Actonel and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
- The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with Actonel should be used under appropriate supervision.
- There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
### Mineral Metabolism
- Hypocalcemia has been reported in patients taking Actonel. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting Actonel therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated.
### Jaw Osteonecrosis
- Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including Actonel. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
- For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
- Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
### Musculoskeletal Pain
- In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.
### Atypical Subtrochanteric and Diaphyseal Femoral Fractures
- Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
- Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (for example, prednisone) at the time of fracture.
- Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
### Renal Impairment
- Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
### Glucocorticoid-Induced Osteoporosis
- Before initiating Actonel treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.
### Laboratory Test Interactions
- Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Actonel have not been performed.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### Treatment of Postmenopausal Osteoporosis
Daily Dosing
- The safety of Actonel 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to Actonel 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.
- The incidence of all-cause mortality was 2.0% in the placebo group and 1.7% in the Actonel 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Actonel 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the Actonel 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality.
- Gastrointestinal Adverse Events: The incidence of adverse events in the placebo and Actonel 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10.0% versus 10.8%), dyspepsia (10.6% versus 10.8%), and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the Actonel 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and Actonel 5 mg daily groups.
Musculoskeletal Adverse Events: The incidence of adverse events in the placebo and Actonel 5 mg daily groups were: back pain (26.1% versus 28.0%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%), and bone pain (4.8% versus 5.3%).
- Laboratory Test Findings: Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with Actonel 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and Actonel 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, 9 (0.5%) in each treatment arm (placebo and Actonel 5 mg once daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, 3 (0.2%) treated with placebo and 11 (0.6%) treated with Actonel 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests.
- Endoscopic Findings: In the Actonel clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients between the placebo and treated groups [75 (14.5%) placebo; 75 (11.9%) Actonel]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% Actonel).
Once-a-Week Dosing
- The safety of Actonel 35 mg once-a-week in the treatment of Postmenopausal osteoporosis was assessed in a 1-year, double-blind, multicenter study comparing Actonel 5 mg daily and Actonel 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to ACTONEL 5 mg daily and 485 exposed to Actonel 35 mg once-a-week. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.
- The incidence of all-cause mortality was 0.4% in the Actonel 5 mg daily group and 1.0% in the Actonel 35 mg once-a-week group.The incidence of serious adverse events was 7.1% in the Actonel 5 mg daily group and 8.2% in the Actonel 35 mg once-a-week group.The percentage of patients who withdrew from the study due to adverse events was 11.9% in the Actonel 5 mg daily group and 11.5% in the Actonel 35 mg once-a-week group.The overall safety and tolerability profiles of the two dosing regimens were similar.
- Gastrointestinal Adverse Events: The incidence of gastrointestinal adverse events was similar between the Actonel 5 mg daily group and the Actonel 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%), and abdominal pain (7.3% versus 7.6%).
- Musculoskeletal Adverse Events: Arthralgia was reported in 11.5% of patients in the Actonel 5 mg daily group and 14.2% of patients in the Actonel 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the Actonel 5 mg daily group and 6.2% of patients in the Actonel 35 mg once-a-week group.
- Laboratory Test Findings: The mean percent changes from baseline at 12 months were similar between the Actonel 5 mg daily and Actonel 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%).
Monthly Dosing
Two Consecutive Days per Month
- The safety of Actonel 75 mg administered on two consecutive days per month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 86 years. The duration of the trial was two years; 613 patients were exposed to Actonel 5 mg daily and 616 were exposed to Actonel 75 mg two consecutive days per month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus 400 to 800 international units of vitamin D supplementation per day.
- The incidence of all-cause mortality was 1.0% for the Actonel 5 mg daily group and 0.5% for the Actonel 75 mg two consecutive days per month group. The incidence of serious adverse events was 10.8% in the Actonel 5 mg daily group and 14.4% in the Actonel 75 mg two consecutive days per month group. The percentage of patients who withdrew from treatment due to adverse events was 14.2% in the Actonel 5 mg daily group and 13.0% in the Actonel 75 mg two consecutive days per month group. The overall safety and tolerability profiles of the two dosing regimens were similar.
- Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 3.6% of patients on Actonel 5 mg daily and 7.6% of patients on Actonel 75 mg two consecutive days per month. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 5 days of the first dose. Fever or influenza-like illness with onset within the same period were reported by 0.0% of patients on Actonel 5 mg daily and 0.6% of patients on Actonel 75 mg two consecutive days per month.
- Gastrointestinal Adverse Events: The Actonel 75 mg two consecutive days per month group resulted in a higher incidence of discontinuation due to vomiting (1.0% versus 0.2%) and diarrhea (1.0% versus 0.3%) compared to the Actonel 5 mg daily group. Most of these events occurred within a few days of dosing.
- Ocular Adverse Events: None of the patients treated with Actonel 75 mg two consecutive days per month reported ocular inflammation such as uveitis, scleritis, or iritis; 1 patient treated with Actonel 5 mg daily reported uveitis.
- Laboratory Test Findings: When Actonel 5 mg daily and Actonel 75 mg two consecutive days per month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 24 months were 0.2% and 0.8% for serum calcium, -1.9% and -1.3% for phosphate, and -10.4% and -17.2% for PTH, respectively. Compared to the Actonel 5 mg daily group, Actonel 75 mg two consecutive days per month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (4.5% versus 3.0%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.
Once-a-Month
- The safety of Actonel 150 mg administered once-a-month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to Actonel 5 mg daily and 650 exposed to Actonel 150 mg once-a-month. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 international units of vitamin D supplementation per day.
- The incidence of all-cause mortality was 0.5% for the Actonel 5 mg daily group and 0.0% for the Actonel 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the Actonel 5 mg daily group and 6.2% in the Actonel 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the Actonel 5 mg daily group and 8.6% in the Actonel 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar.
- Acute Phase Reactions: Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the Actonel 5 mg daily group and 5.2% in the Actonel 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on Actonel 5 mg daily and 1.4% of patients on Actonel 150 mg once-a-month.
- Gastrointestinal Adverse Events: A greater percentage of patients experienced diarrhea with Actonel 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The Actonel 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0.0%) compared to the Actonel 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%).
- Ocular Adverse Events: None of the patients treated with Actonel 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; 2 patients treated with Actonel 5 mg daily reported iritis.
- Laboratory Test Findings: When Actonel 5 mg daily and Actonel 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the Actonel 5 mg daily regimen, Actonel 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.
### Prevention of Postmenopausal Osteoporosis
Daily Dosing
- The safety of Actonel 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and Actonel-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to Actonel 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to Actonel 5 mg. All women received 1000 mg of elemental calcium per day.
- In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the Actonel 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the Actonel 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the Actonel 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of Actonel 5 mg group.
- In the second trial, the incidence of all-cause mortality was 0.0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the Actonel 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the Actonel 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the Actonel 5 mg group.
Once-a-Week Dosing
- There were no deaths in a 1-year, double-blind, placebo-controlled study of Actonel 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on Actonel reported arthralgia (placebo 7.8%; Actonel 13.9%), myalgia (placebo 2.1%; Actonel 5.1%), and nausea (placebo 4.3%; Actonel 7.3%) than subjects on placebo.
### Treatment to Increase Bone Mass in Men with Osteoporosis
- In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo (N = 93) or Actonel 35 mg once-a-week (N = 191). The overall safety and tolerability profile of Actonel in men with osteoporosis was similar to the adverse events reported in the Actonel Postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; Actonel 35 mg 5%), nephrolithiasis (placebo 0%; Actonel 35 mg 3%), and arrhythmia (placebo 0%; Actonel 35 mg 2%).
### Treatment and Prevention of Glucocorticoid-Induced osteoporosis
- The safety of Actonel 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to Actonel 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day.
- The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the Actonel 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the Actonel 5 mg daily group. The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the Actonel 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the Actonel 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the Actonel 5 mg daily group.
### Treatment of Paget’s Disease
- Actonel has been studied in 392 patients with Paget’s Disease of bone. As in trials of Actonel for other indications, the adverse experiences reported in the Paget’s Disease trials have generally been mild or moderate, have not required discontinuation of treatment, and have not appeared to be related to patient age, gender, or race.
- The safety of Actonel was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years. The duration of the trial was 540 days, with 61 patients exposed to Actonel and 61 patients exposed to Didronel®. The adverse event profile was similar for Actonel and Didronel: 6.6% (4/61) of patients treated with Actonel 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel 400 mg daily for 6 months. Table 2 lists adverse events reported in greater than or equal to 5% of Actonel-treated patients in Phase 3 Paget's disease trials. Adverse events shown are considered to be possibly or probably causally related in at least one patient.
- Gastrointestinal Adverse Events: During the first year of the study (treatment and non treatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events. The incidence of diarrhea was 19.7% in the Actonel group and 14.8% in the Didronel group; none were serious or resulted in withdrawal.
- Ocular Adverse Events: Three patients who received Actonel 30 mg daily experienced acute iritis in 1 supportive study. All 3 patients recovered from their events; however, in 1 of these patients, the event recurred during Actonel treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.
## Postmarketing Experience
- Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity Reactions
- Hypersensitivity and skin reactions have been reported rarely, including angioedema, generalized rash and bullous skin reactions, some severe.
Gastrointestinal Adverse Events
- Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported.
Musculoskeletal Pain
- Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely.
Eye Inflammation
- Reactions of eye inflammation including iritis and uveitis have been reported rarely.
Jaw Osteonecrosis
- Osteonecrosis of the jaw has been reported rarely.
Pulmonary
- Asthma exacerbations
# Drug Interactions
- No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450).
### Calcium Supplements/Antacids
- Co-administration of Actonel and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of Actonel.
### Hormone Replacement Therapy
- One study of about 500 early postmenopausal women has been conducted to date in which treatment with Actonel 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, Actonel may be used concomitantly with hormone replacement therapy.
### Aspirin/Nonsteroidal Anti-Inflammatory Drugs
- Of over 5700 patients enrolled in the Actonel Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in Actonel-treated patients (24.5%).
### H2 Blockers and Proton Pump Inhibitors (PPIs)
- Of over 5700 patients enrolled in the Actonel Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in Actonel-treated patients.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category C: There are no adequate and well-controlled studies of Actonel in pregnant women. Actonel should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
- Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.
- In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of Actonel is unclear.
- No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.
- Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.
- Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Risedronate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Risedronate during labor and delivery.
### Nursing Mothers
- Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether Actonel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Actonel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Actonel is not indicated for use in pediatric patients.
- The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In Actonel-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.
- The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).
### Geriatic Use
- Of the patients receiving Actonel in postmenopausal osteoporosis studies, 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget’s disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the maleosteoporosis trial, 28% of patients receiving Actonel were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for Actonel compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the Actonel trials, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Risedronate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Risedronate with respect to specific racial populations.
### Renal Impairment
- Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.
### Hepatic Impairment
- No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Risedronate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Risedronate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Risedronate contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind Actonel and reduce absorption of the drug.
- In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.
- Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m2).
# Pharmacology
## Mechanism of Action
- Actonel has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Actonel inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that Actonel treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.
## Structure
- Actonel (risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Actonel tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemi-pentahydrate is C7H10NO7P2Na •2.5 H2O. The chemical name of risedronate sodium is [1-hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:
- Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.
## Pharmacodynamics
- Actonel treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Actonel to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of Actonel for the treatment of osteoporosis in postmenopausal women, Actonel 5 mg daily and Actonel 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the Actonel 5 mg daily and Actonel 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Actonel 5 mg daily or Actonel 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively. In a 1–year study comparing Actonel 5 mg daily versus Actonel 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively.
Osteoporosis in Men
- In a 2-year study of men with osteoporosis, treatment with Actonel 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; Actonel 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; Actonel 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; Actonel 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase.
Glucocorticoid-Induced Osteoporosis
- Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Actonel decreases bone resorption without directly inhibiting bone formation.
- In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, Actonel 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone-specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy.
Paget’s Disease
- Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
- In pagetic patients treated with Actonel 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption).
## Pharmacokinetics
Absorption
- Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (Tmax) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution.
Food Effect
- The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Actonel is effective when administered at least 30 minutes before breakfast.
Distribution
- The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.
Metabolism
- There is no evidence of systemic metabolism of risedronate.
Excretion
- In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting non renal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%).
Specific Populations
- Pediatric: Actonel is not indicated for use in pediatric patients.
- Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.
- Geriatric: Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.
- Race: Pharmacokinetic differences due to race have not been studied.
- Renal Impairment: Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.
- Hepatic Impairment: No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (less than 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.
- Drug Interactions: No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450)
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice.
Mutagenesis
- Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.
Impairment of Fertility
- In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time.
- Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.
### Animal Toxicology and/or Pharmacology
- Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the 5 mg/day human daily dose.
- In dogs treated with an oral dose approximately 5 times the human daily dose, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose.
- The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg. This indicates that Actonel administered at the therapeutic dose is unlikely to induce osteomalacia.
- Dosing multiples provided above are based on the recommended human dose of 5 mg/day and normalized using body surface area (mg/m2).
# Clinical Studies
### Treatment of Osteoporosis in Postmenopausal Women
- The fracture efficacy of Actonel 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Actonel 5 mg, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Actonel 5 mg, N = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline BMD levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low 25-hydroxyvitamin D3 levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 international units/day.
Effect on Vertebral Fractures
- Fractures of previously un deformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (that is, clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient’s first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Actonel 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 3). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.
Effect on Osteoporosis-Related Nonvertebral Fractures
- In VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related non vertebral fractures. Actonel 5 mg daily significantly reduced the incidence of non vertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies.
Effect on Bone Mineral Density
- The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that Actonel 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 4 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. In both VERT studies (VERT MN and VERT NA), Actonel 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points.
# How Supplied
- Actonel® is available as follows:
- 5 mg film-coated, oval, yellow tablets with RSN on 1 face and 5 mg on the other.
- NDC 0430-0471-15 bottle of 30
- 30 mg film-coated, oval, white tablets with RSN on 1 face and 30 mg on the other.
- NDC 0430-0470-15 bottle of 30
35 mg film-coated, oval, orange tablets with RSN on 1 face and 35 mg on the other.
NDC 0430-0472-03 dose pack of 4
NDC 0430-0472-07 dose pack of 12
75 mg film-coated, oval, pink tablets with RSN on 1 face and 75 mg on the other.
NDC 0430-0477-02 dose pack of 2
150 mg film-coated, oval, blue tablets with RSN on 1 face and 150 mg on the other.
NDC 0430-0478-01 dose pack of 1
NDC 0430-0478-02 dose pack of 3
## Storage
- Store at controlled room temperature 20° to 25° C (68° to 77° F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Risedronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Actonel
- Atelvia
# Look-Alike Drug Names
Actonel - Actos[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Actonel | |
469fe8dd53cef1b2659e62e677c46b220892ff25 | wikidoc | Acupuncture | Acupuncture
# Overview
Researchers using the protocols of evidence-based medicine have found good evidence that acupuncture is effective in treating nausea and chronic low back pain, and moderate evidence for neck pain and headache. The WHO, the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (NIH), the American Medical Association (AMA) and various government reports have also studied and commented on the efficacy of acupuncture. There is general agreement that acupuncture is at least safe when administered by well-trained practitioners, and that further research is warranted. Though occasionally charged as pseudoscience, Dr. William F. Williams, author of Encyclopedia of Pseudoscience, notes that acupuncture --"once rejected as 'oriental fakery' -- is now (if grudgingly) recognized as engaged in something quite real."
Traditional Chinese medicine's acupuncture theory, although based on empirical observation, predates use of the modern scientific method, and has received various criticisms based on modern scientific thinking. There is no generally-accepted anatomical or histological basis for the existence of acupuncture points or meridians. Acupuncturists tend to perceive TCM concepts in functional rather than structural terms, i.e. as being useful in guiding evaluation and care of patients. As the NIH consensus statement noted: "Despite considerable efforts to understand the anatomy and physiology of the "acupuncture points", the definition and characterization of these points remains controversial. Even more elusive is the basis of some of the key traditional Eastern medical concepts such as the circulation of Qi, the meridian system, and the five phases theory, which are difficult to reconcile with contemporary biomedical information but continue to play an important role in the evaluation of patients and the formulation of treatment in acupuncture." Finally, neuroimaging research suggests that specific acupuncture points have distinct effects on cerebral activity in specific areas that are not otherwise predictable anatomically.
# Traditional theory
Chinese medicine is based on a different paradigm from scientific biomedicine. Its theory holds the following explanation of acupuncture:
Acupuncture treats the human body as a whole that involves several "systems of function" that are in some cases loosely associated with (but not identified on a one-to-one basis with) physical organs. Some systems of function, such as the "triple heater" (San Jiao, also called the "triple burner") have no corresponding physical organ, rather, represents the various jiaos or levels of the ventral body cavity (upper, middle and lower). Disease is understood as a loss of balance between the yin and yang energies, which bears some resemblance to homeostasis among the several systems of function, and treatment of disease is attempted by modifying the activity of one or more systems of function through the activity of needles, pressure, heat, etc. on sensitive parts of the body of small volume traditionally called "acupuncture points" in English, or "xue" (穴, cavities) in Chinese. This is referred to in TCM as treating "patterns of disharmony".
Treatment of acupuncture points may be performed along several layers of pathways, most commonly the twelve primary pathways meridians, located throughout the body. Other pathways include the Eight Extraordinary Pathways Qi Jing Ba Mai, the Luo Vessels, the Divergents and the Sinew Channels. Unaffiliated, or tender points, called "ah shi" (signifying "that's it", "ouch", or "oh yes") are generally used for treatment of local pain. Of the eight extraordinary pathways, only two have acupuncture points of their own. The other six meridians are "activated" by using a master and couple point technique which involves needling the acupuncture points located on the twelve main meridians that correspond to the particular extraordinary pathway. Ten of the primary pathways are named after organs of the body (Heart, Liver, etc.), one is named for the serous membrane that wraps the heart (Heart Protector or Pericardium), the last is the 'three spaces' (San Jiao). The pathways are capitalized to avoid confusion with a physical organ (for example, we write the "Heart meridian" as opposed to the "heart meridian"). The two independent extraordinary pathways Ren Mai and Du Mai are situated on the midline of the anterior and posterior aspects of the trunk and head respectively.
The twelve primary pathways run vertically, bilaterally, and symmetrically and every channel corresponds to and connects internally with one of the twelve Zang Fu ("organs"). This means that there are six yin and six yang channels. There are three yin and three yang channels on each arm, and three yin and three yang on each leg.
The three yin channels of the hand (Lung, Pericardium, and Heart) begin on the chest and travel along the inner surface (mostly the anterior portion) of the arm to the hand.
The three yang channels of the hand (Large intestine, San Jiao, and Small intestine) begin on the hand and travel along the outer surface (mostly the posterior portion) of the arm to the head.
The three [[Yin and yang|yin channels of the foot (Spleen, Liver, and Kidney) begin on the foot and travel along the inner surface (mostly posterior and medial portion) of the leg to the chest or flank.
The three yang channels of the foot (Stomach, Gallbladder, and Bladder) begin on the face, in the region of the eye, and travel down the body and along the outer surface (mostly the anterior and lateral portion) of the leg to the foot.
The movement of qi through each of the twelve channels is comprised of an internal and an external pathway. The external pathway is what is normally shown on an acupuncture chart and it is relatively superficial. All the acupuncture points of a channel lie on its external pathway. The internal pathways are the deep course of the channel where it enters the body cavities and related Zang-Fu organs. The superficial pathways of the twelve channels describe three complete circuits of the body, chest to hands, hands to head, head to feet, feet to chest, etc.
The distribution of qi through the pathways is said to be as follows (the based on the demarcations in TCM's Chinese Clock):
Lung channel of hand taiyin to Large Intestine channel of hand yangming to Stomach channel of foot yangming to Spleen channel of foot taiyin to Heart channel of hand shaoyin to Small Intestine channel of hand taiyang to Bladder channel of foot taiyang to Kidney channel of foot shaoyin to Pericardium channel of hand jueyin to San Jiao channel of hand shaoyang to Gallbladder channel of foot shaoyang to Liver channel of foot jueyin then back to the Lung channel of hand taiyin. Each channel occupies two hours, beginning with the Lung, 3AM-5AM, and coming full circle with the Liver 1AM-3AM.
Chinese medical theory holds that acupuncture works by normalizing the free flow of qi (a difficult-to-translate concept that pervades Chinese philosophy and is commonly translated as "vital energy"), blood and body fluids (jin ye) throughout the body. Pain or illnesses are treated by attempting to remedy local or systemic accumulations or deficiencies. Pain is considered to indicate blockage or stagnation of the flow of qi, blood and/or fluids, and an axiom of the medical literature of acupuncture is "no pain, no blockage; no blockage, no pain". The delicate balance between qi and blood is of primary concern in Chinese medical theory, hence the axiom blood is the mother of qi, and qi is the commander of blood. Both qi and blood work together to move (qi) and to nourish (blood) the body fluids.
Many patients claim to experience the sensations of stimulus known in Chinese as "deqi" ("obtaining the qi" or "arrival of the qi"). This kind of sensation was historically considered to be evidence of effectively locating the desired point. There are some electronic devices now available which will make a noise when what they have been programmed to describe as the "correct" acupuncture point is pressed.
The acupuncturist decides which points to treat by observing and questioning the patient in order to make a diagnosis according to the tradition which he or she utilizes. In TCM, there are four diagnostic methods: inspection, auscultation and olfaction, inquiring, and palpation (Cheng, 1987, ch. 12). Inspection focuses on the face and particularly on the tongue, including analysis of the tongue size, shape, tension, color and coating, and the absence or presence of teeth marks around the edge. Auscultation and olfaction refer, respectively, to listening for particular sounds (such as wheezing) and attending to body odor. Inquiring focuses on the "seven inquiries", which are: chills and fever; perspiration; appetite, thirst and taste; defecation and urination; pain; sleep; and menses and leukorrhea. Palpation includes feeling the body for tender "ashi" points, and palpation of the left and right radial pulses at two levels of pressure (superficial and deep) and three positions Cun, Guan, Chi(immediately proximal to the wrist crease, and one and two fingers' breadth proximally, usually palpated with the index, middle and ring fingers). Other forms of acupuncture employ additional diagnosic techniques. In many forms of classical Chinese acupuncture, as well as Japanese acupuncture, palpation of the muscles and the hara (abdomen) are central to diagnosis.
## TCM perspective on treatment of disease
Although TCM is based on the treatment of "patterns of disharmony" rather than biomedical diagnoses, practitioners familiar with both systems have commented on relationships between the two. A given TCM pattern of disharmony may be reflected in a certain range of biomedical diagnoses: thus, the pattern called Deficiency of Spleen Qi could manifest as chronic fatigue, diarrhea or uterine prolapse. Likewise, a population of patients with a given biomedical diagnosis may have varying TCM patterns. These observations are encapsulated in the TCM aphorism "One disease, many patterns; one pattern, many diseases". (Kaptchuk, 1982)
Classically, in clinical practice, acupuncture treatment is typically highly-individualized and based on philosophical constructs, and subjective and intuitive impressions" and not on controlled scientific research.
## Criticism of TCM theory
TCM theory predates use of the scientific method and has received various criticisms based on scientific reductionist thinking, since there is no physically verifiable anatomical or histological basis for the existence of acupuncture points or meridians.
Felix Mann, founder and past-president of the Medical Acupuncture Society (1959–1980), the first president of the British Medical Acupuncture Society (1980), and the author of the first comprehensive English language acupuncture textbook Acupuncture: The Ancient Chinese Art of Healing' first published in 1962, has stated in his book Reinventing Acupuncture: A New Concept of Ancient Medicine:
and…
Philosopher Robert Todd Carroll deems acupuncture a pseudoscience because it "confuse(s) metaphysical claims with empirical claims". Carroll states that:
A report for CSICOP on pseudoscience in China written by Wallace Sampson and Barry L. Beyerstein said:
George A. Ulett, MD, PhD, Clinical Professor of Psychiatry, University of Missouri School of Medicine states: "Devoid of metaphysical thinking, acupuncture becomes a rather simple technique that can be useful as a nondrug method of pain control." He believes that the traditional Chinese variety is primarily a placebo treatment, but electrical stimulation of about 80 acupuncture points has been proven useful for pain control.
Ted J. Kaptchuk, author of The Web That Has No Weaver, refers to acupuncture as "prescientific." Regarding TCM theory, Kaptchuk states:
According to the NIH consensus statement on acupuncture:
# History
In China, the practice of acupuncture can perhaps be traced as far back as the stone age, with the Bian shi, or sharpened stones.
Stone acupuncture needles dating back to 3000 B.C. have been found by archeologists in Inner Mongolia. Clearer evidence exists from the 1st millennium BCE, and archeological evidence has been identified with the period of the Han dynasty (202 BC–220 AD). Forms of it are also described in the literature of traditional Korean medicine where it is called chimsul. It is also important in Kampo, the traditional medicine system of Japan.
Recent examinations of Ötzi, a 5,000-year-old mummy found in the Alps, have identified over 50 tattoos on his body, some of which are located on acupuncture points that would today be used to treat ailments Ötzi suffered from. Some scientists believe that this is evidence that practices similar to acupuncture were practised elsewhere in Eurasia during the early bronze age. According to an article published in The Lancet by Dorfer et al., "We hypothesised that there might have been a medical system similar to acupuncture (Chinese Zhenjiu: needling and burning) that was practised in Central Europe 5,200 years ago... A treatment modality similar to acupuncture thus appears to have been in use long before its previously known period of use in the medical tradition of ancient China. This raises the possibility of acupuncture having originated in the Eurasian continent at least 2000 years earlier than previously recognised.", .
Acupuncture's origins in China are uncertain. The earliest Chinese medical text that first describes acupuncture is the Yellow Emperor’s Classic of Internal Medicine (History of Acupuncture) Huangdi Neijing, which was compiled around 305–204 B.C. However, the Chinese medical texts (Ma-wang-tui graves, 68 BC) do not mention acupuncture. Some hieroglyphics have been found dating back to 1000 B.C. that may indicate an early use of acupuncture. Bian stones, sharp pointed rocks used to treat diseases in ancient times, have also been discovered in ruins; some scholars believe that the bloodletting for which these stones were likely used presages certain acupuncture techniques.
R.C. Crozier in the book Traditional medicine in modern China (Harvard University Press, Cambridge, 1968) says the early Chinese Communist Party expressed considerable antipathy towards classical forms of Chinese medicine, ridiculing it as superstitious, irrational and backward, and claiming that it conflicted with the Party’s dedication to science as the way of progress. Acupuncture was included in this criticism. Reversing this position, Communist Party Chairman Mao later said that "Chinese medicine and pharmacology are a great treasure house and efforts should be made to explore them and raise them to a higher level."
Representatives were sent out across China to collect information about the theories and practices of Chinese medicine. Traditional Chinese Medicine is the formalized system of Chinese medicine that was created out of this effort. TCM combines the use of acupuncture, Chinese herbal medicine, tui na, and other modalities. After the Cultural Revolution, TCM instruction was incorporated into university medical curricula under the "Three Roads" policy, wherein TCM, biomedicine, and a synthesis of the two would all be encouraged and permitted to develop. After this time, forms of classical Chinese medicine other than TCM were outlawed, and some practitioners left China.
The first forms of acupuncture to reach the United States were brought by non-TCM practitioners -such as Chinese rail road workers- many employing styles that had been handed down in family lineages, or from master to apprentice (collectively known as "Classical Chinese Acupuncture").
In Vietnam, Dr. Van Nghi and colleagues used the classical Chinese medical texts and applied them in clinical conditions without reference to political screening. They rewrote the modern version: Trung E Hoc. Van Nghi was made the first President of the First World Congress of Chinese Medicine at Bejing in 1988 in recognition of his work.
In the 1970s, acupuncture became vogue in America after American visitors to China brought back firsthand reports of patients undergoing major surgery using acupuncture as their sole form of anesthesia. Since then, tens of thousands of treatments are now performed in this country each year for many types of conditions such as back pain, headaches, infertility, stress, and many other illnesses.
# Clinical practice
## Finding a Qualified Practitioner
Health care providers can be a resource for referral to acupuncturists, and some conventional medical practitioners—including physicians and dentists—practice acupuncture. In addition, national acupuncture organizations (which can be found through libraries or Web search engines) may provide referrals to acupuncturists.
- Check a practitioner's credentials. Most states require a license to practice acupuncture; however, education and training standards and requirements for obtaining a license to practice vary from state to state. Although a license does not ensure quality of care, it does indicate that the practitioner meets certain standards regarding the knowledge and use of acupuncture.
- Do not rely on a diagnosis of disease by an acupuncture practitioner who does not have substantial conventional medical training. If you have received a diagnosis from a doctor, you may wish to ask your doctor whether acupuncture might help.
## Methods and Instruments
Most modern acupuncturists use disposable stainless steel needles of fine diameter (0.007" to 0.020", 0.18 mm to 0.51 mm), sterilized with ethylene oxide or by autoclave. These needles are far smaller in diameter (and therefore less painful) than the needles used to give shots, since they do not have to be hollow for purposes of injection. The upper third of these needles is wound with a thicker wire (typically bronze), or covered in plastic, to stiffen the needle and provide a handle for the acupuncturist to grasp while inserting. The size and type of needle used, and the depth of insertion, depend on the acupuncture style being practised.
Warming an acupuncture point, typically by moxibustion (the burning of a combination of herbs, primarily mugwort), is a different treatment than acupuncture itself and is often, but not exclusively, used as a supplemental treatment. The Chinese term zhēn jǐu (針灸), commonly used to refer to acupuncture, comes from zhen meaning "needle", and jiu meaning "moxibustion". Moxibustion is still used in the 21st century to varying degrees among the schools of oriental medicine. For example, one well known technique is to insert the needle at the desired acupuncture point, attach dried moxa to the external end of an acupuncture needle, and then ignite it. The moxa will then smolder for several minutes (depending on the amount adhered to the needle) and conduct heat through the needle to the tissue surrounding the needle in the patient's body. Another common technique is to hold a large glowing stick of moxa over the needles. Moxa is also sometimes burned at the skin surface, usually by applying an ointment to the skin to protect from burns, though burning of the skin is general practice in China.
## An example of acupuncture treatment
In western medicine, vascular headaches (the kind that are accompanied by throbbing veins in the temples) are typically treated with analgesics such as aspirin and/or by the use of agents such as niacin that dilate the affected blood vessels in the scalp, but in acupuncture a common treatment for such headaches is to stimulate the sensitive points that are located roughly in the center of the webs between the thumbs and the palms of the patient, the hé gǔ points. These points are described by acupuncture theory as "targeting the face and head" and are considered to be the most important point when treating disorders affecting the face and head. The patient reclines, and the points on each hand are first sterilized with alcohol, and then thin, disposable needles are inserted to a depth of approximately 3-5 mm until a characteristic "twinge" is felt by the patient, often accompanied by a slight twitching of the area between the thumb and hand. Most patients report a pleasurable "tingling" sensation and feeling of relaxation while the needles are in place. The needles are retained for 15-20 minutes while the patient rests, and then are removed.
In the clinical practice of acupuncturists, patients frequently report one or more of certain kinds of sensation that are associated with this treatment, sensations that are stronger than those that would be felt by a patient not suffering from a vascular headache:
- Extreme sensitivity to pain at the points in the webs of the thumbs.
- In bad headaches, a feeling of nausea that persists for roughly the same period as the stimulation being administered to the webs of the thumbs.
- Simultaneous relief of the headache. (See Zhen Jiu Xue, p. 177f et passim.)
## Indications according to acupuncturists in the West
According to the American Academy of Medical Acupuncture (2004), acupuncture may be considered as a complementary therapy for the conditions in the list below. The conditions labeled with - are also included in the World Health Organization list of acupuncture indications.. These cases, however, are based on clinical experience, and not necessarily on controlled clinical research: furthermore, the inclusion of specific diseases are not meant to indicate the extent of acupuncture's efficacy in treating them.
- Abdominal distention/flatulence*
- Acute and chronic pain control*
- Allergic sinusitis *
- Anesthesia for high-risk patients or patients with previous adverse responses to anesthetics
- Anorexia
- Anxiety, fright, panic*
- Arthritis/arthrosis *
- Atypical chest pain (negative workup)
- Bursitis, tendinitis, carpal tunnel syndrome*
- Certain functional gastrointestinal disorders (nausea and vomiting, esophageal spasm, hyperacidity, irritable bowel) *
- Cervical and lumbar spine syndromes*
- Constipation, diarrhea *
- Cough with contraindications for narcotics
- Drug detoxification *
- Dysmenorrhea, pelvic pain *
- Frozen shoulder *
- Headache (migraine and tension-type), vertigo (Meniere disease), tinnitus *
- Idiopathic palpitations, sinus tachycardia
- In fractures, assisting in pain control, edema, and enhancing healing process
- Muscle spasms, tremors, tics, contractures*
- Neuralgias (trigeminal, herpes zoster, postherpetic pain, other)
- Paresthesias *
- Persistent hiccups*
- Phantom pain
- Plantar fasciitis*
- Post-traumatic and post-operative ileus *
- Premenstrual syndrome
- Selected dermatoses (urticaria, pruritus, eczema, psoriasis)
- Sequelae of stroke syndrome (aphasia, hemiplegia) *
- Seventh nerve palsy
- Severe hyperthermia
- Sprains and contusions
- Temporo-mandibular joint derangement, bruxism *
- Urinary incontinence, retention (neurogenic, spastic, adverse drug effect) *
Additionally, other sources advocate the use of acupuncture for the following conditions:
- Infertility, regarding in vitro fertilization, see Expansions of in vitro fertilization - acupuncture
# Scientific theories and mechanisms of action
Many hypotheses have been proposed to address the physiological mechanisms of action of acupuncture. To date, more than 10,000 scientific research studies have been published on acupuncture as cataloged by the National Library of Medicine database.
## Neurohormonal theory
Pain transmission can also be modulated at many other levels in the brain along the pain pathways, including the periaqueductal gray, thalamus, and the feedback pathways from the cerebral cortex back to the thalamus. Each of these brain structure processes different aspect of the pain — from experiencing emotional pain to the perception of what the pain feels like to the recognition of how harmful the pain is to localizing where the pain is coming from. Pain blockade at these brain locations are often mediated by neurohormones, especially those that bind to the opioid receptors (pain-blockade site). Pain relief by morphine drug (exogenous opioid) is acting on the same opioid receptor (where pain blockade occurs) as endorphins (endogenous opioids) that the brain produces and releases.
Some studies suggest that the Analgesic (pain-killing) action of acupuncture is mediated by stimulating the release of natural endorphins in the brain. This can be proven scientifically by blocking the action of endorphins (or morphine) using a drug called naloxone. When naloxone is administered to the patient, the analgesic effects of morphine can be reversed, causing the patient to feel pain again. When naloxone is administered to an acupunctured patient, the analgesic effect of acupuncture can also be reversed, causing the patient to report an increased level of pain. This demonstrates that the site of action of acupuncture may be mediated through the natural release of endorphins by the brain, which can be reversed by naloxone. Such analgesic effect can also be shown to last more than an hour after acupuncture stimulation by recording the neural activity directly in the thalamus (pain processing site) of the monkey's brain. Furthermore, there is a large overlap between the nervous system and acupuncture trigger points (points of maximum tenderness in myofascial pain syndrome.
The sites of action of acupuncture-induced analgesia are also confirmed to be mediated through the thalamus (where emotional pain/suffering is processed) using modern-day powerful non-invasive fMRI (functional magnetic resonance imaging) and PET (positron emission tomography) brain imaging techniques, and via the feedback pathway from the cerebral cortex (where cognitive feedback signal to the thalamus distinguishing whether the pain is noxious (painful) or innocuous (non-harmful)) using electrophysiological recording of the nerve impulses of neurons directly in the cortex, which shows inhibitory action when acupuncture stimulus was applied.
Recently acupuncture has been shown to increase the nitric oxide levels in treated regions and resulting in increased local blood circulation, an outcome found in other studies. Effects on local inflammation and ischemia have also been previously reported.
## Histological studies
Bonghan Kim proposed that meridians and acupuncture points exist in the form of distinctive anatomical structures in his Bonghan Theory.
## Scientific Method and the Assessment of Chinese Medical Theory and Techniques
### Views of proponents
Criticism of TCM theory hinges on the question of how to assess 'intangible' concerns. There is an assumption that all knowledge can be tested by randomly-controlled double-blind studies, and that anything not susceptible to this method of assessment must be jettisoned as unverifiable. Yet the difficulty is not in the methodology, but rather that the nature of Traditional Chinese Medicine itself makes it difficult to subject it as a whole, or subsets of the medical theory, to this type of assessment.
The theory, practice and techniques of Chinese medicine evolved over many thousands of years, well in advance of a formal articulation of the scientific method. Nevertheless, the principles of the scientific method have been used throughout the development of Chinese medical knowledge. Documentation of developments allowed practitioners to evaluate each other's theoretical and practical hypotheses, and what was shown to be effective and/or consistent with observable phenomena was kept, and the remainder discarded over time.
Chinese medicine is inherently individually applied. Given that the health of the entire individual is taken into account for each patient, any two patients, even with the same diagnosis, will receive different treatments based on their constitutional differences, their pattern of response to treatment, and so on. In addition, each treatment may vary from the previous one, in the same way that a masseur might use strokes in a different order, or different strokes, to treat exactly the same condition, from one treatment to the next.
Thus the very complexity and flexibility of this medical system makes it extremely difficult to run clinical trials – a cohort of many thousands would have to be evaluated in order to even begin to assess any claims made for or against the medicine. Clinical trials are still a valuable exercise, but they are not sufficient to determine conclusively whether either the individual constituents of the medical theory (e.g. acupuncture points), or the medical theory as a whole, are valid.
### Views of critics
One of the major criticisms of studies which purport to find that acupuncture is anything more than a placebo is that most such studies are not (in the view of critics) properly conducted. Many are not double blinded and are not randomized. However, double-blinding is not a trivial issue in acupuncture: since acupuncture is a procedure and not a pill, it is difficult to design studies in which the person providing treatment is blinded as to the treatment being given. The same problem arises in double-blinding procedures used in biomedicine, including virtually all surgical procedures, dentistry, physical therapy, etc.; the 1997 National Institute for Health Consensus Statement notes such issues with regard to sham acupuncture (needling performed superficially a/o at non-acupuncture sites), a technique often used in studies purporting to be double-blinded. See also Criticism of evidence-based medicine. Tonelli, a prominent critic of EBM, argues that complementary and alternative medicine (CAM) cannot be EBM-based unless the definition of evidence is changed. Tonelli also says "the methods of developing knowledge within CAM currently have limitations and are subject to bias and varied interpretation. CAM must develop and defend a rational and coherent method for assessing causality and efficacy, though not necessarily one based on the results of controlled clinical trials."
Some researchers argue that there is no evidence that acupuncture has any affect on the pathogenesis of viruses and microorganisms, or on human physiology, with the exception of the neurological pathways associated with the nerve cells that were stimulated by them. Thus, the most promising clinical application of acupuncture is in the area of pain control.
Some researchers argue that to date there is no conclusive scientific evidence indicating that the procedure has any effectiveness beyond that of a placebo. They argue that studies on acupuncture that meet scientific standards of experimentation have concluded two things: acupuncture is usually more effective than no treatment or a placebo in pill form, and that there is no significant difference in the effectiveness of acupuncture and “sham” acupuncture, which is often used as a control. These researchers therefore conclude that acupuncture's effect is either caused by the tendency of extended, invasive procedures to generate more powerful placebo effects than pills or by the general stimulation of afferent nerve endings at the surface of the skin, causing the release of pain relieving biochemical compounds such as endorphins (this can also be done with jalapeno peppers, electricity, and various other form of stimulation). It may also be a combination of these two effects.
The vast majority of research on acupuncture is conducted by researchers in China, and Ernst et al. argue that there exist major flaws in the design of the experiments, as well as selective reporting of results, and conclude that no conclusions can be drawn from them. Some researchers argue that numerous experimental difficulties have prevented the conclusive establishment of a causative relationship (if it exists) between pain relief and the administration of acupuncture. These include the subjective nature of pain measurement and the pervasive influence of psychological factors such as suggestion, confirmation bias, and the distraction of being poked by a needle. Also, they argue, the tendency of chronic pain to ebb and flow on its own without any external intervention leads people to falsely perceive that the last measure they took before the pain subsided was the cause of the relief. This is a logical fallacy known as post hoc ergo propter hoc.
# Scientific research into efficacy
## Evidence-based medicine
There is scientific agreement that an evidence-based medicine (EBM) framework should be used to assess health outcomes and that systematic reviews with strict protocols are essential. Organisations such as the Cochrane Collaboration and Bandolier publish such reviews.
For low back pain, a Cochrane review (2005) stated:
For nausea and vomiting: The Cochrane review (2006) on the use of the P6 acupoint for the reduction of post-operative nausea and vomiting concluded that "compared with anti emetic prophylaxis, P6 acupoint stimulation seems to reduce the risk of nausea but not vomiting". Cochrane also stated: "Electroacupuncture is effective for first day vomiting after chemotherapy, but trials considering modern antivomiting drugs are needed." Bandolier said "P6 acupressure in two studies showed 52% of patients with control having a success, compared with 75% with P6 acupressure" and that one in five adults, but not children showed reduction in early postoperative nausea. A review published by the Scientific Review of Alternative Medicine, however, argued that at the time of writing (2005) the data "are insufficiently reliable to confirm such an effect".
A 2007 Cochrane Review for the use of acupuncture for neck pain stated:
For headache, Cochrane concluded (2006) that "(o)verall, the existing evidence supports the value of acupuncture for the treatment of idiopathic headaches. However, the quality and amount of evidence are not fully convincing. There is an urgent need for well-planned, large-scale studies to assess the effectiveness and cost-effectiveness of acupuncture under real-life conditions." . Bandolier (1999) states: "There is no evidence from high quality trials that acupuncture is effective for the treatment of migraine and other forms of headache. The trials showing a significant benefit of acupuncture were of dubious methodological quality. Overall, the trials were of poor methodological quality."
For osteoarthritis, Bandolier, commenting on a 1997 review by Edzard Ernst, stated: "There is no evidence that acupuncture is more effective than sham/placebo acupuncture for the relief of joint pain due to osteoarthritis (OA)."
For fibromyalgia, a systematic review of the best 5 randomized controlled trials available found mixed results. Three positive studies, all using electro-acupunture, found short term benefits.
For the following conditions, the Cochrane Collaboration concluded there is insufficient evidence that acupuncture is beneficial, often because of the paucity and poor quality of the research and that further research would be needed to support claims for efficacy:
- Giving up smoking
- Chronic asthma
- Bell's palsy
- Shoulder pain
- Lateral elbow pain
- Acute stroke
- Rheumatoid arthritis
- Depression
- Induction of labour
In practice, EBM does not demand that doctors ignore research outside its "top-tier" criteria .
## Evidence from neuroimaging studies
Acupuncture appears to have distinct effects on cortical activity, as demonstrated by MRI (magnetic resonance imaging) and PET (positron emission tomography). Researchers from the University of Southampton, UK and Purpan Hospital of Toulouse, France, summarize the literature:
- Investigating Acupuncture Using Brain Imaging Techniques: The Current State of Play: George T. Lewith, Peter J. White and Jeremie Pariente. "We have systematically researched and reviewed the literature looking at the effect of acupuncture on brain activation as measured by functional magnetic resonance imaging and positron emission tomography. These studies show that specific and largely predictable areas of brain activation and deactivation occur when considering the traditional Chinese functions attributable to certain specific acupuncture points. For example, points associated with hearing and vision stimulates the visual and auditory cerebral areas respectively."
## NIH consensus statement
According to the National Institutes of Health:
In 1997, the National Institutes of Health (NIH) issued a consensus statement on acupuncture that concluded that
The statement was not a policy statement of the NIH but rather the assessment of a panel convened by the NIH.
The NIH consensus statement said that
and added that
The NIH consensus statement summarized and made a prediction:
The NIH's National Center For Complementary And Alternative Medicine continues to abide by the recommendations of the NIH Consensus Statement .
## American Medical Association statement
In 1997, the following statement was adopted as policy of the American Medical Association (AMA),
an association of medical doctors and medical students, after a report on a number of alternative therapies including acupuncture:
"There is little evidence to confirm the safety or efficacy of most alternative therapies. Much of the information currently known about these therapies makes it clear that many have not been shown to be efficacious. Well-designed, stringently controlled research should be done to evaluate the efficacy of alternative therapies."
## German study
A German study published in the September 2007 issue of the Archives of Internal Medicine found that nearly half of patients treated with acupuncture or a sham treatment felt relief from chronic low back pain over a period of months compared to just nearly a quarter of those receiving a variety of more conventional treatments (drugs, heat, massage, etc.) The greater benefit of the real and sham treatments were not significantly different.
# Safety and risks
Because acupuncture needles penetrate the skin, many forms of acupuncture are invasive procedures, and therefore not without risk. Injuries are rare among patients treated by trained practitioners.
Certain forms of acupuncture such as the Japanese Tōyōhari and Shōnishin often use non-invasive techniques, in which specially-designed needles are rubbed or pressed against the skin. These methods are common in Japanese pediatric use.
## Acupuncture Side Effects and Risks
The U.S. Food and Drug Administration (FDA) regulates acupuncture needles for use by licensed practitioners, requiring that needles be manufactured and labeled according to certain standards. For example, the FDA requires that needles be sterile, nontoxic, and labeled for single use by qualified practitioners only.
Relatively few complications from the use of acupuncture have been reported to the FDA, in light of the millions of people treated each year and the number of acupuncture needles used. Still, complications have resulted from inadequate sterilization of needles and from improper delivery of treatments. Practitioners should use a new set of disposable needles taken from a sealed package for each patient and should swab treatment sites with alcohol or another disinfectant before inserting needles. When not delivered properly, acupuncture can cause serious adverse effects, including infections and punctured organs.
## Common, minor adverse events
A survey by Ernst et al. of over 400 patients receiving over 3500 acupuncture treatments found that the most common adverse effects from acupuncture were:
- Minor bleeding after removal of the needles, seen in roughly 3% of patients. (Holding a cotton ball for about one minute over the site of puncture is usually sufficient to stop the bleeding.)
- Hematoma, seen in about 2% of patients, which manifests as bruises. These usually go away after a few days.
- Dizziness, seen in about 1% of patients. Some patients have a conscious or unconscious fear of needles which can produce dizziness and other symptoms of anxiety. Patients are usually treated lying down in order to reduce likelihood of fainting.
The survey concluded: "Acupuncture has adverse effects, like any therapeutic approach. If it is used according to established safety rules and carefully at appropriate anatomic regions, it is a safe treatment method."
## Other injury
Other risks of injury from the insertion of acupuncture needles include:
- Nerve injury, resulting from the accidental puncture of any nerve.
- Brain damage or stroke, which is possible with very deep needling at the base of the skull.
- Pneumothorax from deep needling into the lung.
- Kidney damage from deep needling in the low back.
- Haemopericardium, or puncture of the protective membrane surrounding the heart, which may occur with needling over a sternal foramen (an undetectable hole in the breastbone which can occur in up to 10% of people).
- Risk of terminating pregnancy with the use of certain acupuncture points that have been shown to stimulate the production of adrenocorticotropic hormone (ACTH) and oxytocin.
These risks are slight and can all be avoided through proper training of acupuncturists. For correct perspective, their risk should be compared to the level of side effects of common drugs and biomedical treatment - see below. Graduates of medical schools and (in the US) accreditated acupuncture schools receive thorough instruction in proper technique so as to avoid these events. (Cf. Cheng, 1987)
## Risks from omitting orthodox medical care
Some doctors believe that receiving any form of alternative medical care without also receiving orthodox western medical care is inherently risky, since undiagnosed disease may go untreated and could worsen. For this reason many acupuncturists and doctors prefer to consider acupuncture a complementary therapy rather than an alternative therapy.
Critics also express concern that unethical or naive practitioners may induce patients to exhaust financial resources by pursuing ineffective treatment. However, many recent public health departments in modern countries have acknowledged the benefits of acupuncture by instituting regulations, ultimately raising the level of medicine practiced in these jurisdictions.
## Safety compared to other treatments
Commenting on the relative safety of acupuncture compared to other treatments, the NIH consensus panel stated that "(a)dverse side effects of acupuncture are extremely low and often lower than conventional treatments." They also stated:
In a Japanese survey of 55,291 acupuncture treatments given over five years by 73 acupuncturists, 99.8% of them were performed with no significant minor adverse effects and zero major adverse incidents (Hitoshi Yamashita, Bac, Hiroshi Tsukayama, BA, Yasuo Tanno, MD, PhD. Kazushi Nishijo, PhD, JAMA). Two combined studies in the UK of 66,229 acupuncture treatments yielded only 134 minor adverse events. (British Medical Journal 2001 Sep 1). The total of 121,520 treatments with acupuncture therapy were given with no major adverse incidents (for comparison, a single such event would have indicated a 0.0008% incidence).
This is in comparison to 2,216,000 serious adverse drug reactions that occurred in hospitals 1994. (Lazarou J, Pomeranz BH, Corey PN., JAMA. 1998 Apr 15;279(15):1200-5.) So to compare indirectly, Acupuncture has a 0.2% chance of causing a minor adverse effect compared to prescription medications having a 6.7% chance of causing a serious adverse event in a hospital setting.
# Legal and political status
Acupuncturists may also practice herbal medicine or tui na, or may be medical acupuncturists, who are trained in allopathic medicine but also practice acupuncture in a simplified form. License is regulated by the state or province in many countries, and often requires passage of a board exam.
## United States
In the United States, acupuncturists are generally referred to by the professional title "Licensed Acupuncturist", abbreviated "L.Ac.". They are also known as Acupuncture Physicians in the state of Florida, and are treated as primary care physicians there. Other states, like Illinois, which are considered conservative, not progressive, in their acupuncture licensing, now allow acupuncturists to practice without a referral from another medical practitioner. Thus, effectively, acupuncturists are recognized as independent physicians in these states as well. The abbreviation "Dipl. Ac." stands for "Diplomate of Acupuncture" and signifies that the holder is board-certified by the National Certification Commission for Acupuncture and Oriental Medicine. Professional degrees are usually at the level of a Master's degree and include "M.Ac." (Master's in Acupuncture), "M.S.Ac." (Master's of Science in Acupuncture), "M.S.O.M" (Master's of Science in Oriental Medicine), and "M.A.O.M." (Master's of Acupuncture and Oriental Medicine). "O.M.D." signifies Doctor of Oriental Medicine, and "C.M.D." signifies Doctor in Chinese Medicine (zhong Yi,中医）; these titles may be used by graduates of Chinese medical schools, or by American graduates of certain postgraduate programs. The O.M.D. and C.M.D. are not recognized by the Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM), which accredits American educational programs in acupuncture. However, the O.M.D. (Doctor of Oriental Medicine) and D.O.M. (Doctor of Oriental Medine) degrees have been approved by some states. Each state regulates the practice of acupuncture within its territory. The ACAOM is currently beginning the process of accrediting the "Doctor of Acupuncture and Oriental Medicine" (DAOM) degree, and this new degree will represent the terminal degree in the field. The Oregon College of Oriental Medicine and Bastyr University were the first two institutions in the United States to offer the DAOM, and it is estimated that within the next ten years the DAOM degree will replace all master's level training programs in the United States.
In the USA, acupuncture is practiced by a variety of healthcare providers. Practitioners who specialize in Acupuncture and Oriental Medicine are usually referred to as "licensed acupuncturists", or L.Ac.'s. Other healthcare providers such as physicians, dentists and chiropractors sometimes also practice acupuncture, though they may often receive less training than L.Ac.'s. L.Ac.'s generally receive from 2500 to 4000 hours of training in Chinese medical theory, acupuncture, and basic biosciences. Some also receive training in Chinese herbology and/or bodywork. The amount of training required for healthcare providers who are not L.Ac.'s varies from none to a few hundred hours, and in Hawaii the practice of acupuncture requires full training as a licensed acupuncturist. The National Certification Commission for Acupuncture and Oriental Medicine tests practitioners to ensure they are knowledgeable about Chinese medicine and appropriate sterile technique. Many states require this test for licensing, but each state has its own laws and requirements. In some states, acupuncturists are required to work with an M.D. in a subservient relationship, even if the M.D. has no training in acupuncture.
Acupuncture is becoming accepted by the general public and by doctors. Over fifteen million Americans tried acupuncture in 1994. A poll of American doctors in 2005 showed that 60% believe acupuncture was at least somewhat effective, with the percentage increasing to 75% if acupuncture is considered as a complement to conventional treatment.
In 1996, the Food and Drug Administration changed the status of acupuncture needles from Class III to Class II medical devices, meaning that needles are regarded as safe and effective when used appropriately by licensed practitioners .
## Canada
In the province of British Columbia the TCM practitioners and Acupuncturists Bylaws were approved by the provincial government on April 12, 2001. The governing body, College of Traditional Chinese Medicine Practitioners and Acupuncturists of British Columbia provides professional licensing. Acupuncturists began lobbying the B.C. government in the 1970s for regulation of the profession which was achieved in 2003.
In Ontario, the practice of acupuncture is now regulated by the Traditional Chinese Medicine Act, 2006, S.o. 2006, chapter 27. The government is in the process of establishing a College whose mandate will be to oversee the implementation of policies and regulations relating to the profession. Practitioners of Traditional Chinese medicine will be permitted to use the title 'Doctor of Traditional Chinese medicine'. In addition, they will be permitted to communicate a diagnosis to patients based on Traditional Chinese medicine techniques for diagnosis. Other regulated Health Care Professionals, such as naturopaths, physicians, physiotherapists, chiropractors, dentists, or massage therapists can perform acupuncture treatments when they fulfill educational requirements set up by their regulatory colleges. It is noteworthy, however, that the school (philosophy and approach) and style of acupuncture differs depending on the training of the practitioner.
## United Kingdom
In the United Kingdom, British Acupuncture Council (BAcC) members observe the Code of Safe Practice with standards of hygiene and sterilisation of equipment. Members use single-use pre-sterilised disposable needles. Similar standards apply in most jurisdictions in the United States and Australia.
Acupuncture is also practiced by a number of registered medical practitioners, many of whom belong to the British Medical Acupunture Society (BMAS), which also publishes a quarterly journal "Acupuncture in Medicine". Medical practitioners of acupuncture in the UK vary in the degree to which they take account of traditional concepts like meridians, some thinking them to be very useful whilst others tend to concentrate on palpable "trigger points". Other acupuncture groups are the British Academy of Western Medical Acupuncture (BAWMA) - nurses trained in acupuncture, the Acupuncture Association of Chartered Physiotherapists (AACP), and qualified ear acupuncturists trained either in restricted practice NADA and SMART or full ear acupuncture EAR and SAA.
## Australia
In Australia, the legalities of practicing acupuncture also vary by state. In 2000, an independent government agency was established to oversee the practice of Chinese Herbal Medicine and Acupuncture in the state of Victoria. The Chinese Medicine Registration Board of Victoria aims to protect the public, ensuring that only appropriately experienced or qualified practitioners are registered to practice Chinese Medicine. The legislation put in place stipulates that only practitioners who are state registered may use the following titles: Acupuncture, Chinese Medicine, Chinese Herbal Medicine, Registered Acupuncturist, Registered Chinese Medicine Practitioner, and Registered Chinese Herbal Medicine Practitioner.
The Parliamentary Committee on the Health Care Complaints Commission in the Australian state of New South Wales commissioned a report investigating Traditional Chinese medicine practice. They recommended the introduction of a government appointed registration board that would regulate the profession by restricting use of the titles "acupuncturist", "Chinese herbal medicine practitioner" and "Chinese medicine practitioner". The aim of registration is to protect the public from the risks of acupuncture by ensuring a high baseline level of competency and education of registered acupuncturists, enforcing guidelines regarding continuing professional education and investigating complaints of practitioner conduct. The registration board will hold more power than local councils in respect to enforcing compliance with legal requirements and investigating and punishing misconduct. Victoria is the only state of Australia with an operational registration board. Currently acupuncturists in NSW are bound by the guidelines in the Public Health (Skin Penetration) Regulation 2000 which is enforced at local council level. Other states of Australia have their own skin penetration acts. The act describes explicitly that single-use disposable needles should be used wherever possible, and that a needle labelled as "single-use" should be disposed of in a sharps container and never reused. Any other type of needle that penetrates the skin should be appropriately sterilised (by autoclave) before reuse.
Many other countries do not license acupuncturists or require them be trained. | Acupuncture
Template:Alternative medical systems
# Overview
Researchers using the protocols of evidence-based medicine have found good evidence that acupuncture is effective in treating nausea[1][2] and chronic low back pain[3][4], and moderate evidence for neck pain[5] and headache.[6] The WHO, the National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (NIH), the American Medical Association (AMA) and various government reports have also studied and commented on the efficacy of acupuncture. There is general agreement that acupuncture is at least safe when administered by well-trained practitioners, and that further research is warranted. Though occasionally charged as pseudoscience, Dr. William F. Williams, author of Encyclopedia of Pseudoscience, notes that acupuncture --"once rejected as 'oriental fakery' -- is now (if grudgingly) recognized as engaged in something quite real."[7][8][9][10]
Traditional Chinese medicine's acupuncture theory, although based on empirical observation, predates use of the modern scientific method, and has received various criticisms based on modern scientific thinking. There is no generally-accepted anatomical or histological basis for the existence of acupuncture points or meridians.[11] Acupuncturists tend to perceive TCM concepts in functional rather than structural terms, i.e. as being useful in guiding evaluation and care of patients. [12] As the NIH consensus statement noted: "Despite considerable efforts to understand the anatomy and physiology of the "acupuncture points", the definition and characterization of these points remains controversial. Even more elusive is the basis of some of the key traditional Eastern medical concepts such as the circulation of Qi, the meridian system, and the five phases theory, which are difficult to reconcile with contemporary biomedical information but continue to play an important role in the evaluation of patients and the formulation of treatment in acupuncture."[8] Finally, neuroimaging research suggests that specific acupuncture points have distinct effects on cerebral activity in specific areas that are not otherwise predictable anatomically.[13]
# Traditional theory
Chinese medicine is based on a different paradigm from scientific biomedicine. Its theory holds the following explanation of acupuncture:
Acupuncture treats the human body as a whole that involves several "systems of function" that are in some cases loosely associated with (but not identified on a one-to-one basis with) physical organs. Some systems of function, such as the "triple heater" (San Jiao, also called the "triple burner") have no corresponding physical organ, rather, represents the various jiaos or levels of the ventral body cavity (upper, middle and lower). Disease is understood as a loss of balance between the yin and yang energies, which bears some resemblance to homeostasis among the several systems of function, and treatment of disease is attempted by modifying the activity of one or more systems of function through the activity of needles, pressure, heat, etc. on sensitive parts of the body of small volume traditionally called "acupuncture points" in English, or "xue" (穴, cavities) in Chinese. This is referred to in TCM as treating "patterns of disharmony".
Treatment of acupuncture points may be performed along several layers of pathways, most commonly the twelve primary pathways meridians, located throughout the body. Other pathways include the Eight Extraordinary Pathways Qi Jing Ba Mai, the Luo Vessels, the Divergents and the Sinew Channels. Unaffiliated, or tender points, called "ah shi" (signifying "that's it", "ouch", or "oh yes") are generally used for treatment of local pain. Of the eight extraordinary pathways, only two have acupuncture points of their own. The other six meridians are "activated" by using a master and couple point technique which involves needling the acupuncture points located on the twelve main meridians that correspond to the particular extraordinary pathway. Ten of the primary pathways are named after organs of the body (Heart, Liver, etc.), one is named for the serous membrane that wraps the heart (Heart Protector or Pericardium), the last is the 'three spaces' (San Jiao). The pathways are capitalized to avoid confusion with a physical organ (for example, we write the "Heart meridian" as opposed to the "heart meridian"). The two independent extraordinary pathways Ren Mai and Du Mai are situated on the midline of the anterior and posterior aspects of the trunk and head respectively.
The twelve primary pathways run vertically, bilaterally, and symmetrically and every channel corresponds to and connects internally with one of the twelve Zang Fu ("organs"). This means that there are six yin and six yang channels. There are three yin and three yang channels on each arm, and three yin and three yang on each leg.
The three yin channels of the hand (Lung, Pericardium, and Heart) begin on the chest and travel along the inner surface (mostly the anterior portion) of the arm to the hand.
The three yang channels of the hand (Large intestine, San Jiao, and Small intestine) begin on the hand and travel along the outer surface (mostly the posterior portion) of the arm to the head.
The three [[Yin and yang|yin channels of the foot (Spleen, Liver, and Kidney) begin on the foot and travel along the inner surface (mostly posterior and medial portion) of the leg to the chest or flank.
The three yang channels of the foot (Stomach, Gallbladder, and Bladder) begin on the face, in the region of the eye, and travel down the body and along the outer surface (mostly the anterior and lateral portion) of the leg to the foot.
The movement of qi through each of the twelve channels is comprised of an internal and an external pathway. The external pathway is what is normally shown on an acupuncture chart and it is relatively superficial. All the acupuncture points of a channel lie on its external pathway. The internal pathways are the deep course of the channel where it enters the body cavities and related Zang-Fu organs. The superficial pathways of the twelve channels describe three complete circuits of the body, chest to hands, hands to head, head to feet, feet to chest, etc.
The distribution of qi through the pathways is said to be as follows (the based on the demarcations in TCM's Chinese Clock):
Lung channel of hand taiyin to Large Intestine channel of hand yangming to Stomach channel of foot yangming to Spleen channel of foot taiyin to Heart channel of hand shaoyin to Small Intestine channel of hand taiyang to Bladder channel of foot taiyang to Kidney channel of foot shaoyin to Pericardium channel of hand jueyin to San Jiao channel of hand shaoyang to Gallbladder channel of foot shaoyang to Liver channel of foot jueyin then back to the Lung channel of hand taiyin. Each channel occupies two hours, beginning with the Lung, 3AM-5AM, and coming full circle with the Liver 1AM-3AM.
Chinese medical theory holds that acupuncture works by normalizing the free flow of qi (a difficult-to-translate concept that pervades Chinese philosophy and is commonly translated as "vital energy"), blood and body fluids (jin ye) throughout the body. Pain or illnesses are treated by attempting to remedy local or systemic accumulations or deficiencies. Pain is considered to indicate blockage or stagnation of the flow of qi, blood and/or fluids, and an axiom of the medical literature of acupuncture is "no pain, no blockage; no blockage, no pain". The delicate balance between qi and blood is of primary concern in Chinese medical theory, hence the axiom blood is the mother of qi, and qi is the commander of blood. Both qi and blood work together to move (qi) and to nourish (blood) the body fluids.
Many patients claim to experience the sensations of stimulus known in Chinese as "deqi" ("obtaining the qi" or "arrival of the qi"). This kind of sensation was historically considered to be evidence of effectively locating the desired point. There are some electronic devices now available which will make a noise when what they have been programmed to describe as the "correct" acupuncture point is pressed.
The acupuncturist decides which points to treat by observing and questioning the patient in order to make a diagnosis according to the tradition which he or she utilizes. In TCM, there are four diagnostic methods: inspection, auscultation and olfaction, inquiring, and palpation (Cheng, 1987, ch. 12). Inspection focuses on the face and particularly on the tongue, including analysis of the tongue size, shape, tension, color and coating, and the absence or presence of teeth marks around the edge. Auscultation and olfaction refer, respectively, to listening for particular sounds (such as wheezing) and attending to body odor. Inquiring focuses on the "seven inquiries", which are: chills and fever; perspiration; appetite, thirst and taste; defecation and urination; pain; sleep; and menses and leukorrhea. Palpation includes feeling the body for tender "ashi" points, and palpation of the left and right radial pulses at two levels of pressure (superficial and deep) and three positions Cun, Guan, Chi(immediately proximal to the wrist crease, and one and two fingers' breadth proximally, usually palpated with the index, middle and ring fingers). Other forms of acupuncture employ additional diagnosic techniques. In many forms of classical Chinese acupuncture, as well as Japanese acupuncture, palpation of the muscles and the hara (abdomen) are central to diagnosis.
## TCM perspective on treatment of disease
Although TCM is based on the treatment of "patterns of disharmony" rather than biomedical diagnoses, practitioners familiar with both systems have commented on relationships between the two. A given TCM pattern of disharmony may be reflected in a certain range of biomedical diagnoses: thus, the pattern called Deficiency of Spleen Qi could manifest as chronic fatigue, diarrhea or uterine prolapse. Likewise, a population of patients with a given biomedical diagnosis may have varying TCM patterns. These observations are encapsulated in the TCM aphorism "One disease, many patterns; one pattern, many diseases". (Kaptchuk, 1982)
Classically, in clinical practice, acupuncture treatment is typically highly-individualized and based on philosophical constructs, and subjective and intuitive impressions" and not on controlled scientific research[14].
## Criticism of TCM theory
TCM theory predates use of the scientific method and has received various criticisms based on scientific reductionist thinking, since there is no physically verifiable anatomical or histological basis for the existence of acupuncture points or meridians.
Felix Mann, founder and past-president of the Medical Acupuncture Society (1959–1980), the first president of the British Medical Acupuncture Society (1980), and the author of the first comprehensive English language acupuncture textbook Acupuncture: The Ancient Chinese Art of Healing' first published in 1962, has stated in his book Reinventing Acupuncture: A New Concept of Ancient Medicine:
and…
Philosopher Robert Todd Carroll deems acupuncture a pseudoscience because it "confuse(s) metaphysical claims with empirical claims".[16] Carroll states that:
A report for CSICOP on pseudoscience in China written by Wallace Sampson and Barry L. Beyerstein said:
George A. Ulett, MD, PhD, Clinical Professor of Psychiatry, University of Missouri School of Medicine states: "Devoid of metaphysical thinking, acupuncture becomes a rather simple technique that can be useful as a nondrug method of pain control." He believes that the traditional Chinese variety is primarily a placebo treatment, but electrical stimulation of about 80 acupuncture points has been proven useful for pain control.[19]
Ted J. Kaptchuk, author of The Web That Has No Weaver, refers to acupuncture as "prescientific." Regarding TCM theory, Kaptchuk states:
According to the NIH consensus statement on acupuncture:
# History
In China, the practice of acupuncture can perhaps be traced as far back as the stone age, with the Bian shi, or sharpened stones.
Stone acupuncture needles dating back to 3000 B.C. have been found by archeologists in Inner Mongolia. [20][21] Clearer evidence exists from the 1st millennium BCE, and archeological evidence has been identified with the period of the Han dynasty (202 BC–220 AD). Forms of it are also described in the literature of traditional Korean medicine where it is called chimsul. It is also important in Kampo, the traditional medicine system of Japan.
Recent examinations of Ötzi, a 5,000-year-old mummy found in the Alps, have identified over 50 tattoos on his body, some of which are located on acupuncture points that would today be used to treat ailments Ötzi suffered from. Some scientists believe that this is evidence that practices similar to acupuncture were practised elsewhere in Eurasia during the early bronze age. According to an article published in The Lancet by Dorfer et al., "We hypothesised that there might have been a medical system similar to acupuncture (Chinese Zhenjiu: needling and burning) that was practised in Central Europe 5,200 years ago... A treatment modality similar to acupuncture thus appears to have been in use long before its previously known period of use in the medical tradition of ancient China. This raises the possibility of acupuncture having originated in the Eurasian continent at least 2000 years earlier than previously recognised."[1], [2].
Acupuncture's origins in China are uncertain. The earliest Chinese medical text that first describes acupuncture is the Yellow Emperor’s Classic of Internal Medicine (History of Acupuncture) Huangdi Neijing, which was compiled around 305–204 B.C. However, the Chinese medical texts (Ma-wang-tui graves, 68 BC) do not mention acupuncture. Some hieroglyphics have been found dating back to 1000 B.C. that may indicate an early use of acupuncture. Bian stones, sharp pointed rocks used to treat diseases in ancient times, have also been discovered in ruins; some scholars believe that the bloodletting for which these stones were likely used presages certain acupuncture techniques.[3]
R.C. Crozier in the book Traditional medicine in modern China (Harvard University Press, Cambridge, 1968) says the early Chinese Communist Party expressed considerable antipathy towards classical forms of Chinese medicine, ridiculing it as superstitious, irrational and backward, and claiming that it conflicted with the Party’s dedication to science as the way of progress. Acupuncture was included in this criticism. Reversing this position, Communist Party Chairman Mao later said that "Chinese medicine and pharmacology are a great treasure house and efforts should be made to explore them and raise them to a higher level."[4]
Representatives were sent out across China to collect information about the theories and practices of Chinese medicine. Traditional Chinese Medicine is the formalized system of Chinese medicine that was created out of this effort. TCM combines the use of acupuncture, Chinese herbal medicine, tui na, and other modalities. After the Cultural Revolution, TCM instruction was incorporated into university medical curricula under the "Three Roads" policy, wherein TCM, biomedicine, and a synthesis of the two would all be encouraged and permitted to develop. After this time, forms of classical Chinese medicine other than TCM were outlawed, and some practitioners left China.
The first forms of acupuncture to reach the United States were brought by non-TCM practitioners -such as Chinese rail road workers- many employing styles that had been handed down in family lineages, or from master to apprentice (collectively known as "Classical Chinese Acupuncture").
In Vietnam, Dr. Van Nghi and colleagues used the classical Chinese medical texts and applied them in clinical conditions without reference to political screening. They rewrote the modern version: Trung E Hoc. Van Nghi was made the first President of the First World Congress of Chinese Medicine at Bejing in 1988 in recognition of his work.
In the 1970s, acupuncture became vogue in America after American visitors to China brought back firsthand reports of patients undergoing major surgery using acupuncture as their sole form of anesthesia. Since then, tens of thousands of treatments are now performed in this country each year for many types of conditions such as back pain, headaches, infertility, stress, and many other illnesses.
# Clinical practice
## Finding a Qualified Practitioner
Health care providers can be a resource for referral to acupuncturists, and some conventional medical practitioners—including physicians and dentists—practice acupuncture. In addition, national acupuncture organizations (which can be found through libraries or Web search engines) may provide referrals to acupuncturists.
- Check a practitioner's credentials. Most states require a license to practice acupuncture; however, education and training standards and requirements for obtaining a license to practice vary from state to state. Although a license does not ensure quality of care, it does indicate that the practitioner meets certain standards regarding the knowledge and use of acupuncture.
- Do not rely on a diagnosis of disease by an acupuncture practitioner who does not have substantial conventional medical training. If you have received a diagnosis from a doctor, you may wish to ask your doctor whether acupuncture might help.
## Methods and Instruments
Most modern acupuncturists use disposable stainless steel needles of fine diameter (0.007" to 0.020", 0.18 mm to 0.51 mm), sterilized with ethylene oxide or by autoclave. These needles are far smaller in diameter (and therefore less painful) than the needles used to give shots, since they do not have to be hollow for purposes of injection. The upper third of these needles is wound with a thicker wire (typically bronze), or covered in plastic, to stiffen the needle and provide a handle for the acupuncturist to grasp while inserting. The size and type of needle used, and the depth of insertion, depend on the acupuncture style being practised.
Warming an acupuncture point, typically by moxibustion (the burning of a combination of herbs, primarily mugwort), is a different treatment than acupuncture itself and is often, but not exclusively, used as a supplemental treatment. The Chinese term zhēn jǐu (針灸), commonly used to refer to acupuncture, comes from zhen meaning "needle", and jiu meaning "moxibustion". Moxibustion is still used in the 21st century to varying degrees among the schools of oriental medicine. For example, one well known technique is to insert the needle at the desired acupuncture point, attach dried moxa to the external end of an acupuncture needle, and then ignite it. The moxa will then smolder for several minutes (depending on the amount adhered to the needle) and conduct heat through the needle to the tissue surrounding the needle in the patient's body. Another common technique is to hold a large glowing stick of moxa over the needles. Moxa is also sometimes burned at the skin surface, usually by applying an ointment to the skin to protect from burns, though burning of the skin is general practice in China.
## An example of acupuncture treatment
In western medicine, vascular headaches (the kind that are accompanied by throbbing veins in the temples) are typically treated with analgesics such as aspirin and/or by the use of agents such as niacin that dilate the affected blood vessels in the scalp, but in acupuncture a common treatment for such headaches is to stimulate the sensitive points that are located roughly in the center of the webs between the thumbs and the palms of the patient, the hé gǔ points. These points are described by acupuncture theory as "targeting the face and head" and are considered to be the most important point when treating disorders affecting the face and head. The patient reclines, and the points on each hand are first sterilized with alcohol, and then thin, disposable needles are inserted to a depth of approximately 3-5 mm until a characteristic "twinge" is felt by the patient, often accompanied by a slight twitching of the area between the thumb and hand. Most patients report a pleasurable "tingling" sensation and feeling of relaxation while the needles are in place. The needles are retained for 15-20 minutes while the patient rests, and then are removed.
In the clinical practice of acupuncturists, patients frequently report one or more of certain kinds of sensation that are associated with this treatment, sensations that are stronger than those that would be felt by a patient not suffering from a vascular headache:
- Extreme sensitivity to pain at the points in the webs of the thumbs.
- In bad headaches, a feeling of nausea that persists for roughly the same period as the stimulation being administered to the webs of the thumbs.
- Simultaneous relief of the headache. (See Zhen Jiu Xue, p. 177f et passim.)
## Indications according to acupuncturists in the West
According to the American Academy of Medical Acupuncture (2004), acupuncture may be considered as a complementary therapy for the conditions in the list below[22]. The conditions labeled with * are also included in the World Health Organization list of acupuncture indications.[23]. These cases, however, are based on clinical experience, and not necessarily on controlled clinical research: furthermore, the inclusion of specific diseases are not meant to indicate the extent of acupuncture's efficacy in treating them.[23]
- Abdominal distention/flatulence*
- Acute and chronic pain control*
- Allergic sinusitis *
- Anesthesia for high-risk patients or patients with previous adverse responses to anesthetics
- Anorexia
- Anxiety, fright, panic*
- Arthritis/arthrosis *
- Atypical chest pain (negative workup)
- Bursitis, tendinitis, carpal tunnel syndrome*
- Certain functional gastrointestinal disorders (nausea and vomiting, esophageal spasm, hyperacidity, irritable bowel) *
- Cervical and lumbar spine syndromes*
- Constipation, diarrhea *
- Cough with contraindications for narcotics
- Drug detoxification *
- Dysmenorrhea, pelvic pain *
- Frozen shoulder *
- Headache (migraine and tension-type), vertigo (Meniere disease), tinnitus *
- Idiopathic palpitations, sinus tachycardia
- In fractures, assisting in pain control, edema, and enhancing healing process
- Muscle spasms, tremors, tics, contractures*
- Neuralgias (trigeminal, herpes zoster, postherpetic pain, other)
- Paresthesias *
- Persistent hiccups*
- Phantom pain
- Plantar fasciitis*
- Post-traumatic and post-operative ileus *
- Premenstrual syndrome [24]
- Selected dermatoses (urticaria, pruritus, eczema, psoriasis)
- Sequelae of stroke syndrome (aphasia, hemiplegia) *
- Seventh nerve palsy
- Severe hyperthermia
- Sprains and contusions
- Temporo-mandibular joint derangement, bruxism *
- Urinary incontinence, retention (neurogenic, spastic, adverse drug effect) *
Additionally, other sources advocate the use of acupuncture for the following conditions:
- Infertility, regarding in vitro fertilization, see Expansions of in vitro fertilization - acupuncture
# Scientific theories and mechanisms of action
Many hypotheses have been proposed to address the physiological mechanisms of action of acupuncture. To date, more than 10,000 scientific research studies have been published on acupuncture as cataloged by the National Library of Medicine database.
## Neurohormonal theory
Pain transmission can also be modulated at many other levels in the brain along the pain pathways, including the periaqueductal gray, thalamus, and the feedback pathways from the cerebral cortex back to the thalamus. Each of these brain structure processes different aspect of the pain — from experiencing emotional pain to the perception of what the pain feels like to the recognition of how harmful the pain is to localizing where the pain is coming from. Pain blockade at these brain locations are often mediated by neurohormones, especially those that bind to the opioid receptors (pain-blockade site). Pain relief by morphine drug (exogenous opioid) is acting on the same opioid receptor (where pain blockade occurs) as endorphins (endogenous opioids) that the brain produces and releases.
Some studies suggest that the Analgesic (pain-killing) action of acupuncture is mediated by stimulating the release of natural endorphins in the brain. This can be proven scientifically by blocking the action of endorphins (or morphine) using a drug called naloxone. When naloxone is administered to the patient, the analgesic effects of morphine can be reversed, causing the patient to feel pain again. When naloxone is administered to an acupunctured patient, the analgesic effect of acupuncture can also be reversed, causing the patient to report an increased level of pain. This demonstrates that the site of action of acupuncture may be mediated through the natural release of endorphins by the brain, which can be reversed by naloxone.[25][26][27][28] Such analgesic effect can also be shown to last more than an hour after acupuncture stimulation by recording the neural activity directly in the thalamus (pain processing site) of the monkey's brain.[29] Furthermore, there is a large overlap between the nervous system and acupuncture trigger points (points of maximum tenderness in myofascial pain syndrome.[30]
The sites of action of acupuncture-induced analgesia are also confirmed to be mediated through the thalamus (where emotional pain/suffering is processed) using modern-day powerful non-invasive fMRI (functional magnetic resonance imaging)[31] and PET (positron emission tomography)[32] brain imaging techniques,[33] and via the feedback pathway from the cerebral cortex (where cognitive feedback signal to the thalamus distinguishing whether the pain is noxious (painful) or innocuous (non-harmful)) using electrophysiological recording of the nerve impulses of neurons directly in the cortex, which shows inhibitory action when acupuncture stimulus was applied.[34]
Recently acupuncture has been shown to increase the nitric oxide levels in treated regions and resulting in increased local blood circulation,[35] an outcome found in other studies.[36] Effects on local inflammation and ischemia have also been previously reported.[37]
## Histological studies
Bonghan Kim proposed that meridians and acupuncture points exist in the form of distinctive anatomical structures in his Bonghan Theory.[38]
[39]
[40]
## Scientific Method and the Assessment of Chinese Medical Theory and Techniques
### Views of proponents
Criticism of TCM theory hinges on the question of how to assess 'intangible' concerns. There is an assumption that all knowledge can be tested by randomly-controlled double-blind studies, and that anything not susceptible to this method of assessment must be jettisoned as unverifiable. Yet the difficulty is not in the methodology, but rather that the nature of Traditional Chinese Medicine itself makes it difficult to subject it as a whole, or subsets of the medical theory, to this type of assessment.
The theory, practice and techniques of Chinese medicine evolved over many thousands of years, well in advance of a formal articulation of the scientific method. Nevertheless, the principles of the scientific method have been used throughout the development of Chinese medical knowledge. Documentation of developments allowed practitioners to evaluate each other's theoretical and practical hypotheses, and what was shown to be effective and/or consistent with observable phenomena was kept, and the remainder discarded over time.
Chinese medicine is inherently individually applied. Given that the health of the entire individual is taken into account for each patient, any two patients, even with the same diagnosis, will receive different treatments based on their constitutional differences, their pattern of response to treatment, and so on. In addition, each treatment may vary from the previous one, in the same way that a masseur might use strokes in a different order, or different strokes, to treat exactly the same condition, from one treatment to the next.
Thus the very complexity and flexibility of this medical system makes it extremely difficult to run clinical trials – a cohort of many thousands would have to be evaluated in order to even begin to assess any claims made for or against the medicine. Clinical trials are still a valuable exercise, but they are not sufficient to determine conclusively whether either the individual constituents of the medical theory (e.g. acupuncture points), or the medical theory as a whole, are valid.
### Views of critics
One of the major criticisms of studies which purport to find that acupuncture is anything more than a placebo is that most such studies are not (in the view of critics) properly conducted. Many are not double blinded and are not randomized. However, double-blinding is not a trivial issue in acupuncture: since acupuncture is a procedure and not a pill, it is difficult to design studies in which the person providing treatment is blinded as to the treatment being given. The same problem arises in double-blinding procedures used in biomedicine, including virtually all surgical procedures, dentistry, physical therapy, etc.; the 1997 National Institute for Health Consensus Statement notes such issues with regard to sham acupuncture (needling performed superficially a/o at non-acupuncture sites), a technique often used in studies purporting to be double-blinded.[8] See also Criticism of evidence-based medicine. Tonelli, a prominent critic of EBM, argues that complementary and alternative medicine (CAM) cannot be EBM-based unless the definition of evidence is changed. Tonelli also says "the methods of developing knowledge within CAM currently have limitations and are subject to bias and varied interpretation. CAM must develop and defend a rational and coherent method for assessing causality and efficacy, though not necessarily one based on the results of controlled clinical trials."[41]
Some researchers argue that there is no evidence that acupuncture has any affect on the pathogenesis of viruses and microorganisms, or on human physiology, with the exception of the neurological pathways associated with the nerve cells that were stimulated by them. Thus, the most promising clinical application of acupuncture is in the area of pain control.
Some researchers argue that to date there is no conclusive scientific evidence indicating that the procedure has any effectiveness beyond that of a placebo. They argue that studies on acupuncture that meet scientific standards of experimentation have concluded two things: acupuncture is usually more effective than no treatment or a placebo in pill form, and that there is no significant difference in the effectiveness of acupuncture and “sham” acupuncture, which is often used as a control.[42] These researchers therefore conclude that acupuncture's effect is either caused by the tendency of extended, invasive procedures to generate more powerful placebo effects than pills or by the general stimulation of afferent nerve endings at the surface of the skin, causing the release of pain relieving biochemical compounds such as endorphins (this can also be done with jalapeno peppers, electricity, and various other form of stimulation). It may also be a combination of these two effects.
The vast majority of research on acupuncture is conducted by researchers in China, and Ernst et al. argue that there exist major flaws in the design of the experiments, as well as selective reporting of results, and conclude that no conclusions can be drawn from them.[43] Some researchers argue that numerous experimental difficulties have prevented the conclusive establishment of a causative relationship (if it exists) between pain relief and the administration of acupuncture. These include the subjective nature of pain measurement and the pervasive influence of psychological factors such as suggestion, confirmation bias, and the distraction of being poked by a needle. Also, they argue, the tendency of chronic pain to ebb and flow on its own without any external intervention leads people to falsely perceive that the last measure they took before the pain subsided was the cause of the relief. This is a logical fallacy known as post hoc ergo propter hoc.
# Scientific research into efficacy
## Evidence-based medicine
There is scientific agreement that an evidence-based medicine (EBM) framework should be used to assess health outcomes and that systematic reviews with strict protocols are essential. Organisations such as the Cochrane Collaboration and Bandolier publish such reviews.
For low back pain, a Cochrane review (2005) stated:
For nausea and vomiting: The Cochrane review (2006) on the use of the P6 acupoint for the reduction of post-operative nausea and vomiting concluded that "compared with anti emetic prophylaxis, P6 acupoint stimulation seems to reduce the risk of nausea but not vomiting".[46] Cochrane also stated: "Electroacupuncture is effective for first day vomiting after chemotherapy, but trials considering modern antivomiting drugs are needed."[47] Bandolier said "P6 acupressure in two studies showed 52% of patients with control having a success, compared with 75% with P6 acupressure"[2] and that one in five adults, but not children showed reduction in early postoperative nausea.[48] A review published by the Scientific Review of Alternative Medicine, however, argued that at the time of writing (2005) the data "are insufficiently reliable to confirm such an effect".[49]
A 2007 Cochrane Review for the use of acupuncture for neck pain stated:
For headache, Cochrane concluded (2006) that "(o)verall, the existing evidence supports the value of acupuncture for the treatment of idiopathic headaches. However, the quality and amount of evidence are not fully convincing. There is an urgent need for well-planned, large-scale studies to assess the effectiveness and cost-effectiveness of acupuncture under real-life conditions." [5]. Bandolier (1999) states: "There is no evidence from high quality trials that acupuncture is effective for the treatment of migraine and other forms of headache. The trials showing a significant benefit of acupuncture were of dubious methodological quality. Overall, the trials were of poor methodological quality."[6]
For osteoarthritis, Bandolier, commenting on a 1997 review by Edzard Ernst, stated: [7] "There is no evidence that acupuncture is more effective than sham/placebo acupuncture for the relief of joint pain due to osteoarthritis (OA)."
For fibromyalgia, a systematic review of the best 5 randomized controlled trials available found mixed results.[50] Three positive studies, all using electro-acupunture, found short term benefits.
For the following conditions, the Cochrane Collaboration concluded there is insufficient evidence that acupuncture is beneficial, often because of the paucity and poor quality of the research and that further research would be needed to support claims for efficacy:
- Giving up smoking
- Chronic asthma
- Bell's palsy
- Shoulder pain
- Lateral elbow pain
- Acute stroke
- Rheumatoid arthritis
- Depression
- Induction of labour
In practice, EBM does not demand that doctors ignore research outside its "top-tier" criteria [51].
## Evidence from neuroimaging studies
Acupuncture appears to have distinct effects on cortical activity, as demonstrated by MRI (magnetic resonance imaging) and PET (positron emission tomography). Researchers from the University of Southampton, UK and Purpan Hospital of Toulouse, France, summarize the literature:
- Investigating Acupuncture Using Brain Imaging Techniques: The Current State of Play: George T. Lewith, Peter J. White and Jeremie Pariente. "We have systematically researched and reviewed the literature looking at the effect of acupuncture on brain activation as measured by functional magnetic resonance imaging and positron emission tomography. These studies show that specific and largely predictable areas of brain activation and deactivation occur when considering the traditional Chinese functions attributable to certain specific acupuncture points. For example, points associated with hearing and vision stimulates the visual and auditory cerebral areas respectively."[13]
## NIH consensus statement
According to the National Institutes of Health:[9]
In 1997, the National Institutes of Health (NIH) issued a consensus statement on acupuncture that concluded that
The statement was not a policy statement of the NIH [9] but rather the assessment of a panel convened by the NIH.
The NIH consensus statement said that
and added that
The NIH consensus statement summarized and made a prediction:
The NIH's National Center For Complementary And Alternative Medicine continues to abide by the recommendations of the NIH Consensus Statement [10].
## American Medical Association statement
In 1997, the following statement was adopted as policy of the American Medical Association (AMA),
an association of medical doctors and medical students, after a report on a number of alternative therapies including acupuncture:[52]
"There is little evidence to confirm the safety or efficacy of most alternative therapies. Much of the information currently known about these therapies makes it clear that many have not been shown to be efficacious. Well-designed, stringently controlled research should be done to evaluate the efficacy of alternative therapies."
## German study
A German study published in the September 2007 issue of the Archives of Internal Medicine found that nearly half of patients treated with acupuncture or a sham treatment felt relief from chronic low back pain over a period of months compared to just nearly a quarter of those receiving a variety of more conventional treatments (drugs, heat, massage, etc.)[53][54] The greater benefit of the real and sham treatments were not significantly different.
# Safety and risks
Because acupuncture needles penetrate the skin, many forms of acupuncture are invasive procedures, and therefore not without risk. Injuries are rare among patients treated by trained practitioners.[55][56]
Certain forms of acupuncture such as the Japanese Tōyōhari and Shōnishin often use non-invasive techniques, in which specially-designed needles are rubbed or pressed against the skin. These methods are common in Japanese pediatric use.
## Acupuncture Side Effects and Risks
The U.S. Food and Drug Administration (FDA) regulates acupuncture needles for use by licensed practitioners, requiring that needles be manufactured and labeled according to certain standards. For example, the FDA requires that needles be sterile, nontoxic, and labeled for single use by qualified practitioners only.
Relatively few complications from the use of acupuncture have been reported to the FDA, in light of the millions of people treated each year and the number of acupuncture needles used. Still, complications have resulted from inadequate sterilization of needles and from improper delivery of treatments. Practitioners should use a new set of disposable needles taken from a sealed package for each patient and should swab treatment sites with alcohol or another disinfectant before inserting needles. When not delivered properly, acupuncture can cause serious adverse effects, including infections and punctured organs.
## Common, minor adverse events
A survey by Ernst et al. of over 400 patients receiving over 3500 acupuncture treatments found that the most common adverse effects from acupuncture were:[10]
- Minor bleeding after removal of the needles, seen in roughly 3% of patients. (Holding a cotton ball for about one minute over the site of puncture is usually sufficient to stop the bleeding.)
- Hematoma, seen in about 2% of patients, which manifests as bruises. These usually go away after a few days.
- Dizziness, seen in about 1% of patients. Some patients have a conscious or unconscious fear of needles which can produce dizziness and other symptoms of anxiety. Patients are usually treated lying down in order to reduce likelihood of fainting.
The survey concluded: "Acupuncture has adverse effects, like any therapeutic approach. If it is used according to established safety rules and carefully at appropriate anatomic regions, it is a safe treatment method."[10]
## Other injury
Other risks of injury from the insertion of acupuncture needles include:
- Nerve injury, resulting from the accidental puncture of any nerve.
- Brain damage or stroke, which is possible with very deep needling at the base of the skull.
- Pneumothorax from deep needling into the lung.[57]
- Kidney damage from deep needling in the low back.
- Haemopericardium, or puncture of the protective membrane surrounding the heart, which may occur with needling over a sternal foramen (an undetectable hole in the breastbone which can occur in up to 10% of people).
- Risk of terminating pregnancy with the use of certain acupuncture points that have been shown to stimulate the production of adrenocorticotropic hormone (ACTH) and oxytocin.
These risks are slight and can all be avoided through proper training of acupuncturists. For correct perspective, their risk should be compared to the level of side effects of common drugs and biomedical treatment - see below. Graduates of medical schools and (in the US) accreditated acupuncture schools receive thorough instruction in proper technique so as to avoid these events. (Cf. Cheng, 1987)
## Risks from omitting orthodox medical care
Some doctors believe that receiving any form of alternative medical care without also receiving orthodox western medical care is inherently risky, since undiagnosed disease may go untreated and could worsen. For this reason many acupuncturists and doctors prefer to consider acupuncture a complementary therapy rather than an alternative therapy.
Critics also express concern that unethical or naive practitioners may induce patients to exhaust financial resources by pursuing ineffective treatment.[11][12] However, many recent public health departments in modern countries have acknowledged the benefits of acupuncture by instituting regulations, ultimately raising the level of medicine practiced in these jurisdictions.[13][14][15]
## Safety compared to other treatments
Commenting on the relative safety of acupuncture compared to other treatments, the NIH consensus panel stated that "(a)dverse side effects of acupuncture are extremely low and often lower than conventional treatments." They also stated:
In a Japanese survey of 55,291 acupuncture treatments given over five years by 73 acupuncturists, 99.8% of them were performed with no significant minor adverse effects and zero major adverse incidents (Hitoshi Yamashita, Bac, Hiroshi Tsukayama, BA, Yasuo Tanno, MD, PhD. Kazushi Nishijo, PhD, JAMA). Two combined studies in the UK of 66,229 acupuncture treatments yielded only 134 minor adverse events. (British Medical Journal 2001 Sep 1). The total of 121,520 treatments with acupuncture therapy were given with no major adverse incidents (for comparison, a single such event would have indicated a 0.0008% incidence).
This is in comparison to 2,216,000 serious adverse drug reactions that occurred in hospitals 1994. (Lazarou J, Pomeranz BH, Corey PN., JAMA. 1998 Apr 15;279(15):1200-5.) So to compare indirectly, Acupuncture has a 0.2% chance of causing a minor adverse effect compared to prescription medications having a 6.7% chance of causing a serious adverse event in a hospital setting.
# Legal and political status
Acupuncturists may also practice herbal medicine or tui na, or may be medical acupuncturists, who are trained in allopathic medicine but also practice acupuncture in a simplified form. License is regulated by the state or province in many countries, and often requires passage of a board exam.
## United States
In the United States, acupuncturists are generally referred to by the professional title "Licensed Acupuncturist", abbreviated "L.Ac.". They are also known as Acupuncture Physicians in the state of Florida, and are treated as primary care physicians there. Other states, like Illinois, which are considered conservative, not progressive, in their acupuncture licensing, now allow acupuncturists to practice without a referral from another medical practitioner. Thus, effectively, acupuncturists are recognized as independent physicians in these states as well. The abbreviation "Dipl. Ac." stands for "Diplomate of Acupuncture" and signifies that the holder is board-certified by the National Certification Commission for Acupuncture and Oriental Medicine. Professional degrees are usually at the level of a Master's degree and include "M.Ac." (Master's in Acupuncture), "M.S.Ac." (Master's of Science in Acupuncture), "M.S.O.M" (Master's of Science in Oriental Medicine), and "M.A.O.M." (Master's of Acupuncture and Oriental Medicine). "O.M.D." signifies Doctor of Oriental Medicine, and "C.M.D." signifies Doctor in Chinese Medicine (zhong Yi,中医）; these titles may be used by graduates of Chinese medical schools, or by American graduates of certain postgraduate programs. The O.M.D. and C.M.D. are not recognized by the Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM), which accredits American educational programs in acupuncture. However, the O.M.D. (Doctor of Oriental Medicine) and D.O.M. (Doctor of Oriental Medine) degrees have been approved by some states. Each state regulates the practice of acupuncture within its territory. The ACAOM is currently beginning the process of accrediting the "Doctor of Acupuncture and Oriental Medicine" (DAOM) degree, and this new degree will represent the terminal degree in the field. The Oregon College of Oriental Medicine[16] and Bastyr University were the first two institutions in the United States to offer the DAOM, and it is estimated that within the next ten years the DAOM degree will replace all master's level training programs in the United States.
In the USA, acupuncture is practiced by a variety of healthcare providers. Practitioners who specialize in Acupuncture and Oriental Medicine are usually referred to as "licensed acupuncturists", or L.Ac.'s. Other healthcare providers such as physicians, dentists and chiropractors sometimes also practice acupuncture, though they may often receive less training than L.Ac.'s. L.Ac.'s generally receive from 2500 to 4000 hours of training in Chinese medical theory, acupuncture, and basic biosciences. Some also receive training in Chinese herbology and/or bodywork. The amount of training required for healthcare providers who are not L.Ac.'s varies from none to a few hundred hours, and in Hawaii the practice of acupuncture requires full training as a licensed acupuncturist. The National Certification Commission for Acupuncture and Oriental Medicine tests practitioners to ensure they are knowledgeable about Chinese medicine and appropriate sterile technique. Many states require this test for licensing, but each state has its own laws and requirements. In some states, acupuncturists are required to work with an M.D. in a subservient relationship, even if the M.D. has no training in acupuncture.
Acupuncture is becoming accepted by the general public and by doctors. Over fifteen million Americans tried acupuncture in 1994. A poll of American doctors in 2005 showed that 60% believe acupuncture was at least somewhat effective, with the percentage increasing to 75% if acupuncture is considered as a complement to conventional treatment.
In 1996, the Food and Drug Administration changed the status of acupuncture needles from Class III to Class II medical devices, meaning that needles are regarded as safe and effective when used appropriately by licensed practitioners [17] [18].
## Canada
In the province of British Columbia the TCM practitioners and Acupuncturists Bylaws were approved by the provincial government on April 12, 2001. The governing body, College of Traditional Chinese Medicine Practitioners and Acupuncturists of British Columbia provides professional licensing. Acupuncturists began lobbying the B.C. government in the 1970s for regulation of the profession which was achieved in 2003.
In Ontario, the practice of acupuncture is now regulated by the Traditional Chinese Medicine Act, 2006, S.o. 2006, chapter 27. The government is in the process of establishing a College whose mandate will be to oversee the implementation of policies and regulations relating to the profession. Practitioners of Traditional Chinese medicine will be permitted to use the title 'Doctor of Traditional Chinese medicine'. In addition, they will be permitted to communicate a diagnosis to patients based on Traditional Chinese medicine techniques for diagnosis. Other regulated Health Care Professionals, such as naturopaths, physicians, physiotherapists, chiropractors, dentists, or massage therapists can perform acupuncture treatments when they fulfill educational requirements set up by their regulatory colleges. It is noteworthy, however, that the school (philosophy and approach) and style of acupuncture differs depending on the training of the practitioner.
## United Kingdom
In the United Kingdom, British Acupuncture Council (BAcC) members observe the Code of Safe Practice with standards of hygiene and sterilisation of equipment. Members use single-use pre-sterilised disposable needles. Similar standards apply in most jurisdictions in the United States and Australia.
Acupuncture is also practiced by a number of registered medical practitioners, many of whom belong to the British Medical Acupunture Society (BMAS), which also publishes a quarterly journal "Acupuncture in Medicine". Medical practitioners of acupuncture in the UK vary in the degree to which they take account of traditional concepts like meridians, some thinking them to be very useful whilst others tend to concentrate on palpable "trigger points". Other acupuncture groups are the British Academy of Western Medical Acupuncture (BAWMA) - nurses trained in acupuncture, the Acupuncture Association of Chartered Physiotherapists (AACP), and qualified ear acupuncturists trained either in restricted practice NADA and SMART or full ear acupuncture EAR and SAA.
## Australia
In Australia, the legalities of practicing acupuncture also vary by state. In 2000, an independent government agency was established to oversee the practice of Chinese Herbal Medicine and Acupuncture in the state of Victoria. The Chinese Medicine Registration Board of Victoria [19] aims to protect the public, ensuring that only appropriately experienced or qualified practitioners are registered to practice Chinese Medicine. The legislation put in place stipulates that only practitioners who are state registered may use the following titles: Acupuncture, Chinese Medicine, Chinese Herbal Medicine, Registered Acupuncturist, Registered Chinese Medicine Practitioner, and Registered Chinese Herbal Medicine Practitioner.
The Parliamentary Committee on the Health Care Complaints Commission in the Australian state of New South Wales commissioned a report investigating Traditional Chinese medicine practice. [20] They recommended the introduction of a government appointed registration board that would regulate the profession by restricting use of the titles "acupuncturist", "Chinese herbal medicine practitioner" and "Chinese medicine practitioner". The aim of registration is to protect the public from the risks of acupuncture by ensuring a high baseline level of competency and education of registered acupuncturists, enforcing guidelines regarding continuing professional education and investigating complaints of practitioner conduct. The registration board will hold more power than local councils in respect to enforcing compliance with legal requirements and investigating and punishing misconduct. Victoria is the only state of Australia with an operational registration board. [21] Currently acupuncturists in NSW are bound by the guidelines in the Public Health (Skin Penetration) Regulation 2000 [22]which is enforced at local council level. Other states of Australia have their own skin penetration acts. The act describes explicitly that single-use disposable needles should be used wherever possible, and that a needle labelled as "single-use" should be disposed of in a sharps container and never reused. Any other type of needle that penetrates the skin should be appropriately sterilised (by autoclave) before reuse.
Many other countries do not license acupuncturists or require them be trained. | https://www.wikidoc.org/index.php/Acupuncture | |
ca86f68dd93723d1a3f0114958aa77434c5ecbf4 | wikidoc | Thyroiditis | Thyroiditis
# Overview
Thyroiditis refers to an inflammation of the thyroid gland. It is classified into Hashimoto's thyroiditis, de Quervain's Thyroiditis, silent thyroiditis, postpartum thyroiditis, Riedel's thyroiditis, and suppurative thyroiditis. These forms of thyroiditis can be differentiated from each other on the basis of pathological and laboratory findings. Thyroiditis can lead to hypothyroidism or transient hyperthyroidism. The hypothyroid phase of thyroiditis results from the gradual depletion of stored thyroid hormones. Chronic hypothyroidism is predominantly associated with hashimoto’s thyroiditis. However, all the types of thyroiditis may progress to permanent hypothyroidism. Painless sporadic thyroiditis (silent thyroiditis), painless postpartum thyroiditis, and painful subacute thyroiditis (de Quervain's thyroiditis) usually lead to transient hyperthyroidism (thyrotoxicosis) when the preformed thyroid hormones are released from the damaged gland. As thyroid hormone stores are depleted, there is often a progression through a period of euthyroidism to hypothyroidism. Suppurative thyroiditis is the result of an infection usually in the patients with preexisting thyroid disease (Hashimoto's thyroiditis, thyroid cancer, or multinodular goiter), immunosuppression, and congenital anomalies (pyriform sinus fistula). The diagnosis of thyroiditis is usually made on the physical examination, thyroid function tests, thyroid ultrasound, iodine uptake, thyroglobulin, and thyroid peroxidase antibodies. Histopathological analysis is also helpful to differentiate thyroiditis from other thyroid diseases. The treatment of thyroiditis is usually symptomatic. Beta blockers are used for the symptoms of thyrotoxicosis and levothyroxine is helpful to improve the symptoms of hypothyroidism. NSAIDs are helpful in alleviating the pain in de Quervain's thyroiditis and corticosteroids are specifically used in Riedel's thyroiditis. Antibiotics are usually reserved for the suppurative thyroiditis.
# Classification
Thyroiditis is classified into the following types:
- Hashimoto's thyroiditis
- De Quervain's Thyroiditis or granulomatous thyroiditis
- Silent thyroiditis
- Postpartum thyroiditis
- Riedel's thyroiditis
- Suppurative thyroiditis
# Differentiating Thyroiditis from Other Diseases
Various forms of thyroiditis can be differentiated from each other on the basis of pathological and laboratory findings:
## Differentiating thyroiditis from other causes of hypothyroidism
- The diagnosis of thyroiditis is usually made on the physical examination, thyroid function tests and various other diagnostic tests are listed in the table below:
†:T3RU; Triiodothyronine Resin Uptake
^: TPOAb; Thyroid peroxidase antibodies
*: TSH may be decreased transiently in the thyrotoxicosis
: TPOAb may be present in drug-induced hypo/hyperthyroidism such as Interferon-alpha, interleukin-2, and lithium
## Differentiating thyroiditis causing thyrotoxicosis from other causes of hyperthyroidism
- Hashimoto's thyroiditis can initially present with thyrotoxicosis (hashitoxicosis) which must be differentiated from other causes of thyrotoxicosis.
†T3RU; Triiodothyronine Resin uptake
^TPOAb; Thyroid peroxidase antibodies
# Diagnosis
The following flowchart describes the clinical approach to the diagnosis of thyroiditis.
## Stepwise clinical diagnosis of thyroiditis
‡TFT: Thyroid function tests (TSH, T4, and T3)
†: Grave's disease is not a thyroiditis
*: RAIU; Radioiodine uptake
††: One third of Riedel's thyroiditis presents with hypothyroidism
# Treatment
## Treatment of Hashimoto's thyroiditis
The drugs used in the treatment of Hashimoto's thyroiditis are:
Levothyroxine:
- lifelong synthetic levothyroxine (L-T4) is used to treat the hypothyroidism in Hashimoto's disease.
- Main goals of levothyroxine replacement therapy are:
Resolution of the hypothyroid symptoms and signs including biological and physiologic markers of hypothyroidism
Normalization of serum thyrotropin with improvement in thyroid hormone concentrations
To avoid overtreatment (iatrogenic thyrotoxicosis)
- Resolution of the hypothyroid symptoms and signs including biological and physiologic markers of hypothyroidism
- Normalization of serum thyrotropin with improvement in thyroid hormone concentrations
- To avoid overtreatment (iatrogenic thyrotoxicosis)
- Side effects include atrial fibrillation and osteoporosis
Corticosteroids:
- A short course of glucocorticoids can be used in the treatment of IgG4-related variant of Hashimoto's thyroiditis.
Selenium:
- Dietary selenium supplementation is considered to be protective against the autoimmune diseases of the thyroid.
### Drug Regimen for Hashimoto's thyroiditis
- Synthetic levothyroxine (L-T4) 1.6–1.8 μg/kg of body weight per day orally.
## Treatment of de Quervain's thyroiditis thyroiditis
The drugs used in the treatment of de Quervain's thyroiditis are:
- NSAIDs
- Prednisone
- Atenolol
- Synthetic levothyroxine
### Drug Regimens for de Quervain's thyroiditis
- For pain
Preferred regimen (1): Naproxen: 500 to 1000 mg per day in two divided doses
Preferred regimen (2): Ibuprofen: 1200 to 3200 mg per day in three or four divided doses
- Preferred regimen (1): Naproxen: 500 to 1000 mg per day in two divided doses
- Preferred regimen (2): Ibuprofen: 1200 to 3200 mg per day in three or four divided doses
- For severe condition
Preferred regimen (1): Prednisone: 40 mg per day orally
- Preferred regimen (1): Prednisone: 40 mg per day orally
- For hypothyroidism
- Preferred regimen (1): Synthetic levothyroxine (L-T4): 1.6–1.8 μg/kg per day orally
- For thyrotoxic symptoms
Preferred regimen (1): atenolol: 25-200mg per day orally
Preferred regimen (2): metoprolol: 25-200mg per day orally
- Preferred regimen (1): atenolol: 25-200mg per day orally
- Preferred regimen (2): metoprolol: 25-200mg per day orally
## Treatment of silent thyroiditis
The drugs used in the treatment of silent thyroiditis are:
- Atenolol
- Metoprolol
- Synthetic levothyroxine
### Drug Regimen for silent thyroidits
- For thyrotoxic symptoms
Preferred regimen (1): atenolol: 25-200mg per day orally
Preferred regimen (2): metoprolol: 25-200mg per day orally
- Preferred regimen (1): atenolol: 25-200mg per day orally
- Preferred regimen (2): metoprolol: 25-200mg per day orally
- For hypothyroidism
- Preferred regimen (1): Synthetic levothyroxine (L-T4): 1.6–1.8 μg/kg per day orally
## Treatment of Riedel's thyroidtis
- The drugs used in the treatment of silent thyroiditis are:
- Corticosteroids
- Tamoxifen
- Mycophenolate mofetil(used in combination with corticosteroids)
### Drug Regimens for Riedel's thyroidtis
The effectiveness of therapy and dosages for Riedel's thyroiditis have not yet been assessed completely. As a result, the exact dosage regimens and duration of therapy cannot be defined. The current recommendations are based on the clinical manifestations, associated conditions, and the response to treatment.
- Preferred regimen (1): Prednisone 15-60mg PO q24h for 6 months to 2 years
- Preferred regimen (2): Prednisone 500 mg PO q24h for 6 months to 2 years
- Alternative regimen (1): Tamoxifen 10-20 mg PO q24h for 6 months to 2 years
- Alternative regimen (1): Mycophenolate mofetil 1 g PO q12h for 6 months to 2 years
# Related Chapters
- Hypothyroidism
- Hyperthyroidism
- Graves-Basedow disease | Thyroiditis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2], Usama Talib, BSc, MD [3]
# Overview
Thyroiditis refers to an inflammation of the thyroid gland. It is classified into Hashimoto's thyroiditis, de Quervain's Thyroiditis, silent thyroiditis, postpartum thyroiditis, Riedel's thyroiditis, and suppurative thyroiditis. These forms of thyroiditis can be differentiated from each other on the basis of pathological and laboratory findings. Thyroiditis can lead to hypothyroidism or transient hyperthyroidism. The hypothyroid phase of thyroiditis results from the gradual depletion of stored thyroid hormones. Chronic hypothyroidism is predominantly associated with hashimoto’s thyroiditis. However, all the types of thyroiditis may progress to permanent hypothyroidism. Painless sporadic thyroiditis (silent thyroiditis), painless postpartum thyroiditis, and painful subacute thyroiditis (de Quervain's thyroiditis) usually lead to transient hyperthyroidism (thyrotoxicosis) when the preformed thyroid hormones are released from the damaged gland. As thyroid hormone stores are depleted, there is often a progression through a period of euthyroidism to hypothyroidism. Suppurative thyroiditis is the result of an infection usually in the patients with preexisting thyroid disease (Hashimoto's thyroiditis, thyroid cancer, or multinodular goiter), immunosuppression, and congenital anomalies (pyriform sinus fistula). The diagnosis of thyroiditis is usually made on the physical examination, thyroid function tests, thyroid ultrasound, iodine uptake, thyroglobulin, and thyroid peroxidase antibodies. Histopathological analysis is also helpful to differentiate thyroiditis from other thyroid diseases. The treatment of thyroiditis is usually symptomatic. Beta blockers are used for the symptoms of thyrotoxicosis and levothyroxine is helpful to improve the symptoms of hypothyroidism. NSAIDs are helpful in alleviating the pain in de Quervain's thyroiditis and corticosteroids are specifically used in Riedel's thyroiditis. Antibiotics are usually reserved for the suppurative thyroiditis.
# Classification
Thyroiditis is classified into the following types:
- Hashimoto's thyroiditis
- De Quervain's Thyroiditis or granulomatous thyroiditis
- Silent thyroiditis
- Postpartum thyroiditis
- Riedel's thyroiditis
- Suppurative thyroiditis
# Differentiating Thyroiditis from Other Diseases
Various forms of thyroiditis can be differentiated from each other on the basis of pathological and laboratory findings:[1]
## Differentiating thyroiditis from other causes of hypothyroidism
- The diagnosis of thyroiditis is usually made on the physical examination, thyroid function tests and various other diagnostic tests are listed in the table below:[2][3][1][4][5][6]
†:T3RU; Triiodothyronine Resin Uptake
^: TPOAb; Thyroid peroxidase antibodies
*: TSH may be decreased transiently in the thyrotoxicosis
**: TPOAb may be present in drug-induced hypo/hyperthyroidism such as Interferon-alpha, interleukin-2, and lithium
## Differentiating thyroiditis causing thyrotoxicosis from other causes of hyperthyroidism
- Hashimoto's thyroiditis can initially present with thyrotoxicosis (hashitoxicosis) which must be differentiated from other causes of thyrotoxicosis.[2][3][1][4][5][6][7][8][9]
†T3RU; Triiodothyronine Resin uptake
^TPOAb; Thyroid peroxidase antibodies
# Diagnosis
The following flowchart describes the clinical approach to the diagnosis of thyroiditis.
## Stepwise clinical diagnosis of thyroiditis
‡TFT: Thyroid function tests (TSH, T4, and T3)
†: Grave's disease is not a thyroiditis
*: RAIU; Radioiodine uptake
††: One third of Riedel's thyroiditis presents with hypothyroidism
# Treatment
## Treatment of Hashimoto's thyroiditis
The drugs used in the treatment of Hashimoto's thyroiditis are:[10][11]
Levothyroxine:
- lifelong synthetic levothyroxine (L-T4) is used to treat the hypothyroidism in Hashimoto's disease.
- Main goals of levothyroxine replacement therapy are:
Resolution of the hypothyroid symptoms and signs including biological and physiologic markers of hypothyroidism
Normalization of serum thyrotropin with improvement in thyroid hormone concentrations
To avoid overtreatment (iatrogenic thyrotoxicosis)
- Resolution of the hypothyroid symptoms and signs including biological and physiologic markers of hypothyroidism
- Normalization of serum thyrotropin with improvement in thyroid hormone concentrations
- To avoid overtreatment (iatrogenic thyrotoxicosis)
- Side effects include atrial fibrillation and osteoporosis
Corticosteroids:
- A short course of glucocorticoids can be used in the treatment of IgG4-related variant of Hashimoto's thyroiditis.
Selenium:
- Dietary selenium supplementation is considered to be protective against the autoimmune diseases of the thyroid.
### Drug Regimen for Hashimoto's thyroiditis
- Synthetic levothyroxine (L-T4) 1.6–1.8 μg/kg of body weight per day orally.
## Treatment of de Quervain's thyroiditis thyroiditis
The drugs used in the treatment of de Quervain's thyroiditis are:[12][13][14][15]
- NSAIDs
- Prednisone
- Atenolol
- Synthetic levothyroxine
### Drug Regimens for de Quervain's thyroiditis
- For pain
Preferred regimen (1): Naproxen: 500 to 1000 mg per day in two divided doses
Preferred regimen (2): Ibuprofen: 1200 to 3200 mg per day in three or four divided doses
- Preferred regimen (1): Naproxen: 500 to 1000 mg per day in two divided doses
- Preferred regimen (2): Ibuprofen: 1200 to 3200 mg per day in three or four divided doses
- For severe condition
Preferred regimen (1): Prednisone: 40 mg per day orally
- Preferred regimen (1): Prednisone: 40 mg per day orally
- For hypothyroidism
- Preferred regimen (1): Synthetic levothyroxine (L-T4): 1.6–1.8 μg/kg per day orally
- For thyrotoxic symptoms
Preferred regimen (1): atenolol: 25-200mg per day orally
Preferred regimen (2): metoprolol: 25-200mg per day orally
- Preferred regimen (1): atenolol: 25-200mg per day orally
- Preferred regimen (2): metoprolol: 25-200mg per day orally
## Treatment of silent thyroiditis
The drugs used in the treatment of silent thyroiditis are:[16][17][18]
- Atenolol
- Metoprolol
- Synthetic levothyroxine
### Drug Regimen for silent thyroidits
- For thyrotoxic symptoms
Preferred regimen (1): atenolol: 25-200mg per day orally
Preferred regimen (2): metoprolol: 25-200mg per day orally
- Preferred regimen (1): atenolol: 25-200mg per day orally
- Preferred regimen (2): metoprolol: 25-200mg per day orally
- For hypothyroidism
- Preferred regimen (1): Synthetic levothyroxine (L-T4): 1.6–1.8 μg/kg per day orally
## Treatment of Riedel's thyroidtis
- The drugs used in the treatment of silent thyroiditis are:[19][20][21][22][23][24][25][26]
- Corticosteroids
- Tamoxifen
- Mycophenolate mofetil(used in combination with corticosteroids)
### Drug Regimens for Riedel's thyroidtis
The effectiveness of therapy and dosages for Riedel's thyroiditis have not yet been assessed completely. As a result, the exact dosage regimens and duration of therapy cannot be defined. The current recommendations are based on the clinical manifestations, associated conditions, and the response to treatment.
- Preferred regimen (1): Prednisone 15-60mg PO q24h for 6 months to 2 years
- Preferred regimen (2): Prednisone 500 mg PO q24h for 6 months to 2 years
- Alternative regimen (1): Tamoxifen 10-20 mg PO q24h for 6 months to 2 years
- Alternative regimen (1): Mycophenolate mofetil 1 g PO q12h for 6 months to 2 years
# Related Chapters
- Hypothyroidism
- Hyperthyroidism
- Graves-Basedow disease | https://www.wikidoc.org/index.php/Acute_thyroiditis | |
976b1d4c5aa41d2ac36dc35d1b26f8b02bb83cf2 | wikidoc | Acyl halide | Acyl halide
An acyl halide (also known as an acid halide) is a chemical compound derived from an acid by replacing a hydroxyl group with a halide group.
If the acid is a carboxylic acid, the compound contains a –COX functional group, which consists of a
carbonyl group singly bonded to a halogen atom. The general formula for such an acyl
halide can be written RCOX, where R may be, for example, an alkyl group, CO is the carbonyl group, and
X represents the halogen atom, e.g. chlorine: acyl chlorides are the most commonly used acyl halides.
The hydroxyl group of a sulfonic acid may also be replaced by a halogen to produce the corresponding sulfonyl halide. In practical terms this is almost always chlorine to create a sulfonyl chloride.
# Preparation
A common method for the synthesis of acyl halides in the laboratory is by reaction of carboxylic acids with reagents such as thionyl chloride or phosphorus pentachloride for acyl chlorides, phosphorus tribromide for acyl bromides and
cyanuric fluoride for acyl fluorides.
Aromatic acyl chlorides can be prepared by chloroformylation, a specific type of Friedel-Crafts acylation using formaldehyde as the reagent.
# Reactions
Acyl halides are rather reactive compounds often synthesized to be used as intermediates in the synthesis of other organic compounds. For example, an acyl halide can react with:
- water, to form a carboxylic acid
- an alcohol to form an ester
- an amine to form an amide
- an aromatic compound, using a Lewis acid catalyst such as AlCl3, to form an aromatic ketone. See Friedel-Crafts acylation.
In the above reactions, HX (hydrogen halide or hydrohalic acid) is also formed. For example, if the acyl halide is an acyl chloride, HCl (hydrogen chloride or hydrochloric acid) is also formed.
# Multiple functional groups
A molecule can have more than one acyl halide functional group. For example, "adipoyl dichloride", usually simply called adipoyl chloride, has two acyl chloride functional groups; see the structure at right. It is the dichloride (i.e., double chloride) of the 6-carbon dicarboxylic acid adipic acid. An important use of adipoyl chloride is polymerization with an organic di-amino compound to form a polyamide called nylon or polymerization with certain other organic compounds to form polyesters.
Phosgene (carbonyl dichloride, Cl–CO–Cl) is a very toxic gas which may be thought of as the dichloride of carbonic acid (HO–CO–OH). Both chloride radicals in phosgene can undergo reactions analogous to the preceding reactions of acyl halides. Phosgene is used a reactant in the production of polycarbonate polymers, among other industrial applications.
# General hazards
Volatile acyl halides are lachrymatory because they can react with water at the surface of the eye producing hydrohalic and organic acids irritating to the eye. Similar problems can result if one inhales acyl halide vapors. In general, acyl halides (even non-volatile compounds such as tosyl chloride) are irritants to the eyes, skin and mucous membranes. | Acyl halide
An acyl halide (also known as an acid halide) is a chemical compound derived from an acid by replacing a hydroxyl group with a halide group.[1]
If the acid is a carboxylic acid, the compound contains a –COX functional group, which consists of a
carbonyl group singly bonded to a halogen atom. The general formula for such an acyl
halide can be written RCOX, where R may be, for example, an alkyl group, CO is the carbonyl group, and
X represents the halogen atom, e.g. chlorine: acyl chlorides are the most commonly used acyl halides.
The hydroxyl group of a sulfonic acid may also be replaced by a halogen to produce the corresponding sulfonyl halide. In practical terms this is almost always chlorine to create a sulfonyl chloride.
# Preparation
A common method for the synthesis of acyl halides in the laboratory is by reaction of carboxylic acids with reagents such as thionyl chloride or phosphorus pentachloride for acyl chlorides, phosphorus tribromide for acyl bromides and
cyanuric fluoride for acyl fluorides.
Aromatic acyl chlorides can be prepared by chloroformylation, a specific type of Friedel-Crafts acylation using formaldehyde as the reagent.
# Reactions
Acyl halides are rather reactive compounds often synthesized to be used as intermediates in the synthesis of other organic compounds. For example, an acyl halide can react with:
- water, to form a carboxylic acid
- an alcohol to form an ester
- an amine to form an amide
- an aromatic compound, using a Lewis acid catalyst such as AlCl3, to form an aromatic ketone. See Friedel-Crafts acylation.
In the above reactions, HX (hydrogen halide or hydrohalic acid) is also formed. For example, if the acyl halide is an acyl chloride, HCl (hydrogen chloride or hydrochloric acid) is also formed.
# Multiple functional groups
A molecule can have more than one acyl halide functional group. For example, "adipoyl dichloride", usually simply called adipoyl chloride, has two acyl chloride functional groups; see the structure at right. It is the dichloride (i.e., double chloride) of the 6-carbon dicarboxylic acid adipic acid. An important use of adipoyl chloride is polymerization with an organic di-amino compound to form a polyamide called nylon or polymerization with certain other organic compounds to form polyesters.
Phosgene (carbonyl dichloride, Cl–CO–Cl) is a very toxic gas which may be thought of as the dichloride of carbonic acid (HO–CO–OH). Both chloride radicals in phosgene can undergo reactions analogous to the preceding reactions of acyl halides. Phosgene is used a reactant in the production of polycarbonate polymers, among other industrial applications.
# General hazards
Volatile acyl halides are lachrymatory because they can react with water at the surface of the eye producing hydrohalic and organic acids irritating to the eye. Similar problems can result if one inhales acyl halide vapors. In general, acyl halides (even non-volatile compounds such as tosyl chloride) are irritants to the eyes, skin and mucous membranes. | https://www.wikidoc.org/index.php/Acyl_halide | |
34aa5c5ca749909020341811b473173f27c69f5b | wikidoc | Adenomyosis | Adenomyosis
# Overview
Adenomyosis is a medical condition characterized by the presence of ectopic endometrial tissue (the inner lining of the uterus) within the myometrium (the thick, muscular layer of the uterus). The condition is typically found in women between the ages between 35 and 50. Patients with adenomyosis can have painful and/or profuse menses (dysmenorrhea & menorrhagia, respectively).
Adenomyosis may involve the uterus focally, creating an adenomyoma, or diffusely. With diffuse involvement, the uterus becomes bulky and heavier.
# Historical Perspective
- Adenomyosis was first discovered by Carl von Rokitansky, a German pathologist, in 1860 when he found endometrial glands in the myometrium and designated this finding as 'cystosarcoma adenoids uterinum'.
- In 1892 the first systematic investigation of adenomyosis was carried out by 'Thomas Stephen Cullen', a gynecologist. He distinguished 3 types of adenomyoma: intramural, subperitoneal and submucous adenomyoma.
- In 1893, Kelly and Cullen described the pathogenesis of adenomyoma. The 'gradual ascendancy of Cullen’s mucosal theory' stated that endometrium invades the inner myometrium through the presence in it of ‘chinks’, or fissures.
- In 1892, Cullen described that abdominal hysterectomy is indicated for treatment as the endometrial growths are interwoven with the normal muscle of the uterus.
# Classification
- Adenomyosis can be classified according to its histopathology into 2 groups:
- Diffuse adenomyosis: Uniformly enlarged boggy uterus.
- Focal adenomyosis (adenomyoma): Grossly it resembles fibroid but without a surrounding pseudocapsule.
- Other variants of adenomyosis include juvenile cystic adenomyosis; which is the presence of endometrial cysts > 1cm in diameter within the myometrium. It is usually seen in young women <30 years old .
# Pathophysiology
- The pathogenesis of Adenomyosis is poorly understood. There two theories that explain the possible pathogenesis:
- Endomyometrial invagination of the endometrium; due to weakness of the uterine smooth muscles.
- De novo development of adenomyosis from mullerian rests due to metaplasia.
- The basic Fibroblast Growth Factor (bFGF) receptor/ligand system has shown to be upregulated in adenomyosis which explain the abnormal uterine bleeding and menorrhagia.
- Estrogen and progesterone hormones play a role in the pathogenesis of adenomyosis. Other hormones such as oxytocin , FSH, and prolactin also contribute to the pathogenesis of the disease.
- On gross pathology, there is a globular enlargement of the myometrium of the uterus showing cysts filled with hemolysed red blood cells and sideroblasts.
- On microscopic histopathological analysis, there are endometrial glands, and stroma surrounded by hypertrophic smooth muscle bundles haphazardly scattered within the myometrium.
# Causes
The cause of adenomyosis is unknown, although it has been associated with any sort of uterine trauma that may break the barrier between the endometrium and myometrium, such as:
- Caesarean section
- Tubal ligation
- Abortion
- Pregnancy
# Differentiating adenomyosis from other Diseases
For further information about the differential diagnosis, click here.
# Epidemiology and Demographics
- It is generally estimated that adenomyosis is present in 20-35% of women.
- The incidence and prevalence of adenomyosis are, however, difficult to be accurately estimated and biased by studying only women undergoing hysterectomy, so the total population of women having the disease is not known.
## Age
- Adenomyosis is more commonly observed among women aged 40-50 years in those undergoing hysterectomy for diagnosis.
- Adenomyosis is less commonly diagnosed in adolescents who undergo pelvic imaging by transvaginal ultrasound or MRI rather than a hysterectomy for diagnosis.
## Race
- There is no racial predilection for adenomyosis.
- Almost all cases of adenomyosis present in multiparous women, however there is no clear causal relationship between multiparty and the development of the disease
# Risk Factors
- Similar to the epidemiology, the risk factors of adenomyosis are unknown and difficult to be accurately determined as diagnosis is based on examining pathological specimens only in women undergoing hysterectomy.
- Adenomyosis often coexists with other pelvic diseases namely endometriosis and leiomyoma, so it is unknown whether it exhibits specific risk factors.
- Prior uterine surgery has been shown to be a possible risk factor for the development of adenomyosis.
# Natural History, Complications and Prognosis
- Early clinical features of adenomyosis include dysmenorrhea, heavy menstrual bleeding, and chronic pelvic pain.
- Some reported complications of adenomyosis are preterm birth and miscarriage in young women diagnosed by pelvic imaging. The relationship of adenomyosis to infertility is controversial.
- Prognosis is generally good as surgical treatment by hysterectomy is often curable unless there is another associated uterine pathology that requires further attention. There is no increased risk for secondary development of endometrial carcinoma.
# Diagnosis
Adenomyosis is a histopathological diagnosis that is made after hysterectomy. The preoperative diagnosis is suggested by pelvic imaging such as transvaginal ultrasound and MRI along with the classical presentation of heavy menstrual bleeding, dysmenorrhea, and uniformly enlarged globular uterus.
## Symptoms
- Symptoms of adenomyosis may include the following:
- Heavy menstrual bleeding
- Dysmenorrhea
- Chronic pelvic pain
## Physical Examination
- Bimanual pelvic examination may be remarkable for:
- Diffusely enlarged uterus (Boggy soft uterus)
- Uterus is mobile (not fixed as in endometriosis)
- Uterine tenderness may be noted.
## Pelvic Imaging
The uterus may be imaged using ultrasound (US) or magnetic resonance imaging (MRI). Transvaginal ultrasound is the most cost-effective and most available. Either modality will show an enlarged uterus. On ultrasound, the uterus will have a heterogeneous texture, without the focal well-defined masses that characterize uterine fibroids.
### Ultrasonography
- Typical appearances of adenomyosis at transvaginal ultrasound include poorly marginated hypoechoic and heterogeneous areas within the myometrium, myometrial cysts, and a globular or enlarged uterus with asymmetry.
Image courtesy of RadsWiki
- US: Adenomyosis
- US: Adenomyosis
- US: Adenomyosis
### Computed Tomography
Images courtesy of RadsWiki
- CT: Adenomyosis
- CT: Adenomyosis
### Magnetic Resonance Imaging
- MRI provides better diagnostic capability due to the increased spatial and contrast resolution, and to not be limited by the presence of bowel gas or calcified uterine fibroids (as is ultrasound). In particular, MRI is better able to differentiate adenomyosis from multiple small uterine fibroids.
- MRI can be used to classify adenomyosis based on the depth of penetration of the ectopic endometrium into the myometrium.
- Adenomyosis appears as either diffuse or focal thickening (greater than 12 mm )of the junctional zone forming an ill-defined area of low signal intensity, occasionally with embedded bright foci on T2-weighted images.
- Histologically, areas of low signal intensity correspond to smooth muscle hyperplasia, and bright foci on T2-weighted images correspond to islands of ectopic endometrial tissue and cystic dilatation of glands.
Images courtesy of RadsWiki
- T2: Adenomyosis
- T2: Adenomyosis
- T2: Adenomyosis
- T1 fat sat contrast: Adenomyosis
Images courtesy of RadsWiki
# Treatment
## Surgery
- Surgery is the mainstay of therapy for adenomyosis.
- Hysterectomy with preservation of the ovaries is the most common approach to the treatment of adenomyosis, and it is done via abdominal, transvaginal, laparoscopic approach, or robotic surgery. .
- Unlike Leiomyoma, there is no plane of cleavage to excise adenomyomas and preserve the uterus. Uterus sparing resection is an investigational approach especially for young women seeking future pregnancy.
## Medical Therapy
- Medical treatment for dysmenorrhea and menorrhagia can be prescribed as a temporary alternative for young women in the child-bearing period.
- Hormonal therapy to control the symptoms includes levonorgestrel-releasing IUD (most preferred method), combined oral contraceptive pills, GnRH analogs, and oral GnRH antagonists.
- Levonorgestrel-IUD has a direct action on the uterus. It alleviates dysmenorrhea and menorrhagia.
- Once the hormonal therapy is stopped to conceive, symptoms recur within six months.
## Uterine artery embolization
- In women who decline hysterectomy or have contraindications for hysterectomy or women who failed hormonal therapy, uterine artery embolization can be an alternative to control dysmenorrhea and heavy menstrual bleeding..
- The outcomes of the procedure are significantly correlated with the lesion vascularity.. | Adenomyosis
For patient information, click here
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun M.D. PhD.[2], Dina Elantably, MD[3]
# Overview
Adenomyosis is a medical condition characterized by the presence of ectopic endometrial tissue (the inner lining of the uterus) within the myometrium (the thick, muscular layer of the uterus). The condition is typically found in women between the ages between 35 and 50. Patients with adenomyosis can have painful and/or profuse menses (dysmenorrhea & menorrhagia, respectively).
Adenomyosis may involve the uterus focally, creating an adenomyoma, or diffusely. With diffuse involvement, the uterus becomes bulky and heavier.
# Historical Perspective
- Adenomyosis was first discovered by Carl von Rokitansky, a German pathologist, in 1860 when he found endometrial glands in the myometrium and designated this finding as 'cystosarcoma adenoids uterinum'[1].
- In 1892 the first systematic investigation of adenomyosis was carried out by 'Thomas Stephen Cullen', a gynecologist. He distinguished 3 types of adenomyoma: intramural, subperitoneal and submucous adenomyoma[1].
- In 1893, Kelly and Cullen described the pathogenesis of adenomyoma. The 'gradual ascendancy of Cullen’s mucosal theory' stated that endometrium invades the inner myometrium through the presence in it of ‘chinks’, or fissures.
- In 1892, Cullen described that abdominal hysterectomy is indicated for treatment as the endometrial growths are interwoven with the normal muscle of the uterus.
# Classification
- Adenomyosis can be classified according to its histopathology into 2 groups:
- Diffuse adenomyosis: Uniformly enlarged boggy uterus.
- Focal adenomyosis (adenomyoma): Grossly it resembles fibroid but without a surrounding pseudocapsule.
- Other variants of adenomyosis include juvenile cystic adenomyosis; which is the presence of endometrial cysts > 1cm in diameter within the myometrium. It is usually seen in young women <30 years old [2].
# Pathophysiology
- The pathogenesis of Adenomyosis is poorly understood. There two theories that explain the possible pathogenesis[3]:
- Endomyometrial invagination of the endometrium; due to weakness of the uterine smooth muscles.
- De novo development of adenomyosis from mullerian rests due to metaplasia.
- The basic Fibroblast Growth Factor (bFGF) receptor/ligand system has shown to be upregulated in adenomyosis which explain the abnormal uterine bleeding and menorrhagia[4].
- Estrogen and progesterone hormones play a role in the pathogenesis of adenomyosis[5]. Other hormones such as oxytocin [6], FSH[7], and prolactin[8] also contribute to the pathogenesis of the disease.
- On gross pathology, there is a globular enlargement of the myometrium of the uterus showing cysts filled with hemolysed red blood cells and sideroblasts[9].
- On microscopic histopathological analysis, there are endometrial glands, and stroma surrounded by hypertrophic smooth muscle bundles haphazardly scattered within the myometrium[9].
# Causes
The cause of adenomyosis is unknown, although it has been associated with any sort of uterine trauma that may break the barrier between the endometrium and myometrium, such as:
- Caesarean section
- Tubal ligation
- Abortion
- Pregnancy
# Differentiating adenomyosis from other Diseases
For further information about the differential diagnosis, click here.
# Epidemiology and Demographics
- It is generally estimated that adenomyosis is present in 20-35% of women[10].
- The incidence and prevalence of adenomyosis are, however, difficult to be accurately estimated and biased by studying only women undergoing hysterectomy, so the total population of women having the disease is not known[11].
## Age
- Adenomyosis is more commonly observed among women aged 40-50 years in those undergoing hysterectomy for diagnosis[9].
- Adenomyosis is less commonly diagnosed in adolescents who undergo pelvic imaging by transvaginal ultrasound or MRI rather than a hysterectomy for diagnosis[12].
## Race
- There is no racial predilection for adenomyosis.
- Almost all cases of adenomyosis present in multiparous women, however there is no clear causal relationship between multiparty and the development of the disease[9]
# Risk Factors
- Similar to the epidemiology, the risk factors of adenomyosis are unknown and difficult to be accurately determined as diagnosis is based on examining pathological specimens only in women undergoing hysterectomy[11].
- Adenomyosis often coexists with other pelvic diseases namely endometriosis and leiomyoma, so it is unknown whether it exhibits specific risk factors[12].
- Prior uterine surgery has been shown to be a possible risk factor for the development of adenomyosis[13].
# Natural History, Complications and Prognosis
- Early clinical features of adenomyosis include dysmenorrhea, heavy menstrual bleeding, and chronic pelvic pain.
- Some reported complications of adenomyosis are preterm birth and miscarriage in young women diagnosed by pelvic imaging[14]. The relationship of adenomyosis to infertility is controversial[15].
- Prognosis is generally good as surgical treatment by hysterectomy is often curable unless there is another associated uterine pathology that requires further attention. There is no increased risk for secondary development of endometrial carcinoma.
# Diagnosis
Adenomyosis is a histopathological diagnosis that is made after hysterectomy. The preoperative diagnosis is suggested by pelvic imaging such as transvaginal ultrasound and MRI along with the classical presentation of heavy menstrual bleeding, dysmenorrhea, and uniformly enlarged globular uterus.
## Symptoms
- Symptoms of adenomyosis may include the following[16]:
- Heavy menstrual bleeding
- Dysmenorrhea
- Chronic pelvic pain
## Physical Examination
- Bimanual pelvic examination may be remarkable for[16]:
- Diffusely enlarged uterus (Boggy soft uterus)
- Uterus is mobile (not fixed as in endometriosis)
- Uterine tenderness may be noted.
## Pelvic Imaging
The uterus may be imaged using ultrasound (US) or magnetic resonance imaging (MRI). Transvaginal ultrasound is the most cost-effective and most available. Either modality will show an enlarged uterus. On ultrasound, the uterus will have a heterogeneous texture, without the focal well-defined masses that characterize uterine fibroids.
### Ultrasonography
- Typical appearances of adenomyosis at transvaginal ultrasound include poorly marginated hypoechoic and heterogeneous areas within the myometrium, myometrial cysts, and a globular or enlarged uterus with asymmetry.
Image courtesy of RadsWiki
- US: Adenomyosis
- US: Adenomyosis
- US: Adenomyosis
### Computed Tomography
Images courtesy of RadsWiki
- CT: Adenomyosis
- CT: Adenomyosis
### Magnetic Resonance Imaging
- MRI provides better diagnostic capability due to the increased spatial and contrast resolution, and to not be limited by the presence of bowel gas or calcified uterine fibroids (as is ultrasound). In particular, MRI is better able to differentiate adenomyosis from multiple small uterine fibroids.
- MRI can be used to classify adenomyosis based on the depth of penetration of the ectopic endometrium into the myometrium.
- Adenomyosis appears as either diffuse or focal thickening (greater than 12 mm )of the junctional zone forming an ill-defined area of low signal intensity, occasionally with embedded bright foci on T2-weighted images.
- Histologically, areas of low signal intensity correspond to smooth muscle hyperplasia, and bright foci on T2-weighted images correspond to islands of ectopic endometrial tissue and cystic dilatation of glands.
Images courtesy of RadsWiki
- T2: Adenomyosis
- T2: Adenomyosis
- T2: Adenomyosis
- T1 fat sat contrast: Adenomyosis
Images courtesy of RadsWiki
# Treatment
## Surgery
- Surgery is the mainstay of therapy for adenomyosis[17].
- Hysterectomy with preservation of the ovaries is the most common approach to the treatment of adenomyosis, and it is done via abdominal, transvaginal, laparoscopic approach, or robotic surgery. [17].
- Unlike Leiomyoma, there is no plane of cleavage to excise adenomyomas and preserve the uterus. Uterus sparing resection is an investigational approach especially for young women seeking future pregnancy[18].
## Medical Therapy
- Medical treatment for dysmenorrhea and menorrhagia can be prescribed as a temporary alternative for young women in the child-bearing period.
- Hormonal therapy to control the symptoms includes levonorgestrel-releasing IUD (most preferred method), combined oral contraceptive pills, GnRH analogs, and oral GnRH antagonists[19].
- Levonorgestrel-IUD has a direct action on the uterus. It alleviates dysmenorrhea and menorrhagia[20].
- Once the hormonal therapy is stopped to conceive, symptoms recur within six months.
## Uterine artery embolization
- In women who decline hysterectomy or have contraindications for hysterectomy or women who failed hormonal therapy, uterine artery embolization can be an alternative to control dysmenorrhea and heavy menstrual bleeding.[21].
- The outcomes of the procedure are significantly correlated with the lesion vascularity.[21]. | https://www.wikidoc.org/index.php/Adenomyosis | |
462a609bde7f308c2a65e8b7a178c617d160a31b | wikidoc | Phentermine | Phentermine
# Disclaimer
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# Overview
Phentermine is a sympathomimetic that is FDA approved for the treatment of exogenous obesity. Common adverse reactions include xerostomia, nervousness, insomnia, and irritability.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Exogenous Obesity=
- Phentermine hydrochloride tablets USP are indicated as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index greater than or equal to 30 kg/m2, or greater than or equal to 27 kg/m2 in the presence of other risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia).
- Dosage should be individualized to obtain an adequate response with the lowest effective dose.
- The usual adult dose is one tablet as prescribed by the physician, administered in the morning, with or without food. Phentermine is not recommended for use in pediatric patients less than or equal to 16 years of age.
- Late evening medication should be avoided because of the possibility of resulting insomnia.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentermine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phentermine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Phentermine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentermine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phentermine in pediatric patients.
# Contraindications
- History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension)
- During or within 14 days following the administration of monoamine oxidase inhibitors
- Hyperthyroidism
- Glaucoma
- Agitated states
- History of drug abuse
- Pregnancy
- Nursing
- Known hypersensitivity, or idiosyncrasy to the sympathomimetic amines
# Warnings
### Precautions
- Coadministration with Other Drug Products for Weight Loss
- Phentermine hydrochloride tablets are indicated only as short-term (a few weeks) monotherapy for the management of exogenous obesity. The safety and efficacy of combination therapy with phentermine and any other drug products for weight loss including prescribed drugs, over-the-counter preparations, and herbal products, or serotonergic agents such as selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of phentermine and these drug products is not recommended.
- Primary Pulmonary Hypertension
- Primary Pulmonary Hypertension (PPH) - a rare, frequently fatal disease of the lungs - has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between PPH and the use of phentermine alone cannot be ruled out; there have been rare cases of PPH in patients who reportedly have taken phentermine alone. The initial symptom of PPH is usually dyspnea. Other initial symptoms may include angina pectoris, syncope or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope or lower extremity edema, and patients should be evaluated for the possible presence of pulmonary hypertension.
- Valvular Heart Disease
- Serious regurgitant cardiac valvular disease, primarily affecting the mitral, aortic and/or tricuspid valves, has been reported in otherwise healthy persons who had taken a combination of phentermine with fenfluramine or dexfenfluramine for weight loss. The possible role of phentermine in the etiology of these valvulopathies has not been established and their course in individuals after the drugs are stopped is not known. The possibility of an association between valvular heart disease and the use of phentermine alone cannot be ruled out; there have been rare cases of valvular heart disease in patients who reportedly have taken phentermine alone.
- Development of Tolerance, Discontinuation in Case of Tolerance
- When tolerance to the anorectant effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.
- Effect on the Ability to Engage in Potentially Hazardous Tasks
- Phentermine may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly.
- Risk of Abuse and Dependence
- Phentermine is related chemically and pharmacologically to amphetamine (d- and d/l-amphetamine) and other related stimulant drugs that have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program.
- The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.
- Usage with Alcohol
- Concomitant use of alcohol with phentermine may result in an adverse drug reaction.
- Use in Patients with Hypertension
- Use caution in prescribing phentermine for patients with even mild hypertension (risk of increase in blood pressure).
- Use in Patients on Insulin or Oral Hypoglycemic Medications for Diabetes Mellitus
- A reduction in insulin or oral hypoglycemic medications in patients with diabetes mellitus may be required.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions to phentermine have been identified:
Primary pulmonary hypertension and/or regurgitant cardiac valvular disease, palpitation, tachycardia, hypertension, ischemic events.
Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, psychosis.
Dry mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.
Urticaria.
Impotence, changes in libido.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Phentermine in the drug label.
# Drug Interactions
- Monoamine Oxidase Inhibitors
- Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis.
- Alcohol
- Concomitant use of alcohol with phentermine may result in an adverse drug reaction.
- Insulin and Oral Hypoglycemic Medications
- Requirements may be altered.
- Adrenergic Neuron Blocking Drugs
- Phentermine may decrease the hypotensive effect of adrenergic neuron blocking drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Phentermine is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy. Phentermine has pharmacologic activity similar to amphetamine (d- and d/l-amphetamine). Animal reproduction studies have not been conducted with phentermine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phentermine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Phentermine during labor and delivery.
### Nursing Mothers
- It is not known if phentermine is excreted in human milk; however, other amphetamines are present in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Because pediatric obesity is a chronic condition requiring long-term treatment, the use of this product, approved for short-term therapy, is not recommended.
### Geriatic Use
- In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Phentermine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Phentermine with respect to specific racial populations.
### Renal Impairment
- Phentermine was not studied in patients with renal impairment. Based on the reported excretion of phentermine in urine, exposure increases can be expected in patients with renal impairment. Use caution when administering phentermine to patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Phentermine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phentermine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Phentermine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Phentermine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Phentermine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Manifestations of acute overdosage include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include tachycardia, arrhythmia, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Overdosage of pharmacologically similar compounds has resulted in fatal poisoning usually terminates in convulsions and coma.
### Management
- Management of acute phentermine hydrochloride intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendations in this regard. Acidification of the urine increases phentermine excretion. Intravenous phentolamine (Regitine®, CIBA) has been suggested on pharmacologic grounds for possible acute, severe hypertension, if this complicates overdosage.
## Chronic Overdose
- Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. The most severe manifestation of chronic intoxications is psychosis, often clinically indistinguishable from schizophrenia.
# Pharmacology
## Mechanism of Action
- Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." It has not been established that the primary action of such drugs in treating obesity is one of appetite suppression since other central nervous system actions, or metabolic effects, may also be involved.
## Structure
- Phentermine hydrochloride USP is a sympathomimetic amine anorectic. Its chemical name is a,a-dimethylphenethylamine hydrochloride. The structural formula is as follows:
- Phentermine hydrochloride USP is a white, odorless, hygroscopic, crystalline powder which is soluble in water and lower alcohols, slightly soluble in chloroform and insoluble in ether.
- Phentermine hydrochloride tablets USP are available as an oral tablet containing 37.5 mg of phentermine hydrochloride USP (equivalent to 30 mg of phentermine base). Each phentermine hydrochloride tablet USP also contains the inactive ingredients microcrystalline cellulose, pregelatinized starch, anhydrous lactose, crospovidone, colloidal silicon dioxide, magnesium stearate, sucrose, corn starch and FD&C Blue #1.
## Pharmacodynamics
- Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.
## Pharmacokinetics
- Following the administration of phentermine, phentermine reaches peak concentrations (Cmax) after 3 to 4.4 hours.
- Drug Interactions
- In a single-dose study comparing the exposures after oral administration of a combination capsule of 15 mg phentermine and 92 mg topiramate to the exposures after oral administration of a 15 mg phentermine capsule or a 92 mg topiramate capsule, there is no significant topiramate exposure change in the presence of phentermine. However in the presence of topiramate, phentermine Cmax and AUC increase 13% and 42%, respectively.
- Specific Populations
- Renal Impairment
- Phentermine was not studied in patients with renal impairment. The literature reported cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62% to 85%. Exposure increases can be expected in patients with renal impairment. Use caution when administering phentermine to patients with renal impairment.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies have not been performed with phentermine to determine the potential for carcinogenesis, mutagenesis or impairment of fertility.
# Clinical Studies
- In relatively short-term clinical trials, adult obese subjects instructed in dietary management and treated with “anorectic” drugs lost more weight on the average than those treated with placebo and diet.
- The magnitude of increased weight loss of drug-treated patients over placebo-treated patients is only a fraction of a pound a week. The rate of weight loss is greatest in the first weeks of therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an “anorectic” drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drugs prescribed, such as the physician-investigator, the population treated and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss.
- The natural history of obesity is measured over several years, whereas the studies cited are restricted to a few weeks’ duration; thus, the total impact of drug-induced weight loss over that of diet alone must be considered clinically limited.
# How Supplied
- Available as tablets containing 37.5 mg phentermine hydrochloride USP (equivalent to 30 mg phentermine base).
- Phentermine hydrochloride tablets, USP are supplied as white to off-white with blue specks, capsule shaped, uncoated tablets, debossed with “U40” on one side and break line on the other side.
- Bottles of 30 NDC 13107-061-30
- Bottles of 100 NDC 13107-061-01
- Bottles of 500 NDC 13107-061-05
- Bottles of 1000 NDC 13107-061-99
- Store at 20° to 25°C (68° to 77°F).
- Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
- Keep out of the reach of children.
## Storage
There is limited information regarding Phentermine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients must be informed that phentermine hydrochloride is a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity, and that coadministration of phentermine with other drugs for weight loss is not recommended.
- Patients must be instructed on how much phentermine to take, and when and how to take it.
- Advise pregnant women and nursing mothers not to use phentermine.
- Patients must be informed about the risks of use of phentermine, about the symptoms of potential adverse reactions and when to contact a physician and/or take other action. The risks include, but are not limited to:
- Development of primary pulmonary hypertension
- Development of serious valvular heart disease
- Effects on the ability to engage in potentially hazardous tasks
- The risk of an increase in blood pressure
- The risk of interactions
- The patients must also be informed about
- The potential for developing tolerance and actions if they suspect development of tolerance and
- The risk of dependence and the potential consequences of abuse.
- Tell patients to keep phentermine in a safe place to prevent theft, accidental overdose, misuse or abuse. Selling or giving away phentermine may harm others and is against the law.
# Precautions with Alcohol
- Alcohol-Phentermine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PHENTERMINE HYDROCHLORIDE®
# Look-Alike Drug Names
There is limited information regarding Phentermine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Phentermine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Phentermine is a sympathomimetic that is FDA approved for the treatment of exogenous obesity. Common adverse reactions include xerostomia, nervousness, insomnia, and irritability.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Exogenous Obesity=
- Phentermine hydrochloride tablets USP are indicated as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index greater than or equal to 30 kg/m2, or greater than or equal to 27 kg/m2 in the presence of other risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia).
- Dosage should be individualized to obtain an adequate response with the lowest effective dose.
- The usual adult dose is one tablet as prescribed by the physician, administered in the morning, with or without food. Phentermine is not recommended for use in pediatric patients less than or equal to 16 years of age.
- Late evening medication should be avoided because of the possibility of resulting insomnia.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentermine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phentermine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Phentermine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phentermine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phentermine in pediatric patients.
# Contraindications
- History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension)
- During or within 14 days following the administration of monoamine oxidase inhibitors
- Hyperthyroidism
- Glaucoma
- Agitated states
- History of drug abuse
- Pregnancy
- Nursing
- Known hypersensitivity, or idiosyncrasy to the sympathomimetic amines
# Warnings
### Precautions
- Coadministration with Other Drug Products for Weight Loss
- Phentermine hydrochloride tablets are indicated only as short-term (a few weeks) monotherapy for the management of exogenous obesity. The safety and efficacy of combination therapy with phentermine and any other drug products for weight loss including prescribed drugs, over-the-counter preparations, and herbal products, or serotonergic agents such as selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of phentermine and these drug products is not recommended.
- Primary Pulmonary Hypertension
- Primary Pulmonary Hypertension (PPH) - a rare, frequently fatal disease of the lungs - has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between PPH and the use of phentermine alone cannot be ruled out; there have been rare cases of PPH in patients who reportedly have taken phentermine alone. The initial symptom of PPH is usually dyspnea. Other initial symptoms may include angina pectoris, syncope or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope or lower extremity edema, and patients should be evaluated for the possible presence of pulmonary hypertension.
- Valvular Heart Disease
- Serious regurgitant cardiac valvular disease, primarily affecting the mitral, aortic and/or tricuspid valves, has been reported in otherwise healthy persons who had taken a combination of phentermine with fenfluramine or dexfenfluramine for weight loss. The possible role of phentermine in the etiology of these valvulopathies has not been established and their course in individuals after the drugs are stopped is not known. The possibility of an association between valvular heart disease and the use of phentermine alone cannot be ruled out; there have been rare cases of valvular heart disease in patients who reportedly have taken phentermine alone.
- Development of Tolerance, Discontinuation in Case of Tolerance
- When tolerance to the anorectant effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.
- Effect on the Ability to Engage in Potentially Hazardous Tasks
- Phentermine may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly.
- Risk of Abuse and Dependence
- Phentermine is related chemically and pharmacologically to amphetamine (d- and d/l-amphetamine) and other related stimulant drugs that have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program.
- The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.
- Usage with Alcohol
- Concomitant use of alcohol with phentermine may result in an adverse drug reaction.
- Use in Patients with Hypertension
- Use caution in prescribing phentermine for patients with even mild hypertension (risk of increase in blood pressure).
- Use in Patients on Insulin or Oral Hypoglycemic Medications for Diabetes Mellitus
- A reduction in insulin or oral hypoglycemic medications in patients with diabetes mellitus may be required.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions to phentermine have been identified:
Primary pulmonary hypertension and/or regurgitant cardiac valvular disease, palpitation, tachycardia, hypertension, ischemic events.
Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, psychosis.
Dry mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.
Urticaria.
Impotence, changes in libido.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Phentermine in the drug label.
# Drug Interactions
- Monoamine Oxidase Inhibitors
- Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis.
- Alcohol
- Concomitant use of alcohol with phentermine may result in an adverse drug reaction.
- Insulin and Oral Hypoglycemic Medications
- Requirements may be altered.
- Adrenergic Neuron Blocking Drugs
- Phentermine may decrease the hypotensive effect of adrenergic neuron blocking drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Phentermine is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy. Phentermine has pharmacologic activity similar to amphetamine (d- and d/l-amphetamine). Animal reproduction studies have not been conducted with phentermine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phentermine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Phentermine during labor and delivery.
### Nursing Mothers
- It is not known if phentermine is excreted in human milk; however, other amphetamines are present in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Because pediatric obesity is a chronic condition requiring long-term treatment, the use of this product, approved for short-term therapy, is not recommended.
### Geriatic Use
- In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Phentermine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Phentermine with respect to specific racial populations.
### Renal Impairment
- Phentermine was not studied in patients with renal impairment. Based on the reported excretion of phentermine in urine, exposure increases can be expected in patients with renal impairment. Use caution when administering phentermine to patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Phentermine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phentermine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Phentermine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Phentermine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Phentermine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Manifestations of acute overdosage include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include tachycardia, arrhythmia, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Overdosage of pharmacologically similar compounds has resulted in fatal poisoning usually terminates in convulsions and coma.
### Management
- Management of acute phentermine hydrochloride intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendations in this regard. Acidification of the urine increases phentermine excretion. Intravenous phentolamine (Regitine®, CIBA) has been suggested on pharmacologic grounds for possible acute, severe hypertension, if this complicates overdosage.
## Chronic Overdose
- Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. The most severe manifestation of chronic intoxications is psychosis, often clinically indistinguishable from schizophrenia.
# Pharmacology
## Mechanism of Action
- Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." It has not been established that the primary action of such drugs in treating obesity is one of appetite suppression since other central nervous system actions, or metabolic effects, may also be involved.
## Structure
- Phentermine hydrochloride USP is a sympathomimetic amine anorectic. Its chemical name is a,a-dimethylphenethylamine hydrochloride. The structural formula is as follows:
- Phentermine hydrochloride USP is a white, odorless, hygroscopic, crystalline powder which is soluble in water and lower alcohols, slightly soluble in chloroform and insoluble in ether.
- Phentermine hydrochloride tablets USP are available as an oral tablet containing 37.5 mg of phentermine hydrochloride USP (equivalent to 30 mg of phentermine base). Each phentermine hydrochloride tablet USP also contains the inactive ingredients microcrystalline cellulose, pregelatinized starch, anhydrous lactose, crospovidone, colloidal silicon dioxide, magnesium stearate, sucrose, corn starch and FD&C Blue #1.
## Pharmacodynamics
- Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.
## Pharmacokinetics
- Following the administration of phentermine, phentermine reaches peak concentrations (Cmax) after 3 to 4.4 hours.
- Drug Interactions
- In a single-dose study comparing the exposures after oral administration of a combination capsule of 15 mg phentermine and 92 mg topiramate to the exposures after oral administration of a 15 mg phentermine capsule or a 92 mg topiramate capsule, there is no significant topiramate exposure change in the presence of phentermine. However in the presence of topiramate, phentermine Cmax and AUC increase 13% and 42%, respectively.
- Specific Populations
- Renal Impairment
- Phentermine was not studied in patients with renal impairment. The literature reported cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62% to 85%. Exposure increases can be expected in patients with renal impairment. Use caution when administering phentermine to patients with renal impairment.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies have not been performed with phentermine to determine the potential for carcinogenesis, mutagenesis or impairment of fertility.
# Clinical Studies
- In relatively short-term clinical trials, adult obese subjects instructed in dietary management and treated with “anorectic” drugs lost more weight on the average than those treated with placebo and diet.
- The magnitude of increased weight loss of drug-treated patients over placebo-treated patients is only a fraction of a pound a week. The rate of weight loss is greatest in the first weeks of therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an “anorectic” drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drugs prescribed, such as the physician-investigator, the population treated and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss.
- The natural history of obesity is measured over several years, whereas the studies cited are restricted to a few weeks’ duration; thus, the total impact of drug-induced weight loss over that of diet alone must be considered clinically limited.
# How Supplied
- Available as tablets containing 37.5 mg phentermine hydrochloride USP (equivalent to 30 mg phentermine base).
- Phentermine hydrochloride tablets, USP are supplied as white to off-white with blue specks, capsule shaped, uncoated tablets, debossed with “U40” on one side and break line on the other side.
- Bottles of 30 NDC 13107-061-30
- Bottles of 100 NDC 13107-061-01
- Bottles of 500 NDC 13107-061-05
- Bottles of 1000 NDC 13107-061-99
- Store at 20° to 25°C (68° to 77°F).
- Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
- Keep out of the reach of children.
## Storage
There is limited information regarding Phentermine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients must be informed that phentermine hydrochloride is a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity, and that coadministration of phentermine with other drugs for weight loss is not recommended.
- Patients must be instructed on how much phentermine to take, and when and how to take it.
- Advise pregnant women and nursing mothers not to use phentermine.
- Patients must be informed about the risks of use of phentermine, about the symptoms of potential adverse reactions and when to contact a physician and/or take other action. The risks include, but are not limited to:
- Development of primary pulmonary hypertension
- Development of serious valvular heart disease
- Effects on the ability to engage in potentially hazardous tasks
- The risk of an increase in blood pressure
- The risk of interactions
- The patients must also be informed about
- The potential for developing tolerance and actions if they suspect development of tolerance and
- The risk of dependence and the potential consequences of abuse.
- Tell patients to keep phentermine in a safe place to prevent theft, accidental overdose, misuse or abuse. Selling or giving away phentermine may harm others and is against the law.
# Precautions with Alcohol
- Alcohol-Phentermine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PHENTERMINE HYDROCHLORIDE®[1]
# Look-Alike Drug Names
There is limited information regarding Phentermine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Adipex-P | |
3e8a283bde1707574237718e10a1a8ef6109a30c | wikidoc | Adiponectin | Adiponectin
Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ADIPOQ gene and it is produced in adipose tissue.
# Structure
Adiponectin is a 244-amino-acid-long polypeptide (protein). There are four distinct regions of adiponectin. The first is a short signal sequence that targets the hormone for secretion outside the cell; next is a short region that varies between species; the third is a 65-amino acid region with similarity to collagenous proteins; the last is a globular domain. Overall this protein shows similarity to the complement 1Q factors (C1Q). However, when the 3-dimensional structure of the globular region was determined, a striking similarity to TNFα was observed, despite unrelated protein sequences.
# Function
Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation. Adiponectin is secreted from adipose tissue (and also from the placenta in pregnancy) into the bloodstream and is very abundant in plasma relative to many hormones. Many studies have found adiponectin to be inversely correlated with body mass index in patient populations. However, a meta analysis was not able to confirm this association in healthy adults. Circulating adiponectin concentrations increase during caloric restriction in animals and humans, such as in patients with anorexia nervosa. This observation is surprising, given that adiponectin is produced by adipose tissue. However, a recent study suggests that adipose tissue within bone marrow, which increases during caloric restriction, contributes to elevated circulating adiponectin in this context.
Transgenic mice with increased adiponectin show reduced adipocyte differentiation and increased energy expenditure associated with mitochondrial uncoupling. The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes, obesity, atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome. Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice.
Adiponectin is secreted into the bloodstream where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL (mg/L). In adults, plasma concentrations are higher in females than males, and are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating concentrations.
Adiponectin automatically self-associates into larger structures. Initially, three adiponectin molecules bind together to form a homotrimer. The trimers continue to self-associate and form hexamers or dodecamers. Like the plasma concentration, the relative levels of the higher-order structures are sexually dimorphic, where females have increased proportions of the high-molecular weight forms. Recent studies showed that the high-molecular weight form may be the most biologically active form regarding glucose homeostasis. High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin. However, coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.
Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin, but the two hormones perform complementary actions, and can have synergistic effects.
# Receptors
Adiponectin binds to a number of receptors. So far, two receptors have been identified with homology to G protein-coupled receptors, and one receptor similar to the cadherin family:
- Adiponectin receptor 1 (AdipoR1)
- Adiponectin receptor 2 (AdipoR2)
- T-cadherin - CDH13
These have distinct tissue specificities within the body and have different affinities to the various forms of adiponectin. The receptors affect the downstream target AMP kinase, an important cellular metabolic rate control point. Expression of the receptors is correlated with insulin levels, as well as reduced in mouse models of diabetes, particularly in skeletal muscle and adipose tissue.. In 2016, the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on the identification of AdipoR1 and AdipoR2.
# Discovery
Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al.). In 1996 it was characterised in mice as the mRNA transcript most highly expressed in adipocytes. In 2007, adiponectin was identified as a transcript highly expressed in preadipocytes (precursors of fat cells) differentiating into adipocytes.
The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in adipose tissue, adiponectin was found to be decreased in obesity. This downregulation has not been fully explained. The gene was localised to chromosome 3q27, a region highlighted as affecting genetic susceptibility to type 2 diabetes and obesity. Supplementation by differing forms of adiponectin was able to improve insulin control, blood glucose and triglyceride levels in mouse models.
The gene was investigated for variants that predispose to type 2 diabetes. Several single nucleotide polymorphisms in the coding region and surrounding sequence were identified from several different populations, with varying prevalences, degrees of association and strength of effect on type 2 diabetes. Berberine, an isoquinoline alkaloid, has been shown to increase adiponectin expression which partly explains its beneficial effects on metabolic disturbances. Mice fed the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown increased plasma adiponectin. Curcumin, capsaicin, gingerol, and catechins have also been found to increase adiponectin expression.
Phylogenetic distribution includes expression in birds and fish.
# Metabolic
Adiponectin effects:
- glucose flux
decreased gluconeogenesis
increased glucose uptake
- decreased gluconeogenesis
- increased glucose uptake
- lipid catabolism
β-oxidation
triglyceride clearance
- β-oxidation
- triglyceride clearance
- protection from endothelial dysfunction (important facet of atherosclerotic formation)
- insulin sensitivity
- weight loss
- control of energy metabolism.
- upregulation of uncoupling proteins
- reduction of TNF-alpha
Regulation of adiponectin
- Obesity is associated with decreased adiponectin.
The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.
- The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.
# Hypoadiponectinemia
A low level of adiponectin is an independent risk factor for developing:
- Metabolic syndrome
- Diabetes mellitus
# Other
Lower levels of adiponectin are associated with ADHD in adults.
Adiponectin levels were found to be increased in rheumatoid arthritis patients responding to DMARDs or TNF inhibitor therapy.
Exercise induced release of adiponectin increased hippocampal growth and led to antidepressive symptoms in mice.
## As a drug target
Circulating levels of adiponectin can indirectly be increased through lifestyle modifications and certain drugs such as statins.
A small molecule adiponectin receptor AdipoR1 and AdipoR2 agonist, AdipoRon, has been reported. In 2016, the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on AdipoR1, AdipoR2, and AdipoRon.
Extracts of sweet potatoes have been reported to increase levels of adiponectin and thereby improve glycemic control in humans. However, a systematic review concluded there is insufficient evidence to support the consumption of sweet potatoes to treat type 2 diabetes mellitus.
Adiponectin is apparently able to cross the blood-brain-barrier. However, conflicting data on this issue exist. Adiponectin has a half-life of 2.5 hours in humans. | Adiponectin
Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ADIPOQ gene and it is produced in adipose tissue.[1]
# Structure
Adiponectin is a 244-amino-acid-long polypeptide (protein). There are four distinct regions of adiponectin. The first is a short signal sequence that targets the hormone for secretion outside the cell; next is a short region that varies between species; the third is a 65-amino acid region with similarity to collagenous proteins; the last is a globular domain. Overall this protein shows similarity to the complement 1Q factors (C1Q). However, when the 3-dimensional structure of the globular region was determined, a striking similarity to TNFα was observed, despite unrelated protein sequences.[2]
# Function
Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation.[3] Adiponectin is secreted from adipose tissue (and also from the placenta in pregnancy[4]) into the bloodstream and is very abundant in plasma relative to many hormones. Many studies have found adiponectin to be inversely correlated with body mass index in patient populations.[5] However, a meta analysis was not able to confirm this association in healthy adults.[6] Circulating adiponectin concentrations increase during caloric restriction in animals and humans, such as in patients with anorexia nervosa. This observation is surprising, given that adiponectin is produced by adipose tissue. However, a recent study suggests that adipose tissue within bone marrow, which increases during caloric restriction, contributes to elevated circulating adiponectin in this context.[7]
Transgenic mice with increased adiponectin show reduced adipocyte differentiation and increased energy expenditure associated with mitochondrial uncoupling.[8] The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes,[5] obesity, atherosclerosis,[3] non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome.[9] Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice.[10]
Adiponectin is secreted into the bloodstream where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL (mg/L). In adults, plasma concentrations are higher in females than males, and are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating concentrations.[11]
Adiponectin automatically self-associates into larger structures. Initially, three adiponectin molecules bind together to form a homotrimer. The trimers continue to self-associate and form hexamers or dodecamers. Like the plasma concentration, the relative levels of the higher-order structures are sexually dimorphic, where females have increased proportions of the high-molecular weight forms. Recent studies showed that the high-molecular weight form may be the most biologically active form regarding glucose homeostasis.[12] High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.[13] However, coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.[14]
Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin,[15] but the two hormones perform complementary actions, and can have synergistic effects.[clarification needed]
# Receptors
Adiponectin binds to a number of receptors. So far, two receptors have been identified with homology to G protein-coupled receptors, and one receptor similar to the cadherin family:[16][17]
- Adiponectin receptor 1 (AdipoR1)
- Adiponectin receptor 2 (AdipoR2)
- T-cadherin - CDH13
These have distinct tissue specificities within the body and have different affinities to the various forms of adiponectin. The receptors affect the downstream target AMP kinase, an important cellular metabolic rate control point. Expression of the receptors is correlated with insulin levels, as well as reduced in mouse models of diabetes, particularly in skeletal muscle and adipose tissue.[18][19]. In 2016, the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on the identification of AdipoR1 and AdipoR2[20].
# Discovery
Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al.).[21] In 1996 it was characterised in mice as the mRNA transcript most highly expressed in adipocytes[1]. In 2007, adiponectin was identified as a transcript highly expressed in preadipocytes[22] (precursors of fat cells) differentiating into adipocytes.[22][23]
The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in adipose tissue, adiponectin was found to be decreased in obesity.[3][5][15] This downregulation has not been fully explained. The gene was localised to chromosome 3q27, a region highlighted as affecting genetic susceptibility to type 2 diabetes and obesity. Supplementation by differing forms of adiponectin was able to improve insulin control, blood glucose and triglyceride levels in mouse models.
The gene was investigated for variants that predispose to type 2 diabetes.[15][22][24][25][26][27] Several single nucleotide polymorphisms in the coding region and surrounding sequence were identified from several different populations, with varying prevalences, degrees of association and strength of effect on type 2 diabetes. Berberine, an isoquinoline alkaloid, has been shown to increase adiponectin expression[28] which partly explains its beneficial effects on metabolic disturbances. Mice fed the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown increased plasma adiponectin.[29] Curcumin, capsaicin, gingerol, and catechins have also been found to increase adiponectin expression.[30]
Phylogenetic distribution includes expression in birds[31] and fish.[32]
# Metabolic
Adiponectin effects:
- glucose flux
decreased gluconeogenesis
increased glucose uptake[3][15][25]
- decreased gluconeogenesis
- increased glucose uptake[3][15][25]
- lipid catabolism[25]
β-oxidation[15]
triglyceride clearance[15]
- β-oxidation[15]
- triglyceride clearance[15]
- protection from endothelial dysfunction (important facet of atherosclerotic formation)
- insulin sensitivity
- weight loss
- control of energy metabolism.[25]
- upregulation of uncoupling proteins [8]
- reduction of TNF-alpha
Regulation of adiponectin
- Obesity is associated with decreased adiponectin.
The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.[33]
- The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.[33]
# Hypoadiponectinemia
A low level of adiponectin is an independent risk factor for developing:
- Metabolic syndrome[9]
- Diabetes mellitus[15][22][24][26][27]
# Other
Lower levels of adiponectin are associated with ADHD in adults.[34]
Adiponectin levels were found to be increased in rheumatoid arthritis patients responding to DMARDs or TNF inhibitor therapy.[35]
Exercise induced release of adiponectin increased hippocampal growth and led to antidepressive symptoms in mice.[36]
## As a drug target
Circulating levels of adiponectin can indirectly be increased through lifestyle modifications and certain drugs such as statins.[37]
A small molecule adiponectin receptor AdipoR1 and AdipoR2 agonist, AdipoRon, has been reported.[38] In 2016, the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on AdipoR1, AdipoR2, and AdipoRon[20].
Extracts of sweet potatoes have been reported to increase levels of adiponectin and thereby improve glycemic control in humans.[39] However, a systematic review concluded there is insufficient evidence to support the consumption of sweet potatoes to treat type 2 diabetes mellitus.[40]
Adiponectin is apparently able to cross the blood-brain-barrier.[41] However, conflicting data on this issue exist.[42] Adiponectin has a half-life of 2.5 hours in humans.[43] | https://www.wikidoc.org/index.php/Adiponectin | |
c214baf2226b4716fe26df80fc6dc7a28370b292 | wikidoc | Adolescence | Adolescence
Adolescence (lat adolescere = (to) grow) is a transitional stage of human development that occurs between childhood and adulthood. Adolescent humans go through puberty, the process of sexual maturation. Teenagers (ages 13-19) are usually adolescent, though in some individuals, puberty may extend a few years beyond the teenage years, and in some individuals, puberty begins in the pre-teen years.
# Usage
In common usage around the world, "adolescent", "teenager", "teen", "youth", "young adult", "youngster", "young person" and "emerging adult" may be considered synonyms - although the term 'teenager' is an artifact of the English counting system, something which does not occur in all languages. The Oxford English Dictionary cites the first usage of the term to a Popular Science Monthly issue of April, 1941, "I never knew teen-agers could be so serious."
In sociology, adolescence is seen as a cultural phenomenon for the working world and therefore its end points are not easily tied to physical milestones. The time is identified with dramatic changes in the body, along with developments in a person's psychology and academic career. At the onset of adolescence (often referred to as 'puberty'), children usually complete elementary school and enter secondary education, such as middle school or high school. A person between early childhood and the teenage years is sometimes referred to as a pre-teen or tween.
As a transitional stage of human development, adolescence is the period in which a child matures into an adult. This transition involves biological (i.e. pubertal), social, and psychological changes, though the biological or physiological ones are the easiest to measure objectively.
The ages of adolescence vary by culture. The World Health Organization (WHO) defines adolescence as the period of life between 10 and 19 years of age. In contrast, in the United States, adolescence is generally considered to begin somewhere between ages 12 and 14, and end from 19 to 21. As distinct from the varied interpretations of who is considered an "adolescent", the word "teenager" is more easily defined: it describes a person who is thirteen to nineteen years of age.
During this period of life, most children go through the physical stages of puberty which often begins between the ages of nine and thirteen. (See Puberty below)
Most cultures regard people as becoming adults at various ages of the teenage years, often at the age of eighteen. (See Social and cultural below)
# Puberty
Puberty is the stage of the lifespan in which a child develops secondary sex characteristics (for example a deeper voice or larger adam's apple in boys, and development of breasts and hips in girls) as his or her hormonal balance shifts strongly towards an adult state. This is triggered by the pituitary gland, which secretes a surge of hormones, such as testosterone (boys) or estrogen (girls) into the blood stream and begins the rapid maturation of the gonads: the girl's ovaries and the boy's testicles. Some boys may develop Gynecomastia due an imbalance of sex hormones, tissue responsiveness or obesity. Put simply, puberty is the time when a childs body starts changing as to look more like an adult.
The onset of puberty in girls appears to be related to body fat percentage. In most Western countries, the average age of a girl's first menstrual period, or menarche, fell in a decreasing secular trend. Girls start going through puberty earlier than boys. The average age for girls to start puberty is 10-12 while the average age for boys to start puberty is 12-14.
# Psychology
Adolescent psychology is associated with the notable changes in the behavior also known as Mood swing. The characteristics of adolescents, cognitive, emotional and attitudinal changes take place during this period, which can be a cause of conflict on one hand and positive personality development on the other.
Due to the adolescents' experiencing various cognitive and physical changes, it is frequently notable that they start giving more importance to their friends, their peer group, and less to their parents/guardians, due to the aggregated influence of whom they might go on to indulge in activities not deemed as socially acceptable, although this may be more of a social phenomenon than a psychological one.
In the search for a unique social identity for themselves, adolescents are frequently found confused between the 'right' and 'wrong.' G. Stanley Hall denoted this period as one of "Storm and Stress" and, according to him, conflict at this developmental stage is normal and not unusual. Margaret Mead, on the other hand, attributed the behavior of adolescents to their culture and upbringing. However, Piaget, attributed this stage in development with greatly increased cognitive abilities; at this stage of life the individual's thoughts start taking more of an abstract form and the egocentric thoughts decrease, hence the individual is able to think and reason in a wider perspective.
Positive psychology is sometimes brought up when addressing adolescent psychology as well. This approach towards adolescents refers to providing them with motivation to become socially acceptable and notable individuals, since many adolescents find themselves bored, indecisive and/or unmotivated.
It should also be noted that adolescence is the stage of a psychological breakthrough in a person's life when the cognitive development is rapid and the thoughts, ideas and concepts developed at this period of life greatly influence the individual's future life, playing a major role in character and personality formation.
# Sexuality
Adolescent sexuality refers to sexual feelings, behavior and development in adolescents and is a stage of human sexuality. Sexuality and sexual desire usually begins to appear along with the onset of puberty. The expression of sexual desire among adolescents (or anyone, for that matter), might be influenced by family values and influences, the culture and religion they have grown up in social engineering, social control, taboos, and other kinds of social mores.
The risks of adolescent sexual activity is sometimes associated with: emotional distress (fear of abuse or exploitation), sexually transmitted diseases (including HIV/AIDS) and pregnancy through failure or non-use of birth control. In terms of sexual identity, sexual orientation among adolescents may vary greatly across the spectrum from heterosexuality and LGBT orientations to pansexuality and sexual fetishism.
According to anthropologist Racheal and psychologist Albert Bandura, the turmoil found in adolescence in Western society has a cultural rather than a physical cause, and societies where young women engage in free sexual activity have had no such adolescent turmoil until more recently when truthful information about deadly STD's has been made publicly assessible. However many of these studies have been proven false.
The age of consent to sexual activity varies widely between international jurisdictions, ranging from 12 to 21 years, although some governments, such as Canada's, are planning to raise the age to at least 16 in an effort to reduce the incidence of lethal STD's, pregnancy among teenage girls, and the sexual abuse and exploitation of younger teens.
# Culture
In commerce, this generation is seen as an important target. Mobile phones, contemporary popular music, movies, television programs, sports, video games and clothes are heavily marketed and often popular amongst adolescents.
In the past (and still in some cultures) there were ceremonies that celebrated adulthood, typically occurring during adolescence. Seijin shiki (literally "adult ceremony") is a Japanese example of this. Upanayanam is a coming of age ceremony for males in the Hindu world. In Judaism, 12 year old girls and 13-year-old boys become Bat or Bar Mitzvah, respectively, and often have a celebration to mark this coming of age. Among some denominations of Christianity, the rite or sacrament of Confirmation is received by adolescents and may be considered the time at which adolescents becomes members of the church in their own right. African boys also have a coming of age ceremony in which, upon reaching adolescence, the males state a promise to never do anything to shame their families or their village. This was also continued among African-American slaves in the early days of slavery before the practice was outlawed. In United States, girls will often have a "sweet sixteen" party to celebrate turning the aforementioned age, a tradition similar to the quinceañera in Latin culture. In modern America, events such as getting your first driver's license, high school and later on college graduation and first career related job are thought of as being more significant markers in transition to adulthood.
Adolescents have also been an important factor in many movements for positive social change around the world. The popular history of adolescents participating in these movements may perhaps start with Joan of Arc, and extend to present times with popular youth activism, student activism, and other efforts to make youth voice heard.
# Legal issues, rights and privileges
Internationally, those over a certain age (often 18, though this varies) are legally considered to have reached the age of majority and are regarded as adults and are held to be responsible for their actions. People below this age are considered minors and are children. A person below the age of majority may gain adult rights through legal emancipation. Teenagers may be rebellious because they want to have the same rights and freedoms as adults. As a result some of those teens may obtain counterfeit ID/licenses which allow them to partake of those privileges. On the other hand, many teens are in no particular hurry to abandon their younger years, and enjoy their childhood.
Those who are under the age of consent, or legal responsibility, may be considered too young to be held accountable for criminal action. This is called the defense of infancy. The age of criminal responsibility varies from 7 in India to 18 in Belgium. After reaching the initial age, there may be levels of responsibility dictated by age and type of offense, and crimes committed by minors may be tried in a juvenile court.
The legal working age in Western countries is usually 14 to 16, depending on the number of hours and type of employment. In the United Kingdom and Canada, for example, kids between 14 and 16 can work at certain types of light work with some restrictions to allow for schooling; while kids over 16 can work full-time (excluding night work). Many countries also specify a minimum school leaving age, ranging from 10 to 18, at which a person is legally allowed to leave compulsory education.
The age of consent to sexual activity varies widely between jurisdictions, ranging from 12 to 21 years, although 14 to 16 years is more usual. Sexual intercourse with a person below this age is treated as the crime of statutory rape. Some jurisdictions allow an exemption where both partners are close in age - for example, two 15 year olds. The age at which people are allowed to marry also varies, from 9 in Yemen to 22 for males and 20 for females in China. In Western countries, people are typically allowed to marry at 18, although they are sometimes allowed to marry at a younger age with parental or court consent. In developing countries, the legal marriageable age does not always correspond with the age at which people actually marry; for example, the legal age for marriage in Ethiopia is 18 for both males and females, but in rural areas most girls are married by age 16.
In most democratic countries, a citizen is eligible to vote at 18. For example, in the United States, the Twenty-sixth amendment decreased the voting age from 21 to 18. In a minority of countries, the voting age is 17 (for example, Indonesia) or 16 (for example, Brazil). By contrast, some countries have a minimum voting age of 21 (for example, Singapore) whereas the minimum age in Uzbekistan is 25. Age of candidacy is the minimum age at which a person can legally qualify to hold certain elected government offices. In most countries, a person must be 18 or over to stand for elected office, but some countries such as the United States and Italy have further restrictions depending on the type of office.
The sale of selected items such as cigarettes, alcohol, and videos with violent or pornographic content is also restricted by age in most countries. In the U.S, the minimum age to buy an R-rated movie, M-rated game or an album with a parental advisory label is 17 (in some states 18). In practice, it is common that young people engage in underage smoking or drinking, and in some cultures this is tolerated to a certain degree. In the United States, teenagers are allowed to drive between 14-18 (each state sets its own minimum driving age of which a curfew may be imposed), in the US, adolescents 17 years of age can serve in the military. The age at which teens are allowed to serve in the military is generally younger then the legal drinking age. In Europe it is more common for the driving age to be higher (usually 18) while the drinking age is lower than that of the US (usually 16 or 18). In Canada, the drinking age is 18 in some areas and 19 in other areas. In Australia, universally the minimum drinking age is 18, unless a person is in a private residence or is under parental supervision in a licensed premises. The driving age varies from state to state but the more common system is a graduated system of "L plates" (a learning license that requires supervision from a licensed driver) from age 16, "P plates" (probationary license) at 18 and finally a full license after 2 years on P plates i.e. for most people around the age of 21.
The legal gambling age also depends on the jurisdiction, although it is typically 18. You have to be 21 to play cards at a casino.
The minimum age for donating blood in the U.S is 17 although it may be 16 with parental permission in some states such as New York.
A number of social scientists, including anthropologist Margaret Mead and sociologist Mike Males, have noted the contradictory treatment of laws affecting adolescents in the United States. As Males has noted, the US Supreme Court has, "explicitly ruled that policy-makers may impose adult responsibilities and punishments on individual youths as if they were adults at the same time laws and policies abrogate adolescents’ rights en masse as if they were children."
The issue of youth activism affecting political, social, educational, and moral circumstances is of growing significance around the world. Youth-led organizations around the world have fought for social justice, the youth vote seeking to gain teenagers the right to vote, to secure more youth rights, and demanding better schools through student activism.
Since the advent of the Convention on the Rights of the Child in 1989 (children defined as under 18), almost every country (except the U.S. & Somalia) in the world has become voluntarily legally committed to advancing an anti-discriminatory stance towards young people of all ages. This is a legally binding document which secures youth participation throughout society while acting against unchecked child labor, child soldiers, child prostitution, and pornography. | Adolescence
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Adolescence (lat adolescere = (to) grow) is a transitional stage of human development that occurs between childhood and adulthood. Adolescent humans go through puberty, the process of sexual maturation. Teenagers (ages 13-19) are usually adolescent, though in some individuals, puberty may extend a few years beyond the teenage years, and in some individuals, puberty begins in the pre-teen years.
# Usage
In common usage around the world, "adolescent", "teenager", "teen", "youth", "young adult", "youngster", "young person" and "emerging adult" may be considered synonyms - although the term 'teenager' is an artifact of the English counting system, something which does not occur in all languages. The Oxford English Dictionary cites the first usage of the term to a Popular Science Monthly issue of April, 1941, "I never knew teen-agers could be so serious."
In sociology, adolescence is seen as a cultural phenomenon for the working world and therefore its end points are not easily tied to physical milestones. The time is identified with dramatic changes in the body, along with developments in a person's psychology and academic career. At the onset of adolescence (often referred to as 'puberty'), children usually complete elementary school and enter secondary education, such as middle school or high school. A person between early childhood and the teenage years is sometimes referred to as a pre-teen or tween.
As a transitional stage of human development, adolescence is the period in which a child matures into an adult. This transition involves biological (i.e. pubertal), social, and psychological changes, though the biological or physiological ones are the easiest to measure objectively.
The ages of adolescence vary by culture. The World Health Organization (WHO) defines adolescence as the period of life between 10 and 19 years of age.[1] In contrast, in the United States, adolescence is generally considered to begin somewhere between ages 12 and 14, and end from 19 to 21. As distinct from the varied interpretations of who is considered an "adolescent", the word "teenager" is more easily defined: it describes a person who is thirteen to nineteen years of age.
During this period of life, most children go through the physical stages of puberty which often begins between the ages of nine and thirteen. (See Puberty below)
Most cultures regard people as becoming adults at various ages of the teenage years, often at the age of eighteen. (See Social and cultural below)
# Puberty
Puberty is the stage of the lifespan in which a child develops secondary sex characteristics (for example a deeper voice or larger adam's apple in boys, and development of breasts and hips in girls) as his or her hormonal balance shifts strongly towards an adult state. This is triggered by the pituitary gland, which secretes a surge of hormones, such as testosterone (boys) or estrogen (girls) into the blood stream and begins the rapid maturation of the gonads: the girl's ovaries and the boy's testicles. Some boys may develop Gynecomastia due an imbalance of sex hormones, tissue responsiveness or obesity. Put simply, puberty is the time when a childs body starts changing as to look more like an adult.
The onset of puberty in girls appears to be related to body fat percentage. In most Western countries, the average age of a girl's first menstrual period, or menarche, fell in a decreasing secular trend.[citation needed] Girls start going through puberty earlier than boys. The average age for girls to start puberty is 10-12 while the average age for boys to start puberty is 12-14.
# Psychology
Adolescent psychology is associated with the notable changes in the behavior also known as Mood swing. The characteristics of adolescents, cognitive, emotional and attitudinal changes take place during this period, which can be a cause of conflict on one hand and positive personality development on the other.
Due to the adolescents' experiencing various cognitive and physical changes, it is frequently notable that they start giving more importance to their friends, their peer group, and less to their parents/guardians, due to the aggregated influence of whom they might go on to indulge in activities not deemed as socially acceptable, although this may be more of a social phenomenon than a psychological one.[2]
In the search for a unique social identity for themselves, adolescents are frequently found confused between the 'right' and 'wrong.' G. Stanley Hall denoted this period as one of "Storm and Stress" and, according to him, conflict at this developmental stage is normal and not unusual. Margaret Mead, on the other hand, attributed the behavior of adolescents to their culture and upbringing.[3] However, Piaget, attributed this stage in development with greatly increased cognitive abilities; at this stage of life the individual's thoughts start taking more of an abstract form and the egocentric thoughts decrease, hence the individual is able to think and reason in a wider perspective.[4]
Positive psychology is sometimes brought up when addressing adolescent psychology as well. This approach towards adolescents refers to providing them with motivation to become socially acceptable and notable individuals, since many adolescents find themselves bored, indecisive and/or unmotivated.[5]
It should also be noted that adolescence is the stage of a psychological breakthrough in a person's life when the cognitive development is rapid[6] and the thoughts, ideas and concepts developed at this period of life greatly influence the individual's future life, playing a major role in character and personality formation.[7]
# Sexuality
Adolescent sexuality refers to sexual feelings, behavior and development in adolescents and is a stage of human sexuality. Sexuality and sexual desire usually begins to appear along with the onset of puberty. The expression of sexual desire among adolescents (or anyone, for that matter), might be influenced by family values and influences, the culture and religion they have grown up in social engineering, social control, taboos, and other kinds of social mores.
The risks of adolescent sexual activity is sometimes associated with: emotional distress (fear of abuse or exploitation), sexually transmitted diseases (including HIV/AIDS) and pregnancy through failure or non-use of birth control. In terms of sexual identity, sexual orientation among adolescents may vary greatly across the spectrum from heterosexuality and LGBT orientations to pansexuality and sexual fetishism.
According to anthropologist Racheal and psychologist Albert Bandura, the turmoil found in adolescence in Western society has a cultural rather than a physical cause, and societies where young women engage in free sexual activity have had no such adolescent turmoil until more recently when truthful information about deadly STD's has been made publicly assessible. However many of these studies have been proven false. [8][9]
The age of consent to sexual activity varies widely between international jurisdictions, ranging from 12 to 21 years, although some governments, such as Canada's, are planning to raise the age to at least 16 in an effort to reduce the incidence of lethal STD's, pregnancy among teenage girls, and the sexual abuse and exploitation of younger teens.
# Culture
In commerce, this generation is seen as an important target. Mobile phones, contemporary popular music, movies, television programs, sports, video games and clothes are heavily marketed and often popular amongst adolescents.
In the past (and still in some cultures) there were ceremonies that celebrated adulthood, typically occurring during adolescence. Seijin shiki (literally "adult ceremony") is a Japanese example of this. Upanayanam is a coming of age ceremony for males in the Hindu world. In Judaism, 12 year old girls and 13-year-old boys become Bat or Bar Mitzvah, respectively, and often have a celebration to mark this coming of age. Among some denominations of Christianity, the rite or sacrament of Confirmation is received by adolescents and may be considered the time at which adolescents becomes members of the church in their own right. African boys also have a coming of age ceremony in which, upon reaching adolescence, the males state a promise to never do anything to shame their families or their village. This was also continued among African-American slaves in the early days of slavery before the practice was outlawed. In United States, girls will often have a "sweet sixteen" party to celebrate turning the aforementioned age, a tradition similar to the quinceañera in Latin culture. In modern America, events such as getting your first driver's license, high school and later on college graduation and first career related job are thought of as being more significant markers in transition to adulthood.
Adolescents have also been an important factor in many movements for positive social change around the world. The popular history of adolescents participating in these movements may perhaps start with Joan of Arc, and extend to present times with popular youth activism, student activism, and other efforts to make youth voice heard.
# Legal issues, rights and privileges
Internationally, those over a certain age (often 18, though this varies) are legally considered to have reached the age of majority and are regarded as adults and are held to be responsible for their actions. People below this age are considered minors and are children. A person below the age of majority may gain adult rights through legal emancipation. Teenagers may be rebellious because they want to have the same rights and freedoms as adults. As a result some of those teens may obtain counterfeit ID/licenses which allow them to partake of those privileges. On the other hand, many teens are in no particular hurry to abandon their younger years, and enjoy their childhood.
Those who are under the age of consent, or legal responsibility, may be considered too young to be held accountable for criminal action. This is called the defense of infancy. The age of criminal responsibility varies from 7 in India to 18 in Belgium. After reaching the initial age, there may be levels of responsibility dictated by age and type of offense, and crimes committed by minors may be tried in a juvenile court.
The legal working age in Western countries is usually 14 to 16, depending on the number of hours and type of employment. In the United Kingdom and Canada, for example, kids between 14 and 16 can work at certain types of light work with some restrictions to allow for schooling; while kids over 16 can work full-time (excluding night work). Many countries also specify a minimum school leaving age, ranging from 10 to 18, at which a person is legally allowed to leave compulsory education.
The age of consent to sexual activity varies widely between jurisdictions, ranging from 12 to 21 years, although 14 to 16 years is more usual. Sexual intercourse with a person below this age is treated as the crime of statutory rape. Some jurisdictions allow an exemption where both partners are close in age - for example, two 15 year olds. The age at which people are allowed to marry also varies, from 9 in Yemen to 22 for males and 20 for females in China. In Western countries, people are typically allowed to marry at 18, although they are sometimes allowed to marry at a younger age with parental or court consent. In developing countries, the legal marriageable age does not always correspond with the age at which people actually marry; for example, the legal age for marriage in Ethiopia is 18 for both males and females, but in rural areas most girls are married by age 16.
In most democratic countries, a citizen is eligible to vote at 18. For example, in the United States, the Twenty-sixth amendment decreased the voting age from 21 to 18. In a minority of countries, the voting age is 17 (for example, Indonesia) or 16 (for example, Brazil). By contrast, some countries have a minimum voting age of 21 (for example, Singapore) whereas the minimum age in Uzbekistan is 25. Age of candidacy is the minimum age at which a person can legally qualify to hold certain elected government offices. In most countries, a person must be 18 or over to stand for elected office, but some countries such as the United States and Italy have further restrictions depending on the type of office.
The sale of selected items such as cigarettes, alcohol, and videos with violent or pornographic content is also restricted by age in most countries. In the U.S, the minimum age to buy an R-rated movie, M-rated game or an album with a parental advisory label is 17 (in some states 18). In practice, it is common that young people engage in underage smoking or drinking, and in some cultures this is tolerated to a certain degree. In the United States, teenagers are allowed to drive between 14-18 (each state sets its own minimum driving age of which a curfew may be imposed), in the US, adolescents 17 years of age can serve in the military. The age at which teens are allowed to serve in the military is generally younger then the legal drinking age. In Europe it is more common for the driving age to be higher (usually 18) while the drinking age is lower than that of the US (usually 16 or 18). In Canada, the drinking age is 18 in some areas and 19 in other areas. In Australia, universally the minimum drinking age is 18, unless a person is in a private residence or is under parental supervision in a licensed premises. The driving age varies from state to state but the more common system is a graduated system of "L plates" (a learning license that requires supervision from a licensed driver) from age 16, "P plates" (probationary license) at 18 and finally a full license after 2 years on P plates i.e. for most people around the age of 21.
The legal gambling age also depends on the jurisdiction, although it is typically 18. You have to be 21 to play cards at a casino.[citation needed]
The minimum age for donating blood in the U.S is 17 although it may be 16 with parental permission in some states such as New York.
A number of social scientists, including anthropologist Margaret Mead and sociologist Mike Males, have noted the contradictory treatment of laws affecting adolescents in the United States. As Males has noted, the US Supreme Court has, "explicitly ruled that policy-makers may impose adult responsibilities and punishments on individual youths as if they were adults at the same time laws and policies abrogate adolescents’ rights en masse as if they were children."
The issue of youth activism affecting political, social, educational, and moral circumstances is of growing significance around the world. Youth-led organizations around the world have fought for social justice, the youth vote seeking to gain teenagers the right to vote, to secure more youth rights, and demanding better schools through student activism.
Since the advent of the Convention on the Rights of the Child in 1989 (children defined as under 18), almost every country (except the U.S. & Somalia) in the world has become voluntarily legally committed to advancing an anti-discriminatory stance towards young people of all ages. This is a legally binding document which secures youth participation throughout society while acting against unchecked child labor, child soldiers, child prostitution, and pornography. | https://www.wikidoc.org/index.php/Adolescence | |
f24f30789c4254d3dec65f47ae38596c554c481b | wikidoc | Aerosol-PFC | Aerosol-PFC
# Overview
The applications mission is treatment of pulmonary diseases by aerososolized perfluorocarbon(PFC). This new technology of PFC aerosolization via an introducible jet-nebulizer (Aer-Probe, Trudell) has been demonstrated in several animal studies (Kandler, von der Hardt). Aerosol way of PFC application offers a safe and easy to handle procedure for perfluorocarbon assisted ventilation. Patients with ARDS and neonatal respiratory distress syndrome show sustained improvement in gas exchange and lung mechanics. Ventilator associated lung injury is attenuated by the applied perfluorocarbon, diminishing inflammatory induction of chronic lung disease.
Technology is dedicated to perfluorocabons relatively independent from the molecular structure. It offers the chance to register an appropriate PFC for use as respiratory drug.
Recent invetigations showed after induction of lung injury by repeated saline lung lavage due to surfactant depletion in neonatal piglets, the new ventilatory strategy with aerosolized perfluorocarbon led to a reduction of the initial pulmonary inflammatory reaction and an improvement of gas exchange.
Gene expression of IL-1ß, IL-6, IL-8 and TGF-ß1 in pulmonary tissue was significantly lower in surfactant depleted neonatal piglets with severe respiratory distress syndrome receiving aerosolized perfluorocarbon (Aerosol-PFC) than in the control group ventilated with intermittent mandatory ventilation (von der Hardt, Kandler). In this surfactant piglet model, mRNA expression of inflammation mediated adhesion molecules, such as E-Selectin, P-Selectin and ICAM-1 was effectively diminished by using aerosolized perfluorocarbon (Schoof, von der Hardt). Relative neutrophil infiltration in lung tissue was significantly reduced after treatment with aerosolized perfluorocarbon.
Proinflammatory cytokines and intercellular adhesion molecules in porcine lung tissue participating in acute pulmonary inflammatory response were detected and could be modulated by a new protective respiratory support with aerosolized perfluorocarbon. | Aerosol-PFC
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The applications mission is treatment of pulmonary diseases by aerososolized perfluorocarbon(PFC). This new technology of PFC aerosolization via an introducible jet-nebulizer (Aer-Probe, Trudell) has been demonstrated in several animal studies (Kandler, von der Hardt). Aerosol way of PFC application offers a safe and easy to handle procedure for perfluorocarbon assisted ventilation. Patients with ARDS and neonatal respiratory distress syndrome show sustained improvement in gas exchange and lung mechanics. Ventilator associated lung injury is attenuated by the applied perfluorocarbon, diminishing inflammatory induction of chronic lung disease.
Technology is dedicated to perfluorocabons relatively independent from the molecular structure. It offers the chance to register an appropriate PFC for use as respiratory drug.
Recent invetigations showed after induction of lung injury by repeated saline lung lavage due to surfactant depletion in neonatal piglets, the new ventilatory strategy with aerosolized perfluorocarbon led to a reduction of the initial pulmonary inflammatory reaction and an improvement of gas exchange.
Gene expression of IL-1ß, IL-6, IL-8 and TGF-ß1 in pulmonary tissue was significantly lower in surfactant depleted neonatal piglets with severe respiratory distress syndrome receiving aerosolized perfluorocarbon (Aerosol-PFC) than in the control group ventilated with intermittent mandatory ventilation (von der Hardt, Kandler). In this surfactant piglet model, mRNA expression of inflammation mediated adhesion molecules, such as E-Selectin, P-Selectin and ICAM-1 was effectively diminished by using aerosolized perfluorocarbon (Schoof, von der Hardt). Relative neutrophil infiltration in lung tissue was significantly reduced after treatment with aerosolized perfluorocarbon.
Proinflammatory cytokines and intercellular adhesion molecules in porcine lung tissue participating in acute pulmonary inflammatory response were detected and could be modulated by a new protective respiratory support with aerosolized perfluorocarbon. | https://www.wikidoc.org/index.php/Aerosol-PFC | |
7becf088a9b8c95fdffe8444044f3a7e72e81b55 | wikidoc | Aflibercept | Aflibercept
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Aflibercept is a Ophthalmologic Agent that is FDA approved for the treatment of Macular Edema Following Retinal Vein Occlusion , Diabetic Macular Edema ,Neovascular (Wet) Age-Related Macular Degeneration. Common adverse reactions include conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Neovascular (Wet) Age-Related Macular Degeneration (AMD)
- Macular Edema Following Retinal Vein Occlusion (RVO)
- Diabetic Macular Edema (DME)
### Dosage
- For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician.
- The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks.
- The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly).
- The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks.
### Dosage forms and Strengths
- Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution (2 mg) for intravitreal injection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aflibercept in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aflibercept in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Aflibercept in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aflibercept in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aflibercept in pediatric patients.
# Contraindications
- EYLEA is contraindicated in patients with ocular or periocular infections.
- EYLEA is contraindicated in patients with active intraocular inflammation.
- EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA. Hypersensitivity reactions may manifest as severe intraocular inflammation.
# Warnings
- Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.
- Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA . Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.
- There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies during the first year was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.
- A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3 studies. Among those, 2110 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.
- The data described below reflect exposure to EYLEA in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months
- Less common serious adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis.
- The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following BRVO in one clinical study (VIBRANT).
- Less common adverse reactions reported in <1% of the patients treated with EYLEA in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
- The data described below reflect exposure to EYLEA in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) for 52 weeks
- Less common adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, eyelid edema, corneal edema, retinal detachment, injection site hemorrhage, and retinal tear.
- As with all therapeutic proteins, there is a potential for an immune response in patients treated with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to EYLEA in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other products may be misleading.
- In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-52 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. There were no differences in efficacy or safety between patients with or without immunoreactivity.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Aflibercept in the drug label.
# Drug Interactions
There is limited information regarding Aflibercept Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Aflibercept produced embryo-fetal toxicity when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg.
- There are no adequate and well-controlled studies in pregnant women. EYLEA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aflibercept in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aflibercept during labor and delivery.
### Nursing Mothers
- It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted in human milk, a risk to the breastfed child cannot be excluded. EYLEA is not recommended during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue treatment with EYLEA, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of EYLEA in pediatric patients have not been established.
### Geriatic Use
- In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.
### Gender
There is no FDA guidance on the use of Aflibercept with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aflibercept with respect to specific racial populations.
### Renal Impairment
- Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a RVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, RVO, or DME patients
### Hepatic Impairment
There is no FDA guidance on the use of Aflibercept in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aflibercept in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aflibercept in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician.
- EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used.
- Using aseptic technique, the intravitreal injection should be performed with a 30-gauge × ½-inch injection needle.
- The glass vial is for single use only.
- Remove the protective plastic cap from the vial
- Remove the 19-gauge × 1½-inch, 5-micron, filter needle from its pouch and remove the 1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip
- Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.
- Using aseptic technique withdraw all of the EYLEA vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid
- Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
- Remove the filter needle from the syringe and properly dispose of the filter needle. Note: Filter needle is not to be used for intravitreal injection.
- Remove the 30-gauge × ½-inch injection needle from the plastic pouch and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip
- When ready to administer EYLEA, remove the plastic needle shield from the needle.
- Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top
- To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe
- The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.
- Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay.
- Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYLEA is administered to the other eye.
- After injection, any unused product must be discarded.
### Monitoring
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry.
# IV Compatibility
There is limited information regarding IV Compatibility of Aflibercept in the drug label.
# Overdosage
There is limited information regarding Overdose of Aflibercept in the drug label.
# Pharmacology
## Mechanism of Action
- Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.
- Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.
## Structure
- EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.
- EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of EYLEA (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).
## Pharmacodynamics
- In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions.
- Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions .
- Reductions in mean retinal thickness were observed in VIVID and VISTA at week 52 compared to baseline. Anatomic data were not used to influence EYLEA treatment decisions
## Pharmacokinetics
- EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of EYLEA, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).
- Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD, RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF.
- The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L.
- Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept.
## Nonclinical Toxicology
- No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.
- Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in humans after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies
# Clinical Studies
- The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with EYLEA) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 3 initial monthly doses (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered every 4 weeks (EYLEA 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years.
- In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Data are available through week 52. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group.
- Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in TABLE 4 and FIGURE 8 below.
- The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with EYLEA) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89 years with a mean of 64 years.
- In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.
- Results from the analysis of the COPERNICUS and GALILEO studies are shown in TABLE 5 and FIGURE 9 below.
- Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.
- The safety and efficacy of EYLEA were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with EYLEA) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Patient ages ranged from 42 to 94 years with a mean of 65 years.
- In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.
- Detailed results from the analysis of the VIBRANT study are shown in TABLE 6 and FIGURE 10 below.
- The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Patient ages ranged from 23 to 87 years with a mean of 63 years.
- Of those, 576 were randomized to EYLEA groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 5 initial monthly injections (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the EYLEA groups could receive laser and patients in the laser group could receive EYLEA.
- In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both EYLEA 2Q8 and EYLEA 2Q4 groups was statistically superior to the control group.
- Results from the analysis of the VIVID and VISTA studies are shown in TABLE 7 and FIGURE 11 below.
- Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation.
- Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations.
# How Supplied
- Each Vial is for single eye use only. EYLEA is supplied in the following presentation
## Storage
- EYLEA should be refrigerated at 2°C to 8ºC (36°F to 46ºF). Do Not Freeze. Do not use beyond the date stamped on the carton and container label. Protect from light. Store in the original carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
NDC 61755-005-02
EYLEA®
(aflibercept) Injection
For Intravitreal Injection
2 mg/0.05 mL
Single-use Vial
Rx ONLY
# Patient Counseling Information
- In the days following EYLEA administration, patients are at risk of developing endophthalmitis or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an ophthalmologist.
- Patients may experience temporary visual disturbances after an intravitreal injection with EYLEA and the associated eye examinations. Advise patients not to drive or use machinery until visual function has recovered sufficiently.
# Precautions with Alcohol
- Alcohol-Aflibercept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- EYLEA®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Aflibercept
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Aflibercept is a Ophthalmologic Agent that is FDA approved for the treatment of Macular Edema Following Retinal Vein Occlusion , Diabetic Macular Edema ,Neovascular (Wet) Age-Related Macular Degeneration. Common adverse reactions include conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Neovascular (Wet) Age-Related Macular Degeneration (AMD)
- Macular Edema Following Retinal Vein Occlusion (RVO)
- Diabetic Macular Edema (DME)
### Dosage
- For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician.
- The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks.
- The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly).
- The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks.
### Dosage forms and Strengths
- Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution (2 mg) for intravitreal injection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aflibercept in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aflibercept in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Aflibercept in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aflibercept in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aflibercept in pediatric patients.
# Contraindications
- EYLEA is contraindicated in patients with ocular or periocular infections.
- EYLEA is contraindicated in patients with active intraocular inflammation.
- EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA. Hypersensitivity reactions may manifest as severe intraocular inflammation.
# Warnings
- Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.
- Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA . Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.
- There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies during the first year was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.
- A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3 studies. Among those, 2110 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.
- The data described below reflect exposure to EYLEA in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months
- Less common serious adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis.
- The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following BRVO in one clinical study (VIBRANT).
- Less common adverse reactions reported in <1% of the patients treated with EYLEA in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
- The data described below reflect exposure to EYLEA in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) for 52 weeks
- Less common adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, eyelid edema, corneal edema, retinal detachment, injection site hemorrhage, and retinal tear.
- As with all therapeutic proteins, there is a potential for an immune response in patients treated with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to EYLEA in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other products may be misleading.
- In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-52 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. There were no differences in efficacy or safety between patients with or without immunoreactivity.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Aflibercept in the drug label.
# Drug Interactions
There is limited information regarding Aflibercept Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Aflibercept produced embryo-fetal toxicity when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg.
- There are no adequate and well-controlled studies in pregnant women. EYLEA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aflibercept in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aflibercept during labor and delivery.
### Nursing Mothers
- It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted in human milk, a risk to the breastfed child cannot be excluded. EYLEA is not recommended during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue treatment with EYLEA, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of EYLEA in pediatric patients have not been established.
### Geriatic Use
- In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.
### Gender
There is no FDA guidance on the use of Aflibercept with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aflibercept with respect to specific racial populations.
### Renal Impairment
- Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a RVO study and in patients in a DME study. No dose adjustment based on renal impairment status is needed for either wet AMD, RVO, or DME patients
### Hepatic Impairment
There is no FDA guidance on the use of Aflibercept in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aflibercept in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aflibercept in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician.
- EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used.
- Using aseptic technique, the intravitreal injection should be performed with a 30-gauge × ½-inch injection needle.
- The glass vial is for single use only.
- Remove the protective plastic cap from the vial
- Remove the 19-gauge × 1½-inch, 5-micron, filter needle from its pouch and remove the 1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip
- Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.
- Using aseptic technique withdraw all of the EYLEA vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid
- Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
- Remove the filter needle from the syringe and properly dispose of the filter needle. Note: Filter needle is not to be used for intravitreal injection.
- Remove the 30-gauge × ½-inch injection needle from the plastic pouch and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip
- When ready to administer EYLEA, remove the plastic needle shield from the needle.
- Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top
- To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe
- The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.
- Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay.
- Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYLEA is administered to the other eye.
- After injection, any unused product must be discarded.
### Monitoring
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry.
# IV Compatibility
There is limited information regarding IV Compatibility of Aflibercept in the drug label.
# Overdosage
There is limited information regarding Overdose of Aflibercept in the drug label.
# Pharmacology
## Mechanism of Action
- Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.
- Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.
## Structure
- EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.
- EYLEA is a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of EYLEA (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).
## Pharmacodynamics
- In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions.
- Reductions in mean retinal thickness were observed in COPERNICUS, GALILEO, and VIBRANT at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions [see CLINICAL STUDIES (14.2), (14.3)].
- Reductions in mean retinal thickness were observed in VIVID and VISTA at week 52 compared to baseline. Anatomic data were not used to influence EYLEA treatment decisions
## Pharmacokinetics
- EYLEA is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of EYLEA, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).
- Following intravitreal administration of 2 mg per eye of EYLEA to patients with wet AMD, RVO, and DME, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL), 0.05 mcg/mL (range: 0 to 0.081 mcg/mL), and 0.03 mcg/mL (range: 0 to 0.076 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF.
- The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L.
- Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept.
## Nonclinical Toxicology
- No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.
- Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in humans after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies
# Clinical Studies
- The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with EYLEA) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 3 initial monthly doses (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); 3) EYLEA 0.5 mg administered every 4 weeks (EYLEA 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years.
- In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Data are available through week 52. Both EYLEA 2Q8 and EYLEA 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group.
- Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in TABLE 4 and FIGURE 8 below.
- The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with EYLEA) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89 years with a mean of 64 years.
- In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.
- Results from the analysis of the COPERNICUS and GALILEO studies are shown in TABLE 5 and FIGURE 9 below.
- Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.
- The safety and efficacy of EYLEA were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with EYLEA) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg EYLEA administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Patient ages ranged from 42 to 94 years with a mean of 65 years.
- In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the EYLEA 2 mg Q4 group was superior to the control group for the primary endpoint.
- Detailed results from the analysis of the VIBRANT study are shown in TABLE 6 and FIGURE 10 below.
- The safety and efficacy of EYLEA were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Patient ages ranged from 23 to 87 years with a mean of 63 years.
- Of those, 576 were randomized to EYLEA groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) EYLEA administered 2 mg every 8 weeks following 5 initial monthly injections (EYLEA 2Q8); 2) EYLEA administered 2 mg every 4 weeks (EYLEA 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the EYLEA groups could receive laser and patients in the laser group could receive EYLEA.
- In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both EYLEA 2Q8 and EYLEA 2Q4 groups was statistically superior to the control group.
- Results from the analysis of the VIVID and VISTA studies are shown in TABLE 7 and FIGURE 11 below.
- Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation.
- Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations.
# How Supplied
- Each Vial is for single eye use only. EYLEA is supplied in the following presentation
## Storage
- EYLEA should be refrigerated at 2°C to 8ºC (36°F to 46ºF). Do Not Freeze. Do not use beyond the date stamped on the carton and container label. Protect from light. Store in the original carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
NDC 61755-005-02
EYLEA®
(aflibercept) Injection
For Intravitreal Injection
2 mg/0.05 mL
Single-use Vial
Rx ONLY
# Patient Counseling Information
- In the days following EYLEA administration, patients are at risk of developing endophthalmitis or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an ophthalmologist.
- Patients may experience temporary visual disturbances after an intravitreal injection with EYLEA and the associated eye examinations. Advise patients not to drive or use machinery until visual function has recovered sufficiently.
# Precautions with Alcohol
- Alcohol-Aflibercept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- EYLEA®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aflibercept | |
cac8710ae30017e28c006b38feed5a826d7ec557 | wikidoc | Agomelatine | Agomelatine
Agomelatine (BAN, rINN; trade names Valdoxan, Melitor, Thymanax) is a melatonergic antidepressant developed by the pharmaceutical company Servier. It is marketed for the treatment of major depressive disorder and has been reported not to produce discontinuation syndrome or sexual side effects (compared to SSRIs, SNRIs and the older tricyclic antidepressants). Agomelatine may also have positive effects on sleep and cognition.
# History
Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union.
In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax. On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation of Valdoxan/Thymanax (agomelatine). The major concern was that efficacy had not been sufficiently shown. The CHMP had no special concerns about side effects. In September 2007, Servier submitted a new marketing application for Valdoxan (agomelatine) to the EMA.
In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012. However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.
It received EMA approval for marketing in the European Union in February 2009 and TGA approval for marketing in Australia in August 2010.
# Medical uses
## Major depressive disorder
Agomelatine is indicated for the treatment of major depressive episodes in adults. Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in six of the ten short-term double-blind placebo-controlled studies. Two were considered "failed" trials, as comparators of established efficacy failed to differentiated from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies. The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study.
Results of the meta-analysis of three positive, randomized, double-blind, placebo controlled studies in 357 patients treated with agomelatine and 360 patients treated with placebo show that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In patients with a greater baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points. Controlled studies in humans have shown that agomelatine is at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, venlafaxine and fluoxetine in the treatment of major depression.
A large meta-analysis of 20 trials with 7460 participants found agomelatine to be as effective as standard antidepressants.
A small open-label study has suggested efficacy in the treatment of atypical and melancholic depression. Well-designed clinical trials have demonstrated efficacy in the treatment of anxious depression. Agomelatine’s onset of action has been reported to occur as early as the first week of treatment.
## Investigational
Additionally, possibly because of its action on melatonin receptors, agomelatine appears to improve sleep quality, with no reported daytime drowsiness. Agomelatine has demonstrated anxiolytic properties in rodents. It has been found significantly more effective than placebo in the treatment of generalised anxiety disorder. There is tentative evidence to suggest the efficacy of agomelatine as either a monotherapy or adjunct in the treatment of obsessive-compulsive disorder. A case report documenting the efficacy of agomelatine in the treatment of social anxiety disorder has been published. An open-label study has found agomelatine to be efficacious in the treatment of seasonal affective disorder. Open-label studies have suggested efficacy of adjunctive agomelatine in bipolar depression. A study in mice found that protected against pentylenetetrazole- and pilocarpine-induced seizures. A small placebo-controlled trial found some benefit of agomelatine in ADHD.
## Use in special populations
It is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. Only limited clinical data is available on the use of agomelatine in elderly patients ≥ 65 years old with major depressive episodes. Therefore, caution should be exercised when prescribing it to these patients.
# Adverse effects
Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.
Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine. It appears better tolerated than the SSRIs.
- Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature)
- Abdominal pain
- Nausea
- Vomiting
- Diarrhea
- Constipation
- Back pain
- Fatigue
- Increased ALAT and ASAT (liver enzymes)
- Headache
- Dizziness
- Somnolence
- Insomnia
- Migraine
- Anxiety
- Paraesthesia (abnormal sensations due to malfunctioning of the peripheral nerves)
- Blurred vision
- Eczema
- Pruritus (itching)
- Urticaria
- Agitation
- Irritability
- Restlessness
- Aggression
- Nightmares
- Abnormal dreams
Note the following two side effects are often due to an underlying disease, namely bipolar disorder.
- Mania
- Hypomania
- Suicidal ideation
- Suicidal behaviour
- Hallucinations
- Hepatitis
- Increased GGT and/or alkaline phosphatase
- Liver failure
- Jaundice
- Erythematous rash
- Face oedema and angioedema
- Weight gain or loss, which tends to be less significant than with SSRIs
## Contraindications
Agomelatine is contraindicated in patients with kidney or liver impairment. According to information disclosed by Les Laboratoires Servier on October 10, 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decided whether pursue the treatment or not. No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.
## Interactions
Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19 and hence CYP1A2, CYP2C9 and CYP2C19 inhibitors (e.g. the SSRI antidepressant, fluvoxamine) reduce its clearance and can hence lead to an increase in agomelatine exposure. There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity (liver toxicity).
## Overdose
Agomelatine is expected to be relatively safe in overdose.
## Dependence and withdrawal
No dosage tapering is needed on treatment discontinuation. Agomelatine has no abuse potential as measured in healthy volunteer studies.
# Structure
The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an NH group, agomelatine has an HC=CH group. Thus melatonin contains an indole part, whereas agomelatine has a naphthalene bioisostere instead.
# Mechanism of action
Agomelatine is a melatonin receptor agonist (MT1 (Ki=0.1nM) and MT2 (Ki=0.12nM)) and a 5-HT2C (Ki=631nM) receptor antagonist. Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors, nor other serotonergic receptors.
Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome. By antagonizing 5-HT2C receptors, it disinhibits/increases noradrenaline and dopamine release specifically in the frontal cortex. Therefore, it is sometimes classified as a norepinephrine–dopamine disinhibitor. It has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. | Agomelatine
Agomelatine (BAN, rINN; trade names Valdoxan, Melitor, Thymanax) is a melatonergic antidepressant developed by the pharmaceutical company Servier. It is marketed for the treatment of major depressive disorder and has been reported not to produce discontinuation syndrome or sexual side effects (compared to SSRIs, SNRIs and the older tricyclic antidepressants). Agomelatine may also have positive[clarification needed] effects on sleep and cognition.
# History
Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union.
In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax.[2] On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation of Valdoxan/Thymanax (agomelatine). The major concern was that efficacy had not been sufficiently shown. The CHMP had no special concerns about side effects.[2] In September 2007, Servier submitted a new marketing application for Valdoxan (agomelatine) to the EMA.[3]
In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis.[4] It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012.[5] However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.[6]
It received EMA approval for marketing in the European Union in February 2009[7] and TGA approval for marketing in Australia in August 2010.[1]
# Medical uses
## Major depressive disorder
Agomelatine is indicated for the treatment of major depressive episodes in adults.[7] Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in six of the ten short-term double-blind placebo-controlled studies.[7] Two were considered "failed" trials, as comparators of established efficacy failed to differentiated from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies.[7] The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study.[7]
Results of the meta-analysis of three positive, randomized, double-blind, placebo controlled studies in 357 patients treated with agomelatine and 360 patients treated with placebo show that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In patients with a greater baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points.[8] Controlled studies in humans have shown that agomelatine is at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, venlafaxine and fluoxetine in the treatment of major depression.[9][10][11]
A large meta-analysis of 20 trials with 7460 participants found agomelatine to be as effective as standard antidepressants.[12]
A small open-label study has suggested efficacy in the treatment of atypical and melancholic depression.[13] Well-designed clinical trials have demonstrated efficacy in the treatment of anxious depression.[14][15] Agomelatine’s onset of action has been reported to occur as early as the first week of treatment.[16]
## Investigational
Additionally, possibly because of its action on melatonin receptors, agomelatine appears to improve sleep quality, with no reported daytime drowsiness.[17] Agomelatine has demonstrated anxiolytic properties in rodents.[18] It has been found significantly more effective than placebo in the treatment of generalised anxiety disorder.[19] There is tentative evidence to suggest the efficacy of agomelatine as either a monotherapy or adjunct in the treatment of obsessive-compulsive disorder.[20][21][22][23] A case report documenting the efficacy of agomelatine in the treatment of social anxiety disorder has been published.[24] An open-label study has found agomelatine to be efficacious in the treatment of seasonal affective disorder.[25] Open-label studies have suggested efficacy of adjunctive agomelatine in bipolar depression.[26][27] A study in mice found that protected against pentylenetetrazole- and pilocarpine-induced seizures.[28] A small placebo-controlled trial found some benefit of agomelatine in ADHD.[29]
## Use in special populations
It is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.[7] Only limited clinical data is available on the use of agomelatine in elderly patients ≥ 65 years old with major depressive episodes. Therefore, caution should be exercised when prescribing it to these patients.[7]
# Adverse effects
Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.[1][7]
Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine.[1] It appears better tolerated than the SSRIs.[10]
- Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature)
- Abdominal pain
- Nausea
- Vomiting
- Diarrhea
- Constipation
- Back pain
- Fatigue
- Increased ALAT and ASAT (liver enzymes)
- Headache
- Dizziness
- Somnolence
- Insomnia
- Migraine
- Anxiety
- Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves)
- Blurred vision
- Eczema
- Pruritus (itching)
- Urticaria
- Agitation
- Irritability
- Restlessness
- Aggression
- Nightmares
- Abnormal dreams
Note the following two side effects are often due to an underlying disease, namely bipolar disorder.
- Mania
- Hypomania
- Suicidal ideation
- Suicidal behaviour
- Hallucinations
- Hepatitis
- Increased GGT and/or alkaline phosphatase
- Liver failure
- Jaundice
- Erythematous rash
- Face oedema and angioedema
- Weight gain or loss, which tends to be less significant than with SSRIs[32]
## Contraindications
Agomelatine is contraindicated in patients with kidney or liver impairment.[7] According to information disclosed by Les Laboratoires Servier on October 10, 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decided whether pursue the treatment or not.[33] No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.[7]
## Interactions
Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19 and hence CYP1A2, CYP2C9 and CYP2C19 inhibitors (e.g. the SSRI antidepressant, fluvoxamine) reduce its clearance and can hence lead to an increase in agomelatine exposure.[1][30] There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity (liver toxicity).[1][30]
## Overdose
Agomelatine is expected to be relatively safe in overdose.[34]
## Dependence and withdrawal
No dosage tapering is needed on treatment discontinuation.[7] Agomelatine has no abuse potential as measured in healthy volunteer studies.[1][7]
# Structure
The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an NH group, agomelatine has an HC=CH group. Thus melatonin contains an indole part, whereas agomelatine has a naphthalene bioisostere instead.[35]
# Mechanism of action
Agomelatine is a melatonin receptor agonist (MT1 (Ki=0.1nM) and MT2 (Ki=0.12nM)) and a 5-HT2C (Ki=631nM) receptor antagonist.[36] Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors, nor other serotonergic receptors.[7]
Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome.[37] By antagonizing 5-HT2C receptors, it disinhibits/increases noradrenaline and dopamine release specifically in the frontal cortex. Therefore, it is sometimes classified as a norepinephrine–dopamine disinhibitor. It has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.[7] | https://www.wikidoc.org/index.php/Agomelatine | |
94543beb0009387028d66728fee319e939b716fe | wikidoc | Agoraphobia | Agoraphobia
# Overview
Agoraphobia is an anxiety disorder characterized by intense terror and anxiety over any place or situation from which one might not easily be able to escape. This often leads sufferers to avoid leaving their homes, using public transportation or air travel, or being in crowded spaces. The average age of onset of agoraphobia is 20 years. Agoraphobia is closely associated with panic disorder; the two are commonly comorbid. Patients with agoraphobia often exhibit depressive symptoms, as well as social or specific phobias, which can make the disorder difficult to diagnose. Patients with severe agoraphobia may become confined to their homes. The word "agoraphobia" is an English adoption of the Greek words agora (αγορά) and phobos (φόβος), literally translated as "a fear of the marketplace." This etymology is the reason for the common misconception that agoraphobia is a fear of open spaces.
# Historical Perspective
- In 1871, Agoraphobia was first described by Karl Friedrich Otto Westphal, a German psychiatrist.
- Westphal coined the term after observing three of his patients, who exhibited severe anxiety and dread upon traveling to certain public areas of Berlin, in the city where he worked.
# Classification
- The DSM-V, released in 2013, classifies agoraphobia as a phobia.
- The ICD-10 places agoraphobia under the subcategory of "Phobic anxiety disorders," which falls under the category of "Neurotic, stress-related and somatoform disorders."
- Within the former subcategory, agoraphobia is grouped together with:
Social phobias
Specific/isolated phobias
Other phobic anxiety disorders
Phobic anxiety disorder, unspecified
- Social phobias
- Specific/isolated phobias
- Other phobic anxiety disorders
- Phobic anxiety disorder, unspecified
- Though some experts have argued that agoraphobia can reasonably be thought of as a severe consequence of panic disorder, a comparison of the multivariate comorbidity patterns of agoraphobia and panic disorder supports the independent classification of these disorders.
# Pathophysiology
## Relationship to Balance Disorders
- Agoraphobia may be related to defects in balance. Researchers who noticed a similarity between the situations commonly avoided by sufferers of agoraphobia and the types of environments that trigger disorientation in people with balance disorders administered a battery of audiovestibular tests, coupled with moving platform posturography, to 36 subjects with agoraphobic symptoms and 20 normal, healthy controls.
Over 60% of the former group were destabilized by these disorienting conditions, compared to a mere 10% of the control group.
Postural instability was found to be highly related to agoraphobic avoidance (r = 0.63, P < 0.01), event after the researchers controlled for symptoms, anxiety, and agoraphobic cognitions.
- Over 60% of the former group were destabilized by these disorienting conditions, compared to a mere 10% of the control group.
- Postural instability was found to be highly related to agoraphobic avoidance (r = 0.63, P < 0.01), event after the researchers controlled for symptoms, anxiety, and agoraphobic cognitions.
## Attachment Theory
- Some scholars (e.g., Liotti 1996, Bowlby 1998) have explained agoraphobia as an attachment deficit, i.e., the temporary loss of the ability to tolerate spatial separations from a secure base.
## Spatial Theory
- In the social sciences, there is a perceived clinical bias (e.g., Davidson 2003) in agoraphobia research. Branches of the social sciences, especially geography, have increasingly become interested in what may be thought of as a spatial phenomenon.
## Associated Conditions
- Commonly comorbid conditions include:
Panic disorder
SAD
Specific phobia
- Panic disorder
- SAD
- Specific phobia
# Differential Diagnosis
- Agoraphobia must be differentiated from other disorders with similar symptomology, including:
Acute stress disorder
Major depressive disorder
Other medical conditions
Parkinson's disease
Multiple sclerosis
Panic disorder without agoraphobia
Post traumatic stress disorder
Separation anxiety disorder
Social anxiety disorder (social phobia)
Specific phobia, situational type
- Acute stress disorder
- Major depressive disorder
- Other medical conditions
Parkinson's disease
Multiple sclerosis
- Parkinson's disease
- Multiple sclerosis
- Panic disorder without agoraphobia
- Post traumatic stress disorder
- Separation anxiety disorder
- Social anxiety disorder (social phobia)
- Specific phobia, situational type
# Epidemiology and Demographics
## Prevalence
- The prevalence of agoraphobia is 1,700 per 100,000 (1.7%) of the overall population.
## Age
- Among children, ages 13 to 18, there is a lifetime prevalence of 2,400 per 100,000 (2.4%) for agoraphobia.
- Among adults in the United States, agoraphobia has a 12-month prevalence of 800 per 100,000 (0.8%). 40.6% of these cases are classified as "severe."
## Gender
- No gender disparity in the incidence of agoraphobia has been widely established.
- Some studies have suggested that panic disorder patients with agoraphobia are more likely to be female than patients who have panic disorder but not agoraphobia. Female patients were also found to have a higher prevalence of comorbidities.
## Race
- No racial predilection has been established for agoraphobia.
# Risk Factors
- The exact cause of agoraphobia is unknown. In some instances, someone who has a panic attack may begin to exhibit signs of agoraphobia out of fear that another panic attack will occur.
- Risk factors for agoraphobia include:
Anxiety sensitivity
Behavioral inhibition
Genetic predisposition
Neurotic disposition (neuroticism)
Negative events in childhood
Separation/divorce of parents
Death of parent
Bullying
Stressful or traumatic events (e.g., being attacked or mugged)
- Anxiety sensitivity
- Behavioral inhibition
- Genetic predisposition
- Neurotic disposition (neuroticism)
- Negative events in childhood
Separation/divorce of parents
Death of parent
Bullying
- Separation/divorce of parents
- Death of parent
- Bullying
- Stressful or traumatic events (e.g., being attacked or mugged)
# Natural History, Complications, and Prognosis
## Natural History
- People with agoraphobia may experience panic attacks in situations in which they feel trapped, insecure, out of control, or too far from their personal comfort zone. In severe cases, an agoraphobic person may be completely confined to his or her home.
Some people with agoraphobia are comfortable seeing visitors, but only in a defined space in which they feel in control.
Such people may live for years without leaving their homes, while happily seeing visitors and working, as long as they can stay within their safety zones.
If someone suffering from agoraphobia leaves his or her "safety zone," an anxiety attack may occur.
Agoraphobia patients can experience sudden panic attacks when traveling to places where they fear, where help would be difficult to obtain. During a panic attack, adrenaline is released in large amounts for several minutes causing the classical "fight or flight" condition.
The attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes.
These symptoms include palpitations, sweating, trembling, and shortness of breath. Many patients report a fear of dying, or losing control of emotions or behavior.
- Some people with agoraphobia are comfortable seeing visitors, but only in a defined space in which they feel in control.
Such people may live for years without leaving their homes, while happily seeing visitors and working, as long as they can stay within their safety zones.
If someone suffering from agoraphobia leaves his or her "safety zone," an anxiety attack may occur.
- Such people may live for years without leaving their homes, while happily seeing visitors and working, as long as they can stay within their safety zones.
- If someone suffering from agoraphobia leaves his or her "safety zone," an anxiety attack may occur.
- Agoraphobia patients can experience sudden panic attacks when traveling to places where they fear, where help would be difficult to obtain. During a panic attack, adrenaline is released in large amounts for several minutes causing the classical "fight or flight" condition.
The attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes.
These symptoms include palpitations, sweating, trembling, and shortness of breath. Many patients report a fear of dying, or losing control of emotions or behavior.
- The attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes.
- These symptoms include palpitations, sweating, trembling, and shortness of breath. Many patients report a fear of dying, or losing control of emotions or behavior.
## Complications
- Complications associated with agoraphobia may encompass physical, behavioral, or lifestyle changes.
The avoidance behaviors associated with agoraphobia are established correlates of treatment discontinuation.
Individuals with agoraphobia are more likely to show signs of decreased assertiveness, perhaps because their illness cultivates feelings of helplessness and insecurity.
The avoidance of places or structures in which panic attacks have occurred may limit a patient’s job prospects or proximity to desirable facilities or services.
- The avoidance behaviors associated with agoraphobia are established correlates of treatment discontinuation.
- Individuals with agoraphobia are more likely to show signs of decreased assertiveness, perhaps because their illness cultivates feelings of helplessness and insecurity.
- The avoidance of places or structures in which panic attacks have occurred may limit a patient’s job prospects or proximity to desirable facilities or services.
## Prognosis
- The prognosis of agoraphobia depends upon the severity of the disease.
- The prognosis is generally good with early medical intervention; if left untreated, the disorder may become more difficult for healthcare providers to effectively manage.
# Diagnosis
## Diagnostic Criteria
### DSM-V Diagnostic Criteria for Agoraphobia
The fifth version of the DSM, released in 2013, sets forth the following as diagnostic criteria for agoraphobia:
## History and Symptoms
Symptoms of agoraphobia may include the following:
- Fear of crowds, bridges, and/or being outside alone
- Fear of losing control of oneself in a public place
- Feeling dependent upon others
- Feeling helpless
- Feeling that one’s body or surroundings are not real
- Being easily agitated or angered
- Staying in one’s house for long periods of time
- Self-medication with drugs or alcohol
- Inability to function at work or other inherently social settings
- Depression or suicidal ideation
If agoraphobic patients find themselves in a situation that triggers their anxiety, symptoms may include the following:
- Powerful sensations of panic and distress
- Tachycardia
- Chest pain or discomfort
- Choking
- Dizziness or syncope
- Dyspnea
- Sweating
- Tremors
## Physical Examination
- Healthcare providers will examine a patient who is exhibiting signs of agoraphobia for a history of panic disorders.
- The clinician will also get a description of the relevant symptoms and behaviors of the patient and, if possible, from any family members or friends who might have knowledge of relevant behaviors.
# Treatment
## Medical Therapy
- The mainstay of therapy for agoraphobia is a combination of CBT, talk therapy, and medicine. Certain drugs that are regularly used to treat depression, such as SSRIs and SNRIs, may also be helpful in the treatment of agoraphobia.
Treatment delivery factors, particularly therapist adherence, are important indicators of the potential for successful CBT.
Studies have shown that therapist-directed CBT has a more significant impact on agoraphobic psychopathology in the short-term than do SSRIs/SNRIs.
At a physician’s discretion, sedatives or hypnotics may also be prescribed. A physician may advise an agoraphobic patient to take such drugs when the symptoms of agoraphobia are particularly severe or as a preventive measure, when one expects to be exposed to a triggering situation.
- Treatment delivery factors, particularly therapist adherence, are important indicators of the potential for successful CBT.
- Studies have shown that therapist-directed CBT has a more significant impact on agoraphobic psychopathology in the short-term than do SSRIs/SNRIs.
- At a physician’s discretion, sedatives or hypnotics may also be prescribed. A physician may advise an agoraphobic patient to take such drugs when the symptoms of agoraphobia are particularly severe or as a preventive measure, when one expects to be exposed to a triggering situation.
## Surgery
- Surgical intervention is not recommended for the management of agoraphobia.
## Primary Prevention
- There is no established method for the primary prevention of agoraphobia.
## Secondary Prevention
- Maintenance of a healthy lifestyle may be helpful in the secondary prevention of agoraphobia. This includes:
Eating a balanced diet
Exercising regularly
Getting a sufficient amount of sleep
- Eating a balanced diet
- Exercising regularly
- Getting a sufficient amount of sleep | Agoraphobia
For patient information click here
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2], Haleigh Williams, B.S., Irfan Dotani
# Overview
Agoraphobia is an anxiety disorder characterized by intense terror and anxiety over any place or situation from which one might not easily be able to escape. This often leads sufferers to avoid leaving their homes, using public transportation or air travel, or being in crowded spaces. The average age of onset of agoraphobia is 20 years. Agoraphobia is closely associated with panic disorder; the two are commonly comorbid. Patients with agoraphobia often exhibit depressive symptoms, as well as social or specific phobias, which can make the disorder difficult to diagnose. Patients with severe agoraphobia may become confined to their homes. The word "agoraphobia" is an English adoption of the Greek words agora (αγορά) and phobos (φόβος), literally translated as "a fear of the marketplace." This etymology is the reason for the common misconception that agoraphobia is a fear of open spaces.
# Historical Perspective
- In 1871, Agoraphobia was first described by Karl Friedrich Otto Westphal, a German psychiatrist.
- Westphal coined the term after observing three of his patients, who exhibited severe anxiety and dread upon traveling to certain public areas of Berlin, in the city where he worked.
# Classification
- The DSM-V, released in 2013, classifies agoraphobia as a phobia.[1]
- The ICD-10 places agoraphobia under the subcategory of "Phobic anxiety disorders," which falls under the category of "Neurotic, stress-related and somatoform disorders."[2]
- Within the former subcategory, agoraphobia is grouped together with:[2]
Social phobias
Specific/isolated phobias
Other phobic anxiety disorders
Phobic anxiety disorder, unspecified
- Social phobias
- Specific/isolated phobias
- Other phobic anxiety disorders
- Phobic anxiety disorder, unspecified
- Though some experts have argued that agoraphobia can reasonably be thought of as a severe consequence of panic disorder, a comparison of the multivariate comorbidity patterns of agoraphobia and panic disorder supports the independent classification of these disorders.[3]
# Pathophysiology
## Relationship to Balance Disorders
- Agoraphobia may be related to defects in balance. Researchers who noticed a similarity between the situations commonly avoided by sufferers of agoraphobia and the types of environments that trigger disorientation in people with balance disorders administered a battery of audiovestibular tests, coupled with moving platform posturography, to 36 subjects with agoraphobic symptoms and 20 normal, healthy controls.
Over 60% of the former group were destabilized by these disorienting conditions, compared to a mere 10% of the control group.
Postural instability was found to be highly related to agoraphobic avoidance (r = 0.63, P < 0.01), event after the researchers controlled for symptoms, anxiety, and agoraphobic cognitions.[4]
- Over 60% of the former group were destabilized by these disorienting conditions, compared to a mere 10% of the control group.
- Postural instability was found to be highly related to agoraphobic avoidance (r = 0.63, P < 0.01), event after the researchers controlled for symptoms, anxiety, and agoraphobic cognitions.[4]
## Attachment Theory
- Some scholars (e.g., Liotti 1996, Bowlby 1998) have explained agoraphobia as an attachment deficit, i.e., the temporary loss of the ability to tolerate spatial separations from a secure base.[5][6]
## Spatial Theory
- In the social sciences, there is a perceived clinical bias (e.g., Davidson 2003) in agoraphobia research. Branches of the social sciences, especially geography, have increasingly become interested in what may be thought of as a spatial phenomenon.[7]
## Associated Conditions
- Commonly comorbid conditions include:[8]
Panic disorder
SAD
Specific phobia
- Panic disorder
- SAD
- Specific phobia
# Differential Diagnosis
- Agoraphobia must be differentiated from other disorders with similar symptomology, including:[1]
Acute stress disorder
Major depressive disorder
Other medical conditions
Parkinson's disease
Multiple sclerosis
Panic disorder without agoraphobia
Post traumatic stress disorder
Separation anxiety disorder
Social anxiety disorder (social phobia)
Specific phobia, situational type
- Acute stress disorder
- Major depressive disorder
- Other medical conditions
Parkinson's disease
Multiple sclerosis
- Parkinson's disease
- Multiple sclerosis
- Panic disorder without agoraphobia
- Post traumatic stress disorder
- Separation anxiety disorder
- Social anxiety disorder (social phobia)
- Specific phobia, situational type
# Epidemiology and Demographics
## Prevalence
- The prevalence of agoraphobia is 1,700 per 100,000 (1.7%) of the overall population.[1]
## Age
- Among children, ages 13 to 18, there is a lifetime prevalence of 2,400 per 100,000 (2.4%) for agoraphobia.[9]
- Among adults in the United States, agoraphobia has a 12-month prevalence of 800 per 100,000 (0.8%). 40.6% of these cases are classified as "severe."[10]
## Gender
- No gender disparity in the incidence of agoraphobia has been widely established.[10]
- Some studies have suggested that panic disorder patients with agoraphobia are more likely to be female than patients who have panic disorder but not agoraphobia. Female patients were also found to have a higher prevalence of comorbidities.[11]
## Race
- No racial predilection has been established for agoraphobia.[10]
# Risk Factors
- The exact cause of agoraphobia is unknown. In some instances, someone who has a panic attack may begin to exhibit signs of agoraphobia out of fear that another panic attack will occur.[12]
- Risk factors for agoraphobia include:[1]
Anxiety sensitivity
Behavioral inhibition
Genetic predisposition
Neurotic disposition (neuroticism)
Negative events in childhood
Separation/divorce of parents
Death of parent
Bullying
Stressful or traumatic events (e.g., being attacked or mugged)
- Anxiety sensitivity
- Behavioral inhibition
- Genetic predisposition
- Neurotic disposition (neuroticism)
- Negative events in childhood
Separation/divorce of parents
Death of parent
Bullying
- Separation/divorce of parents
- Death of parent
- Bullying
- Stressful or traumatic events (e.g., being attacked or mugged)
# Natural History, Complications, and Prognosis
## Natural History
- People with agoraphobia may experience panic attacks in situations in which they feel trapped, insecure, out of control, or too far from their personal comfort zone. In severe cases, an agoraphobic person may be completely confined to his or her home.[13]
Some people with agoraphobia are comfortable seeing visitors, but only in a defined space in which they feel in control.
Such people may live for years without leaving their homes, while happily seeing visitors and working, as long as they can stay within their safety zones.
If someone suffering from agoraphobia leaves his or her "safety zone," an anxiety attack may occur.
Agoraphobia patients can experience sudden panic attacks when traveling to places where they fear, where help would be difficult to obtain. During a panic attack, adrenaline is released in large amounts for several minutes causing the classical "fight or flight" condition.
The attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes. [14]
These symptoms include palpitations, sweating, trembling, and shortness of breath. Many patients report a fear of dying, or losing control of emotions or behavior. [14]
- Some people with agoraphobia are comfortable seeing visitors, but only in a defined space in which they feel in control.
Such people may live for years without leaving their homes, while happily seeing visitors and working, as long as they can stay within their safety zones.
If someone suffering from agoraphobia leaves his or her "safety zone," an anxiety attack may occur.
- Such people may live for years without leaving their homes, while happily seeing visitors and working, as long as they can stay within their safety zones.
- If someone suffering from agoraphobia leaves his or her "safety zone," an anxiety attack may occur.
- Agoraphobia patients can experience sudden panic attacks when traveling to places where they fear, where help would be difficult to obtain. During a panic attack, adrenaline is released in large amounts for several minutes causing the classical "fight or flight" condition.
The attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes. [14]
These symptoms include palpitations, sweating, trembling, and shortness of breath. Many patients report a fear of dying, or losing control of emotions or behavior. [14]
- The attack typically has an abrupt onset, building to maximum intensity within 10 to 15 minutes, and rarely lasts longer than 30 minutes. [14]
- These symptoms include palpitations, sweating, trembling, and shortness of breath. Many patients report a fear of dying, or losing control of emotions or behavior. [14]
## Complications
- Complications associated with agoraphobia may encompass physical, behavioral, or lifestyle changes.
The avoidance behaviors associated with agoraphobia are established correlates of treatment discontinuation.[15]
Individuals with agoraphobia are more likely to show signs of decreased assertiveness, perhaps because their illness cultivates feelings of helplessness and insecurity.[16]
The avoidance of places or structures in which panic attacks have occurred may limit a patient’s job prospects or proximity to desirable facilities or services.[17]
- The avoidance behaviors associated with agoraphobia are established correlates of treatment discontinuation.[15]
- Individuals with agoraphobia are more likely to show signs of decreased assertiveness, perhaps because their illness cultivates feelings of helplessness and insecurity.[16]
- The avoidance of places or structures in which panic attacks have occurred may limit a patient’s job prospects or proximity to desirable facilities or services.[17]
## Prognosis
- The prognosis of agoraphobia depends upon the severity of the disease.
- The prognosis is generally good with early medical intervention; if left untreated, the disorder may become more difficult for healthcare providers to effectively manage.[12]
# Diagnosis
## Diagnostic Criteria
### DSM-V Diagnostic Criteria for Agoraphobia
The fifth version of the DSM, released in 2013, sets forth the following as diagnostic criteria for agoraphobia:[1]
## History and Symptoms
Symptoms of agoraphobia may include the following:[12]
- Fear of crowds, bridges, and/or being outside alone
- Fear of losing control of oneself in a public place
- Feeling dependent upon others
- Feeling helpless
- Feeling that one’s body or surroundings are not real
- Being easily agitated or angered
- Staying in one’s house for long periods of time
- Self-medication with drugs or alcohol
- Inability to function at work or other inherently social settings
- Depression or suicidal ideation
If agoraphobic patients find themselves in a situation that triggers their anxiety, symptoms may include the following:[12]
- Powerful sensations of panic and distress
- Tachycardia
- Chest pain or discomfort
- Choking
- Dizziness or syncope
- Dyspnea
- Sweating
- Tremors
## Physical Examination
- Healthcare providers will examine a patient who is exhibiting signs of agoraphobia for a history of panic disorders.
- The clinician will also get a description of the relevant symptoms and behaviors of the patient and, if possible, from any family members or friends who might have knowledge of relevant behaviors.[12]
# Treatment
## Medical Therapy
- The mainstay of therapy for agoraphobia is a combination of CBT, talk therapy, and medicine. Certain drugs that are regularly used to treat depression, such as SSRIs and SNRIs, may also be helpful in the treatment of agoraphobia.[12]
Treatment delivery factors, particularly therapist adherence, are important indicators of the potential for successful CBT.[18]
Studies have shown that therapist-directed CBT has a more significant impact on agoraphobic psychopathology in the short-term than do SSRIs/SNRIs.[19]
At a physician’s discretion, sedatives or hypnotics may also be prescribed. A physician may advise an agoraphobic patient to take such drugs when the symptoms of agoraphobia are particularly severe or as a preventive measure, when one expects to be exposed to a triggering situation.[12]
- Treatment delivery factors, particularly therapist adherence, are important indicators of the potential for successful CBT.[18]
- Studies have shown that therapist-directed CBT has a more significant impact on agoraphobic psychopathology in the short-term than do SSRIs/SNRIs.[19]
- At a physician’s discretion, sedatives or hypnotics may also be prescribed. A physician may advise an agoraphobic patient to take such drugs when the symptoms of agoraphobia are particularly severe or as a preventive measure, when one expects to be exposed to a triggering situation.[12]
## Surgery
- Surgical intervention is not recommended for the management of agoraphobia.
## Primary Prevention
- There is no established method for the primary prevention of agoraphobia.
## Secondary Prevention
- Maintenance of a healthy lifestyle may be helpful in the secondary prevention of agoraphobia. This includes:[12]
Eating a balanced diet
Exercising regularly
Getting a sufficient amount of sleep
- Eating a balanced diet
- Exercising regularly
- Getting a sufficient amount of sleep | https://www.wikidoc.org/index.php/Agoraphobia | |
bd0ce9949bf8616a13feeffe593811124e7c986a | wikidoc | Agrammatism | Agrammatism
# Overview
Agrammatism is a form of expressive aphasia that refers to the inability to speak in a grammatically correct fashion. People with agrammatism may have telegraphic speech, a unique speech pattern with simplified formation of sentences (in which many or all function words are omitted), akin to that found in telegraph messages.
Errors made in agrammatism depend on the severity of aphasia. In severe forms language production is severely telegraphic and in more mild to moderate cases necessary elements for sentence construction are missing. Common errors include errors in tense, number, and gender. Patients also find it very hard to produce sentences involving movement of elements, such as passive sentences, Wh questions or complex sentences.
Agrammatism is seen in many brain disease syndromes, including Broca's aphasia and traumatic brain injury. | Agrammatism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
# Overview
Agrammatism is a form of expressive aphasia that refers to the inability to speak in a grammatically correct fashion.[1] People with agrammatism may have telegraphic speech,[2] a unique speech pattern with simplified formation of sentences (in which many or all function words are omitted), akin to that found in telegraph messages.
Errors made in agrammatism depend on the severity of aphasia. In severe forms language production is severely telegraphic and in more mild to moderate cases necessary elements for sentence construction are missing. Common errors include errors in tense, number, and gender.[3] Patients also find it very hard to produce sentences involving movement of elements, such as passive sentences, Wh questions or complex sentences.
Agrammatism is seen in many brain disease syndromes, including Broca's aphasia and traumatic brain injury. | https://www.wikidoc.org/index.php/Agrammatism | |
19226e68f4ee1adcac080751ef4310ddf779f7c0 | wikidoc | Air ioniser | Air ioniser
An air ioniser is a device which uses high voltage to ionise, or electrically charge, molecules of air. These machines can be designed either to generate specifically charged ions (all positive or all negative), or to create both polarities indiscriminately. However, most commercial air purifiers are designed to generate negative ions. Negative ions are particles that temporarily contain an extra electron, causing the entire molecule to possess a negative electrical charge. Conversely, a positive ion is deficient by one electron and has an overall positive charge. Unfortunately, the high electric fields used to create the air ions can also generate ozone (an energetic allotrope of oxygen), and NOx. Both are toxic. Even in relatively low concentrations, they can irritate lung tissues, cause chest pain, coughing, throat irritation, and can worsen the conditions of persons suffering from asthma.
# Ionic air purifiers
Ionic air purifiers use an electrically charged plate to produce negative gas ions that particulate matter sticks to (in an effect similar to static electricity). Many ionisers are sold as air purifiers, but in this regard they are very inefficient. They will clean the air to a small degree, by charging dust and smoke particles which will then be attracted to a neutral or positively charged surface. Heavier combined particles may precipitate (fall) out of the air should two smaller particles of different charge clump together.
The use of negative ions continues to be a less accepted mainstream therapy in Eastern Europe and the Far East than in Western Europe or the United States, although problems with nosocomial infections (hospital acquired "super-bugs") have led the National Health Service (NHS) in the UK to do extensive research into the effect of negative ions on this area of hygiene.
Recent SARS outbreaks have fueled the desire for personal ionisers in the far east, including Japan (where many products have been specialized to contain negative ion generators, including toothbrushes, refrigerators and washing machines). There are no specific standards for these devices.
# Benefits of negative ions
Cedars-Sinai has a page last reviewed 03-15-2006 which discusses negatively ionized air as an alternative treatment for certain conditions. The Geophysical Institute of the University of Alaska Fairbanks published an article September 26 1981 which discusses the beneficial role of negative ions and the positive ion fields created by CRT (cathode ray tube) computer monitors.
# Air purifier criticisms
Criticisms of ionizers as air purifiers include:
- Cleaning range, as portable units are typically built to clean one room only.
- All the affected airborne particles ultimately wind up on surfaces close to the ioniser, making the area immediately surrounding the ioniser dirty and reducing the unit efficiency as the high voltage emitter is slowly covered in dirt. Overall cleaning efficiency roughly on par with the static charge from the front of a powered-up CRT TV screen.
- Companies or individuals who sell (or support the use of) air ionizing devices claim additional, less easily substantiated effects, including:
Generation of ozone as a beneficial byproduct.
Creation of an ionic wind, caused by the repulsion of similarly charged ions near the electrodes.
- Generation of ozone as a beneficial byproduct.
- Creation of an ionic wind, caused by the repulsion of similarly charged ions near the electrodes.
- Even the best ionizers will produce a small amount of ozone, which is highly toxic (see below). This can be mitigated to some degree by special devices designed to remove ozone.
- Ironically, the ozone generating ionizers can make asthma and other lung conditions worse. This causes precisely the opposite of the desired effect when purchasing an air purifier.
# Ions vs ozone
Ionisers should not be confused with ozone generators, even though both devices operate in a similar way. Ionisers use an electrostatically charged plate to produce positively or negatively charged gas ions that particulate matter sticks to (in an effect similar to static electricity). Ozone generators are optimised to attract an extra oxygen ion to an O2 molecule, using either a corona discharge tube or UV light.
Even the best ionisers will produce a small amount of ozone, and ozone generators will produce gaseous ions of molecules other than ozone (unless fed by pure oxygen, not air).
Ozone is claimed by some alternative medicine proponents Template:Weasel-inline to be relatively harmless to humans, but this is a demonstrable fallacy. Ozone is a highly toxic and extremely reactive gas.
A higher daily average than 0.1 ppm (0.2 mg/m³) is not recommended and can damage the lungs and olfactory bulb cells directly.
At high concentrations, ozone can also be toxic to air-borne bacteria, and may destroy or kill these sometimes infectious organisms. However, the needed concentrations are toxic enough to man and animal that the FDA explicitly demands ozone therapy not be used as medical treatment,
and has taken action against businesses that fail to comply with this regulation.
# Consumer Reports court case
Consumer Reports, a non-profit U.S.-based product-testing magazine, reported in October 2003 that air ionizers do not perform to high enough standards compared to conventional HEPA air filters. In response to this report, The Sharper Image, a manufacturer of air ionizers (among other things), sued Consumer's Union (the publishers of Consumer Reports) for product defamation. The Sharper Image's Ionic Breeze unit did meet all EPA guidelines, including less than 50 ppb ozone production. Consumer Reports gave the Ionic Breeze and other popular units a "fail" because they have a low Clean Air Delivery Rate (CADR). CADR measures the amount of filtered air circulated during a short period of time, and was originally designed to rate media-based air cleaners. The Sharper Image claimed that this test was a poor way to rate the Ionic Breeze, since it does not take into account other features, such as 24-hour a day continuous cleaning, ease of maintenance, and silent operation. The U.S. District Court for the Northern District of California subsequently struck The Sharper Image's complaint and dismissed the case, reasoning that The Sharper Image had failed to demonstrate that it could prove any of the statements made by Consumer Reports were false. The Court's final ruling in May 2005 ordered The Sharper Image to pay $525,000 USD for Consumer Union's legal expenses. | Air ioniser
An air ioniser is a device which uses high voltage to ionise, or electrically charge, molecules of air. These machines can be designed either to generate specifically charged ions (all positive or all negative), or to create both polarities indiscriminately[citation needed]. However, most commercial air purifiers are designed to generate negative ions. Negative ions are particles that temporarily contain an extra electron, causing the entire molecule to possess a negative electrical charge. Conversely, a positive ion is deficient by one electron and has an overall positive charge. Unfortunately, the high electric fields used to create the air ions can also generate ozone (an energetic allotrope of oxygen), and NOx. Both are toxic. Even in relatively low concentrations, they can irritate lung tissues, cause chest pain, coughing, throat irritation, and can worsen the conditions of persons suffering from asthma.
# Ionic air purifiers
Ionic air purifiers use an electrically charged plate to produce negative gas ions that particulate matter sticks to (in an effect similar to static electricity). Many ionisers are sold as air purifiers, but in this regard they are very inefficient. They will clean the air to a small degree, by charging dust and smoke particles which will then be attracted to a neutral or positively charged surface. Heavier combined particles may precipitate (fall) out of the air should two smaller particles of different charge clump together.
The use of negative ions continues to be a less accepted mainstream therapy in Eastern Europe and the Far East than in Western Europe or the United States[citation needed], although problems with nosocomial infections (hospital acquired "super-bugs") have led the National Health Service (NHS) in the UK to do extensive research into the effect of negative ions on this area of hygiene.[1]
Recent SARS outbreaks have fueled the desire for personal ionisers in the far east, including Japan (where many products have been specialized to contain negative ion generators, including toothbrushes, refrigerators and washing machines). There are no specific standards for these devices.
# Benefits of negative ions
Cedars-Sinai has a page last reviewed 03-15-2006 which discusses negatively ionized air as an alternative treatment for certain conditions. The Geophysical Institute of the University of Alaska Fairbanks published an article September 26 1981 which discusses the beneficial role of negative ions and the positive ion fields created by CRT (cathode ray tube) computer monitors.
# Air purifier criticisms
Criticisms of ionizers as air purifiers include:
- Cleaning range, as portable units are typically built to clean one room only.
- All the affected airborne particles ultimately wind up on surfaces close to the ioniser, making the area immediately surrounding the ioniser dirty and reducing the unit efficiency as the high voltage emitter is slowly covered in dirt. Overall cleaning efficiency roughly on par with the static charge from the front of a powered-up CRT TV screen.[citation needed]
- Companies or individuals who sell (or support the use of) air ionizing devices claim additional, less easily substantiated effects, including:
Generation of ozone as a beneficial byproduct.
Creation of an ionic wind, caused by the repulsion of similarly charged ions near the electrodes.
- Generation of ozone as a beneficial byproduct.
- Creation of an ionic wind, caused by the repulsion of similarly charged ions near the electrodes.
- Even the best ionizers will produce a small amount of ozone, which is highly toxic (see below). This can be mitigated to some degree by special devices designed to remove ozone.
- Ironically, the ozone generating ionizers can make asthma and other lung conditions worse. This causes precisely the opposite of the desired effect when purchasing an air purifier.
# Ions vs ozone
Ionisers should not be confused with ozone generators, even though both devices operate in a similar way. Ionisers use an electrostatically charged plate to produce positively or negatively charged gas ions that particulate matter sticks to (in an effect similar to static electricity). Ozone generators are optimised to attract an extra oxygen ion to an O2 molecule, using either a corona discharge tube or UV light.
Even the best ionisers will produce a small amount of ozone, and ozone generators will produce gaseous ions of molecules other than ozone (unless fed by pure oxygen, not air).[citation needed]
Ozone is claimed by some alternative medicine proponents Template:Weasel-inline to be relatively harmless to humans, but this is a demonstrable fallacy. Ozone is a highly toxic and extremely reactive gas.[2]
A higher daily average than 0.1 ppm (0.2 mg/m³) is not recommended and can damage the lungs and olfactory bulb cells directly.[3]
At high concentrations, ozone can also be toxic to air-borne bacteria, and may destroy or kill these sometimes infectious organisms. However, the needed concentrations are toxic enough to man and animal that the FDA explicitly demands ozone therapy not be used as medical treatment,[4]
and has taken action against businesses that fail to comply with this regulation.[5]
# Consumer Reports court case
Consumer Reports, a non-profit U.S.-based product-testing magazine, reported in October 2003 that air ionizers do not perform to high enough standards compared to conventional HEPA air filters. In response to this report, The Sharper Image, a manufacturer of air ionizers (among other things), sued Consumer's Union (the publishers of Consumer Reports) for product defamation. The Sharper Image's Ionic Breeze unit did meet all EPA guidelines, including less than 50 ppb ozone production[citation needed]. Consumer Reports gave the Ionic Breeze and other popular units a "fail" because they have a low Clean Air Delivery Rate (CADR). CADR measures the amount of filtered air circulated during a short period of time, and was originally designed to rate media-based air cleaners. The Sharper Image claimed that this test was a poor way to rate the Ionic Breeze, since it does not take into account other features, such as 24-hour a day continuous cleaning, ease of maintenance, and silent operation. The U.S. District Court for the Northern District of California subsequently struck The Sharper Image's complaint and dismissed the case, reasoning that The Sharper Image had failed to demonstrate that it could prove any of the statements made by Consumer Reports were false. The Court's final ruling in May 2005 ordered The Sharper Image to pay $525,000 USD for Consumer Union's legal expenses.[6] | https://www.wikidoc.org/index.php/Air_ioniser | |
a52e1dd7aac19ce63ee69227ecda2cc37cf68ff5 | wikidoc | Airsickness | Airsickness
# Overview
Airsickness is a sensation which is induced by air travel. It is a specific form of motion sickness, and is considered a normal response in healthy individuals. Airsickness occurs when the central nervous system receives conflicting messages from the body (including the inner ear, eyes and muscles) affecting balance and equilibrium.
The inner ear is particularly important in the maintenance of balance and equilibrium because it contains sensors for both angular (rotational) and linear motion. Airsickness is usually a combination of spatial disorientation, nausea and vomiting. Experimentally, airsickness can be eliminated in monkeys by removing part of the cerebellum, namely the nodulus of the vermis.
# Signs & Symptoms
Common signs and symptoms of airsickness include:
Nausea, vomiting, vertigo, loss of appetite, cold sweating, skin pallor, difficulty concentrating, confusion, drowsiness, headache, and increased fatigue.
Severe airsickness may cause a person to become completely incapacitated.
# Susceptibility to Airsickness
The following factors increase some people's susceptibility to airsickness:
- Fatigue, stress, and anxiety, are some factors that can increase susceptibility to motion sickness of any type.
- The use of alcohol, drugs, and medications may also contribute to airsickness.
- Additionally, airsickness is more common in women (especially during menstruation or pregnancy), young children, and individuals prone to other types of motion sickness.
- Although airsickness is uncommon among experienced pilots, it does occur with some frequency in student pilots.
# Avoiding Airsickness
Travelers who are susceptible to motion sickness can minimize symptoms by:
- Choosing seats with the smoothest ride (the seats over the wings in an airplane).
- Sitting facing forward while focusing on distant objects rather than trying to read or look at something inside the airplane.
- Eating dry crackers, olives or suck on a lemon, to dry out the mouth, lessening nausea.
- Drinking a carbonated beverage.
# Treatment of Airsickness
## Medication
Medications that may alleviate the symptoms of airsickness include:
- meclizine (Antivert, Bonine)
- dimenhydrinate (Dramamine)
- diphenhydramine (Benadryl)
- scopolamine (available in both patch and oral form).
- ginger capsules
Pilots who are susceptible to airsickness should not take anti-motion sickness medications (prescription or over-the-counter). These medications can make one drowsy or affect brain functions in other ways.
## NonPharmacologic Remedies
A method to increase pilot resistance to airsickness consists of repetitive exposure to the flying conditions that initially resulted in airsickness. In other words, repeated exposure to the flight environment decreases an individual’s susceptibility to subsequent airsickness. Recently, several devices have been introduced that are intended to reduce motion sickness through stimulation of various body parts (usually the wrist). There is no clinical evidence of the effectiveness of these products, marketed under the names “Sea Bands", "Relief Band", and others.
## Natural Remedies
There are numerous alternative remedies for motion sickness. The most popular are ginger derivatives, such as ginger tea or powdered ginger capsules. When the hosts of the popular American television program Mythbusters tested motion sickness remedies, they found that ginger was one of the most effective non-prescription remedies. | Airsickness
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:DiseaseDisorder infobox
# Overview
Airsickness is a sensation which is induced by air travel. It is a specific form of motion sickness, and is considered a normal response in healthy individuals. Airsickness occurs when the central nervous system receives conflicting messages from the body (including the inner ear, eyes and muscles) affecting balance and equilibrium.
The inner ear is particularly important in the maintenance of balance and equilibrium because it contains sensors for both angular (rotational) and linear motion. Airsickness is usually a combination of spatial disorientation, nausea and vomiting.[1] Experimentally, airsickness can be eliminated in monkeys by removing part of the cerebellum, namely the nodulus of the vermis.[2]
# Signs & Symptoms
Common signs and symptoms of airsickness include:
Nausea, vomiting, vertigo, loss of appetite, cold sweating, skin pallor, difficulty concentrating, confusion, drowsiness, headache, and increased fatigue.
Severe airsickness may cause a person to become completely incapacitated.[1]
# Susceptibility to Airsickness
The following factors increase some people's susceptibility to airsickness:
- Fatigue, stress, and anxiety, are some factors that can increase susceptibility to motion sickness of any type.
- The use of alcohol, drugs, and medications may also contribute to airsickness.
- Additionally, airsickness is more common in women (especially during menstruation or pregnancy), young children, and individuals prone to other types of motion sickness.[3]
- Although airsickness is uncommon among experienced pilots, it does occur with some frequency in student pilots.[1]
# Avoiding Airsickness
Travelers who are susceptible to motion sickness can minimize symptoms by:
- Choosing seats with the smoothest ride (the seats over the wings in an airplane).
- Sitting facing forward while focusing on distant objects rather than trying to read or look at something inside the airplane.
- Eating dry crackers, olives or suck on a lemon, to dry out the mouth, lessening nausea.
- Drinking a carbonated beverage.
# Treatment of Airsickness
## Medication
Medications that may alleviate the symptoms of airsickness include:
- meclizine (Antivert, Bonine)
- dimenhydrinate (Dramamine)
- diphenhydramine (Benadryl)
- scopolamine (available in both patch and oral form).
- ginger capsules [4]
Pilots who are susceptible to airsickness should not take anti-motion sickness medications (prescription or over-the-counter).[1] These medications can make one drowsy or affect brain functions in other ways.
## NonPharmacologic Remedies
A method to increase pilot resistance to airsickness consists of repetitive exposure to the flying conditions that initially resulted in airsickness. In other words, repeated exposure to the flight environment decreases an individual’s susceptibility to subsequent airsickness. Recently, several devices have been introduced that are intended to reduce motion sickness through stimulation of various body parts (usually the wrist). There is no clinical evidence of the effectiveness of these products, marketed under the names “Sea Bands", "Relief Band", and others.
## Natural Remedies
There are numerous alternative remedies for motion sickness. The most popular are ginger derivatives, such as ginger tea or powdered ginger capsules. When the hosts of the popular American television program Mythbusters tested motion sickness remedies, they found that ginger was one of the most effective non-prescription remedies. | https://www.wikidoc.org/index.php/Airsickness | |
d41991c677b3b9fce4884a966f19dbd63d98e6dc | wikidoc | Alamethicin | Alamethicin
Alamethicin is a peptide antibiotic, produced by the fungus Trichoderma viride. It contains the non-proteinogenic amino acid 2-aminoisobutyric acid (Aib), which strongly induces helical peptide structures. The peptide sequence is:
Ac-Aib-Pro-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-Glu-Gln-Phl
(Ac = acetyl, Phl = phenylalaninol)
- Molecular Formula: C92H150N22O25
- CAS number: 27061-78-5
- Appearance: Off white solid
- UV spectrum maxima: 265, 257
- Melting point: 255°C-270°C
- Solubility information: DMSO, Methanol, Ethanol. Not soluble in water
In cell membranes, it forms voltage-dependent ion channels by aggregation of four to six molecules.
data copied from Fermentek Alamethicin product page | Alamethicin
Alamethicin is a peptide antibiotic, produced by the fungus Trichoderma viride. It contains the non-proteinogenic amino acid 2-aminoisobutyric acid (Aib), which strongly induces helical peptide structures. The peptide sequence is:
Ac-Aib-Pro-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-Glu-Gln-Phl
(Ac = acetyl, Phl = phenylalaninol)
- Molecular Formula: C92H150N22O25
- CAS number: 27061-78-5
- Appearance: Off white solid
- UV spectrum maxima: 265, 257
- Melting point: 255°C-270°C
- Solubility information: DMSO, Methanol, Ethanol. Not soluble in water
In cell membranes, it forms voltage-dependent ion channels by aggregation of four to six molecules.
data copied from Fermentek Alamethicin product page
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Alamethicin | |
82a3f6bff10d00d0ae89ebc1daf87fde02aa0509 | wikidoc | Albendazole | Albendazole
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Albendazole is a anthelmintic and benzimidazole that is FDA approved for the treatment of neurocysticercosis and hydatid disease. Common adverse reactions include abdominal pain, nausea, vomiting, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Albendazole is indicated for the treatment of the following infections:
- Neurocysticercosis
- Albendazole is indicated for the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium.
- Lesions considered responsive to albendazole therapy appear as nonenhancing cysts with no surrounding edema on contrast-enhanced computerized tomography. Clinical studies in patients with lesions of this type demonstrate a 74% to 88% reduction in number of cysts; 40% to 70% of albendazole-treated patients showed resolution of all active cysts.
- Hydatid disease
- Albendazole is indicated for the treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus.
- This indication is based on combined clinical studies which demonstrated non-infectious cyst contents in approximately 80 to 90% of patients given Albendazole for 3 cycles of therapy of 28 days each. Clinical cure (disappearance of cysts) was seen in approximately 30% of these patients, and improvement (reduction in cyst diameter of ≥25%) was seen in an additional 40%.
- NOTE: When medically feasible, surgery is considered the treatment of choice for hydatid disease. When administering albendazole in the pre- or post-surgical setting, optimal killing of cyst contents is achieved when 3 courses of therapy have been given.
- NOTE: The efficacy of albendazole in the therapy of alveolar hydatid disease caused by Echinococcus multilocularis has not been clearly demonstrated in clinical studies.
- Dosing of Albendazole will vary, depending upon which of the following parasitic infections is being treated. In young children, the tablets should be crushed or chewed and swallowed with a drink of water.
- Patients being treated for neurocysticercosis should receive appropriate steroid and anticonvulsant therapy as required. Oral or intravenous corticosteroids should be considered to prevent cerebral hypertensive episodes during the first week of treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Albendazole in adult patients.
### Non–Guideline-Supported Use
- Ancylostomiasis-Necatoriasis
- Dosing Information
400 mg PO as a single dose
- 400 mg PO as a single dose
- Ascariasis
- Dosing Information
- 400 mg PO as a single dose
- Capillaria infection
- Clonorchiasis
- Cutaneous larva migrans
- Enterobiasis
- Dosing Information
400 mg PO as a single dose; repeat in 2 weeks
- 400 mg PO as a single dose; repeat in 2 weeks
- Giardiasis
- HIV infection - Infection by Microsporida (disseminated or intestinal)
- Dosing Information
400 mg PO 2 per day until CD4+ count is greater than 200 cells/mcL for longer than 6 months after initiation of ART; add itraconazole 400 mg PO daily for disseminated disease due to Trachipleistophora or Anncaliia.
- 400 mg PO 2 per day until CD4+ count is greater than 200 cells/mcL for longer than 6 months after initiation of ART; add itraconazole 400 mg PO daily for disseminated disease due to Trachipleistophora or Anncaliia.
- Infection by Gnathostoma
- Infection by Loa loa
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA Labeled indications and dosage of Albendazole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Albendazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Albendazole in pediatric patients.
# Contraindications
- Albrendazole is contraindicated in patients with known hypersensitivity to the benzimidazole class of compounds or any components of Albendazole.
# Warnings
- Rare fatalities associated with the use of Albendazole have been reported due to granulocytopenia or pancytopenia. Albendazole has been shown to cause bone marrow suppression, aplastic anemia, and agranulocytosis in patients with and without underlying hepatic dysfunction. Blood counts should be monitored at the beginning of each 28-day cycle of therapy, and every 2 weeks while on therapy with albendazole in all patients. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk for bone marrow suppression leading to pancytopenia, aplastic anemia, agranulocytosis, and leukopenia attributable to albendazole and warrant closer monitoring of blood counts. Albendazole should be discontinued in all patients if clinically significant decreases in blood cell counts occur.
- Albendazole should not be used in pregnant women except in clinical circumstances where no alternative management is appropriate. Patients should not become pregnant for at least 1 month following cessation of albendazole therapy. If a patient becomes pregnant while taking this drug, albendazole should be discontinued immediately. If pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# Adverse Reactions
## Clinical Trials Experience
- The adverse event profile of albendazole differs between hydatid disease and neurocysticercosis. Adverse events occurring with a frequency of ≥1% in either disease are described in the table below.
- These symptoms were usually mild and resolved without treatment. Treatment discontinuations were predominantly due to leukopenia (0.7%) or hepatic abnormalities (3.8% in hydatid disease). The following incidence reflects events that were reported by investigators to be at least possibly or probably related to albendazole.
- The following adverse events were observed at an incidence of <1%:
- Blood and Lymphatic System Disorders
Leukopenia. There have been rare reports of granulocytopenia, pancytopenia, agranulocytosis, or thrombocytopenia. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk of bone marrow suppression.
- Leukopenia. There have been rare reports of granulocytopenia, pancytopenia, agranulocytosis, or thrombocytopenia. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk of bone marrow suppression.
- Immune System Disorders
Hypersensitivity reactions, including rash and urticaria.
- Hypersensitivity reactions, including rash and urticaria.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been identified during world-wide post-approval use of Albendazole. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Albendazole.
- Blood and Lymphatic System Disorders
- Aplastic anemia, bone marrow suppression, neutropenia.
- Hepatobiliary Disorders
- Elevations of hepatic enzymes, hepatitis, acute liver failure.
- Skin and Subcutaneous Tissue Disorders
- Erythema multiforme, Stevens-Johnson syndrome.
- Renal and Urinary Disorders
- Acute renal failure.
# Drug Interactions
- Dexamethasone
- Steady-state trough concentrations of albendazole sulfoxide were about 56% higher when 8 mg dexamethasone was coadministered with each dose of albendazole (15 mg/kg/day) in 8 neurocysticercosis patients.
- Praziquantel
- In the fed state, praziquantel (40 mg/kg) increased mean maximum plasma concentration and area under the curve of albendazole sulfoxide by about 50% in healthy subjects (n = 10) compared with a separate group of subjects (n = 6) given albendazole alone. Mean Tmax and mean plasma elimination half-life of albendazole sulfoxide were unchanged. The pharmacokinetics of praziquantel were unchanged following coadministration with albendazole (400 mg).
- Cimetidine
- Albendazole sulfoxide concentrations in bile and cystic fluid were increased (about 2-fold) in hydatid cyst patients treated with cimetidine (10 mg/kg/day) (n = 7) compared with albendazole (20 mg/kg/day) alone (n = 12). Albendazole sulfoxide plasma concentrations were unchanged 4 hours after dosing.
- Theophylline
- The pharmacokinetics of theophylline (aminophylline 5.8 mg/kg infused over 20 minutes) were unchanged following a single oral dose of albendazole (400 mg) in 6 healthy subjects.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Albendazole has been shown to be teratogenic (to cause embryotoxicity and skeletal malformations) in pregnant rats and rabbits. The teratogenic response in the rat was shown at oral doses of 10 and 30 mg/kg/day (0.10 times and 0.32 times the recommended human dose based on body surface area in mg/m2, respectively) during gestation days 6 to 15 and in pregnant rabbits at oral doses of 30 mg/kg/day (0.60 times the recommended human dose based on body surface area in mg/m2) administered during gestation days 7 to 19. In the rabbit study, maternal toxicity (33% mortality) was noted at 30 mg/kg/day. In mice, no teratogenic effects were observed at oral doses up to 30 mg/kg/day (0.16 times the recommended human dose based on body surface area in mg/m2), administered during gestation days 6 to 15.
- There are no adequate and well-controlled studies of albendazole administration in pregnant women. Albendazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Template:Levofloxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Levofloxacin during labor and delivery.
### Nursing Mothers
- Albendazole is excreted in animal milk. It is not known whether it is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when albendazole is administered to a nursing woman.
### Pediatric Use
- Experience in children under the age of 6 years is limited. In hydatid disease, infection in infants and young children is uncommon, but no problems have been encountered in those who have been treated. In neurocysticercosis, infection is more frequently encountered. In 5 published studies involving pediatric patients as young as 1 year, no significant problems were encountered, and the efficacy appeared similar to the adult population.
### Geriatic Use
- Experience in patients 65 years of age or older is limited. The number of patients treated for either hydatid disease or neurocysticercosis is limited, but no problems associated with an older population have been observed.
### Gender
There is no FDA guidance on the use of albendazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of albendazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of albendazole in patients with hepatic impairment.
### Hepatic Impairment
There is no FDA guidance on the use of albendazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of albendazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of albendazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- White Blood Cell Count
- Albendazole has been shown to cause occasional (less than 1% of treated patients) reversible reductions in total white blood cell count. Rarely, more significant reductions may be encountered including granulocytopenia, agranulocytosis, or pancytopenia. Blood counts should be performed at the start of each 28-day treatment cycle and every 2 weeks during each 28-day cycle in all patients. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk of bone marrow suppression and warrant closer monitoring of blood counts. Albendazole should be discontinued in all patients if clinically significant decreases in blood cell counts occur.
- Liver Function
- In clinical trials, treatment with albendazole has been associated with mild to moderate elevations of hepatic enzymes in approximately 16% of patients. These elevations have generally returned to normal upon discontinuation of therapy. There have also been case reports of acute liver failure of uncertain causality and hepatitis.
- Liver function tests (transaminases) should be performed before the start of each treatment cycle and at least every 2 weeks during treatment. If hepatic enzymes exceed twice the upper limit of normal, consideration should be given to discontinuing albendazole therapy based on individual patient circumstances. Restarting albendazole treatment in patients whose hepatic enzymes have normalized off treatment is an individual decision that should take into account the risk/benefit of further albendazole usage. Laboratory tests should be performed frequently if albendazole treatment is restarted.
- Patients with abnormal liver function test results are at increased risk for hepatotoxicity and bone marrow suppression. Therapy should be discontinued if liver enzymes are significantly increased or if clinically significant decreases in blood cell counts occur.
# IV Compatibility
There is limited information regarding IV Compatibility albendazole in the drug label.
# Overdosage
- Significant toxicity and mortality were shown in male and female mice at doses exceeding 5,000 mg/kg; in rats, at estimated doses between 1,300 and 2,400 mg/kg; in hamsters, at doses exceeding 10,000 mg/kg; and in rabbits, at estimated doses between 500 and 1,250 mg/kg. In the animals, symptoms were demonstrated in a dose-response relationship and included diarrhea, vomiting, tachycardia, and respiratory distress.
- One overdosage has been reported with Albendazole in a patient who took at least 16 grams over 12 hours. No untoward effects were reported. In case of overdosage, symptomatic therapy and general supportive measures are recommended.
# Pharmacology
## Mechanism of Action
- As a vermicidal, albendazole causes degenerative alterations in the intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. The loss of the cytoplasmic microtubules leads to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores. Degenerative changes occur in the endoplasmic reticulum, the mitochondria of the germinal layer, and the subsequent release of lysosome.
## Structure
- Chemically, it is methyl 5-(propylthio)-2-benzimidazolecarbamate. Its molecular formula is C12H15N3O2S. Its molecular weight is 265.34. It has the following chemical structure:
## Pharmacodynamics
There is limited information regarding pharmacodynamics of albendazole in the drug label.
## Pharmacokinetics
### Absorption and Metabolism=
- Albendazole is poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. Albendazole concentrations are negligible or undetectable in plasma as it is rapidly converted to the sulfoxide metabolite prior to reaching the systemic circulation. The systemic anthelmintic activity has been attributed to the primary metabolite, albendazole sulfoxide. Oral bioavailability appears to be enhanced when albendazole is coadministered with a fatty meal (estimated fat content 40 g) as evidenced by higher (up to 5-fold on average) plasma concentrations of albendazole sulfoxide as compared to the fasted state.
- Maximal plasma concentrations of albendazole sulfoxide are typically achieved 2 to 5 hours after dosing and are on average 1.31 mcg/mL (range 0.46 to 1.58 mcg/mL) following oral doses of albendazole (400 mg) in 6 hydatid disease patients, when administered with a fatty meal. Plasma concentrations of albendazole sulfoxide increase in a dose-proportional manner over the therapeutic dose range following ingestion of a fatty meal (fat content 43.1 g). The mean apparent terminal elimination half-life of albendazole sulfoxide typically ranges from 8 to 12 hours in 25 normal subjects, as well as in 14 hydatid and 8 neurocysticercosis patients.
- Following 4 weeks of treatment with albendazole (200 mg three times daily), 12 patients’ plasma concentrations of albendazole sulfoxide were approximately 20% lower than those observed during the first half of the treatment period, suggesting that albendazole may induce its own metabolism.
- Albendazole sulfoxide is 70% bound to plasma protein and is widely distributed throughout the body; it has been detected in urine, bile, liver, cyst wall, cyst fluid, and cerebral spinal fluid (CSF). Concentrations in plasma were 3- to 10-fold and 2- to 4-fold higher than those simultaneously determined in cyst fluid and CSF, respectively. Limited in vitro and clinical data suggest that albendazole sulfoxide may be eliminated from cysts at a slower rate than observed in plasma.
- Albendazole is rapidly converted in the liver to the primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites that have been identified in human urine. Following oral administration, albendazole has not been detected in human urine. Urinary excretion of albendazole sulfoxide is a minor elimination pathway with less than 1% of the dose recovered in the urine. Biliary elimination presumably accounts for a portion of the elimination as evidenced by biliary concentrations of albendazole sulfoxide similar to those achieved in plasma.
## Nonclinical Toxicology
There is limited information regarding nonclinical toxicology of Estradiol valerate and estradiol valerate/dienogest in the drug label.
# Clinical Studies
There is limited information regarding Albendazole Clinical Studies in the drug label.
# How Supplied
- Albendazole is supplied as 200 mg, white to off-white, circular, biconvex, bevel-edged, film coated TILTAB tablet embossed "ap" and "550". They are supplied as follows:
- Bottles of 2 NDC 52054-550-22
- Bottles of 28 NDC 52054-550-28
- ALBENZA and TILTAB are registered trademarks of GlaxoSmithKline, used with permission.
- Manufactured by:
- GlaxoSmithKline
- Mississauga, Ontario
- L5N 6L4 Canada
- Distributed by:
- Amedra Pharmaceuticals, LLC
- Horsham, PA 19044
- LB# 799-03 Rev. February, 2013
## Storage
- Store at 20° to 25°C (68° to 77°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that:
- Some people, particularly young children, may experience difficulties swallowing the tablets whole. In young children, the tablets should be crushed or chewed and swallowed with a drink of water.
- Albendazole may cause fetal harm, therefore, women of childbearing age should begin treatment after a negative pregnancy test.
- Women of childbearing age should be cautioned against becoming pregnant while on albendazole or within 1 month of completing treatment.
- During albendazole therapy, because of the possibility of harm to the liver or bone marrow, routine (every 2 weeks) monitoring of blood counts and liver function tests should take place.
- Albendazole should be taken with food.
# Precautions with Alcohol
Alcohol-Albendazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Albenza®
# Look-Alike Drug Names
There is limited information regarding Albendazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Albendazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Albendazole is a anthelmintic and benzimidazole that is FDA approved for the treatment of neurocysticercosis and hydatid disease. Common adverse reactions include abdominal pain, nausea, vomiting, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Albendazole is indicated for the treatment of the following infections:
- Neurocysticercosis
- Albendazole is indicated for the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium.
- Lesions considered responsive to albendazole therapy appear as nonenhancing cysts with no surrounding edema on contrast-enhanced computerized tomography. Clinical studies in patients with lesions of this type demonstrate a 74% to 88% reduction in number of cysts; 40% to 70% of albendazole-treated patients showed resolution of all active cysts.
- Hydatid disease
- Albendazole is indicated for the treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus.
- This indication is based on combined clinical studies which demonstrated non-infectious cyst contents in approximately 80 to 90% of patients given Albendazole for 3 cycles of therapy of 28 days each. Clinical cure (disappearance of cysts) was seen in approximately 30% of these patients, and improvement (reduction in cyst diameter of ≥25%) was seen in an additional 40%.
- NOTE: When medically feasible, surgery is considered the treatment of choice for hydatid disease. When administering albendazole in the pre- or post-surgical setting, optimal killing of cyst contents is achieved when 3 courses of therapy have been given.
- NOTE: The efficacy of albendazole in the therapy of alveolar hydatid disease caused by Echinococcus multilocularis has not been clearly demonstrated in clinical studies.
- Dosing of Albendazole will vary, depending upon which of the following parasitic infections is being treated. In young children, the tablets should be crushed or chewed and swallowed with a drink of water.
- Patients being treated for neurocysticercosis should receive appropriate steroid and anticonvulsant therapy as required. Oral or intravenous corticosteroids should be considered to prevent cerebral hypertensive episodes during the first week of treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Albendazole in adult patients.
### Non–Guideline-Supported Use
- Ancylostomiasis-Necatoriasis
- Dosing Information
400 mg PO as a single dose
- 400 mg PO as a single dose
- Ascariasis
- Dosing Information
- 400 mg PO as a single dose
- Capillaria infection
- Clonorchiasis
- Cutaneous larva migrans
- Enterobiasis
- Dosing Information
400 mg PO as a single dose; repeat in 2 weeks
- 400 mg PO as a single dose; repeat in 2 weeks
- Giardiasis
- HIV infection - Infection by Microsporida (disseminated or intestinal)
- Dosing Information
400 mg PO 2 per day until CD4+ count is greater than 200 cells/mcL for longer than 6 months after initiation of ART; add itraconazole 400 mg PO daily for disseminated disease due to Trachipleistophora or Anncaliia.
- 400 mg PO 2 per day until CD4+ count is greater than 200 cells/mcL for longer than 6 months after initiation of ART; add itraconazole 400 mg PO daily for disseminated disease due to Trachipleistophora or Anncaliia.
- Infection by Gnathostoma
- Infection by Loa loa
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA Labeled indications and dosage of Albendazole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Albendazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Albendazole in pediatric patients.
# Contraindications
- Albrendazole is contraindicated in patients with known hypersensitivity to the benzimidazole class of compounds or any components of Albendazole.
# Warnings
- Rare fatalities associated with the use of Albendazole have been reported due to granulocytopenia or pancytopenia. Albendazole has been shown to cause bone marrow suppression, aplastic anemia, and agranulocytosis in patients with and without underlying hepatic dysfunction. Blood counts should be monitored at the beginning of each 28-day cycle of therapy, and every 2 weeks while on therapy with albendazole in all patients. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk for bone marrow suppression leading to pancytopenia, aplastic anemia, agranulocytosis, and leukopenia attributable to albendazole and warrant closer monitoring of blood counts. Albendazole should be discontinued in all patients if clinically significant decreases in blood cell counts occur.
- Albendazole should not be used in pregnant women except in clinical circumstances where no alternative management is appropriate. Patients should not become pregnant for at least 1 month following cessation of albendazole therapy. If a patient becomes pregnant while taking this drug, albendazole should be discontinued immediately. If pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# Adverse Reactions
## Clinical Trials Experience
- The adverse event profile of albendazole differs between hydatid disease and neurocysticercosis. Adverse events occurring with a frequency of ≥1% in either disease are described in the table below.
- These symptoms were usually mild and resolved without treatment. Treatment discontinuations were predominantly due to leukopenia (0.7%) or hepatic abnormalities (3.8% in hydatid disease). The following incidence reflects events that were reported by investigators to be at least possibly or probably related to albendazole.
- The following adverse events were observed at an incidence of <1%:
- Blood and Lymphatic System Disorders
Leukopenia. There have been rare reports of granulocytopenia, pancytopenia, agranulocytosis, or thrombocytopenia. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk of bone marrow suppression.
- Leukopenia. There have been rare reports of granulocytopenia, pancytopenia, agranulocytosis, or thrombocytopenia. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk of bone marrow suppression.
- Immune System Disorders
Hypersensitivity reactions, including rash and urticaria.
- Hypersensitivity reactions, including rash and urticaria.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been identified during world-wide post-approval use of Albendazole. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Albendazole.
- Blood and Lymphatic System Disorders
- Aplastic anemia, bone marrow suppression, neutropenia.
- Hepatobiliary Disorders
- Elevations of hepatic enzymes, hepatitis, acute liver failure.
- Skin and Subcutaneous Tissue Disorders
- Erythema multiforme, Stevens-Johnson syndrome.
- Renal and Urinary Disorders
- Acute renal failure.
# Drug Interactions
- Dexamethasone
- Steady-state trough concentrations of albendazole sulfoxide were about 56% higher when 8 mg dexamethasone was coadministered with each dose of albendazole (15 mg/kg/day) in 8 neurocysticercosis patients.
- Praziquantel
- In the fed state, praziquantel (40 mg/kg) increased mean maximum plasma concentration and area under the curve of albendazole sulfoxide by about 50% in healthy subjects (n = 10) compared with a separate group of subjects (n = 6) given albendazole alone. Mean Tmax and mean plasma elimination half-life of albendazole sulfoxide were unchanged. The pharmacokinetics of praziquantel were unchanged following coadministration with albendazole (400 mg).
- Cimetidine
- Albendazole sulfoxide concentrations in bile and cystic fluid were increased (about 2-fold) in hydatid cyst patients treated with cimetidine (10 mg/kg/day) (n = 7) compared with albendazole (20 mg/kg/day) alone (n = 12). Albendazole sulfoxide plasma concentrations were unchanged 4 hours after dosing.
- Theophylline
- The pharmacokinetics of theophylline (aminophylline 5.8 mg/kg infused over 20 minutes) were unchanged following a single oral dose of albendazole (400 mg) in 6 healthy subjects.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Albendazole has been shown to be teratogenic (to cause embryotoxicity and skeletal malformations) in pregnant rats and rabbits. The teratogenic response in the rat was shown at oral doses of 10 and 30 mg/kg/day (0.10 times and 0.32 times the recommended human dose based on body surface area in mg/m2, respectively) during gestation days 6 to 15 and in pregnant rabbits at oral doses of 30 mg/kg/day (0.60 times the recommended human dose based on body surface area in mg/m2) administered during gestation days 7 to 19. In the rabbit study, maternal toxicity (33% mortality) was noted at 30 mg/kg/day. In mice, no teratogenic effects were observed at oral doses up to 30 mg/kg/day (0.16 times the recommended human dose based on body surface area in mg/m2), administered during gestation days 6 to 15.
- There are no adequate and well-controlled studies of albendazole administration in pregnant women. Albendazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Template:Levofloxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Levofloxacin during labor and delivery.
### Nursing Mothers
- Albendazole is excreted in animal milk. It is not known whether it is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when albendazole is administered to a nursing woman.
### Pediatric Use
- Experience in children under the age of 6 years is limited. In hydatid disease, infection in infants and young children is uncommon, but no problems have been encountered in those who have been treated. In neurocysticercosis, infection is more frequently encountered. In 5 published studies involving pediatric patients as young as 1 year, no significant problems were encountered, and the efficacy appeared similar to the adult population.
### Geriatic Use
- Experience in patients 65 years of age or older is limited. The number of patients treated for either hydatid disease or neurocysticercosis is limited, but no problems associated with an older population have been observed.
### Gender
There is no FDA guidance on the use of albendazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of albendazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of albendazole in patients with hepatic impairment.
### Hepatic Impairment
There is no FDA guidance on the use of albendazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of albendazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of albendazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- White Blood Cell Count
- Albendazole has been shown to cause occasional (less than 1% of treated patients) reversible reductions in total white blood cell count. Rarely, more significant reductions may be encountered including granulocytopenia, agranulocytosis, or pancytopenia. Blood counts should be performed at the start of each 28-day treatment cycle and every 2 weeks during each 28-day cycle in all patients. Patients with liver disease, including hepatic echinococcosis, appear to be more at risk of bone marrow suppression and warrant closer monitoring of blood counts. Albendazole should be discontinued in all patients if clinically significant decreases in blood cell counts occur.
- Liver Function
- In clinical trials, treatment with albendazole has been associated with mild to moderate elevations of hepatic enzymes in approximately 16% of patients. These elevations have generally returned to normal upon discontinuation of therapy. There have also been case reports of acute liver failure of uncertain causality and hepatitis.
- Liver function tests (transaminases) should be performed before the start of each treatment cycle and at least every 2 weeks during treatment. If hepatic enzymes exceed twice the upper limit of normal, consideration should be given to discontinuing albendazole therapy based on individual patient circumstances. Restarting albendazole treatment in patients whose hepatic enzymes have normalized off treatment is an individual decision that should take into account the risk/benefit of further albendazole usage. Laboratory tests should be performed frequently if albendazole treatment is restarted.
- Patients with abnormal liver function test results are at increased risk for hepatotoxicity and bone marrow suppression. Therapy should be discontinued if liver enzymes are significantly increased or if clinically significant decreases in blood cell counts occur.
# IV Compatibility
There is limited information regarding IV Compatibility albendazole in the drug label.
# Overdosage
- Significant toxicity and mortality were shown in male and female mice at doses exceeding 5,000 mg/kg; in rats, at estimated doses between 1,300 and 2,400 mg/kg; in hamsters, at doses exceeding 10,000 mg/kg; and in rabbits, at estimated doses between 500 and 1,250 mg/kg. In the animals, symptoms were demonstrated in a dose-response relationship and included diarrhea, vomiting, tachycardia, and respiratory distress.
- One overdosage has been reported with Albendazole in a patient who took at least 16 grams over 12 hours. No untoward effects were reported. In case of overdosage, symptomatic therapy and general supportive measures are recommended.
# Pharmacology
## Mechanism of Action
- As a vermicidal, albendazole causes degenerative alterations in the intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. The loss of the cytoplasmic microtubules leads to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores. Degenerative changes occur in the endoplasmic reticulum, the mitochondria of the germinal layer, and the subsequent release of lysosome.
## Structure
- Chemically, it is methyl 5-(propylthio)-2-benzimidazolecarbamate. Its molecular formula is C12H15N3O2S. Its molecular weight is 265.34. It has the following chemical structure:
## Pharmacodynamics
There is limited information regarding pharmacodynamics of albendazole in the drug label.
## Pharmacokinetics
### Absorption and Metabolism=
- Albendazole is poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. Albendazole concentrations are negligible or undetectable in plasma as it is rapidly converted to the sulfoxide metabolite prior to reaching the systemic circulation. The systemic anthelmintic activity has been attributed to the primary metabolite, albendazole sulfoxide. Oral bioavailability appears to be enhanced when albendazole is coadministered with a fatty meal (estimated fat content 40 g) as evidenced by higher (up to 5-fold on average) plasma concentrations of albendazole sulfoxide as compared to the fasted state.
- Maximal plasma concentrations of albendazole sulfoxide are typically achieved 2 to 5 hours after dosing and are on average 1.31 mcg/mL (range 0.46 to 1.58 mcg/mL) following oral doses of albendazole (400 mg) in 6 hydatid disease patients, when administered with a fatty meal. Plasma concentrations of albendazole sulfoxide increase in a dose-proportional manner over the therapeutic dose range following ingestion of a fatty meal (fat content 43.1 g). The mean apparent terminal elimination half-life of albendazole sulfoxide typically ranges from 8 to 12 hours in 25 normal subjects, as well as in 14 hydatid and 8 neurocysticercosis patients.
- Following 4 weeks of treatment with albendazole (200 mg three times daily), 12 patients’ plasma concentrations of albendazole sulfoxide were approximately 20% lower than those observed during the first half of the treatment period, suggesting that albendazole may induce its own metabolism.
- Albendazole sulfoxide is 70% bound to plasma protein and is widely distributed throughout the body; it has been detected in urine, bile, liver, cyst wall, cyst fluid, and cerebral spinal fluid (CSF). Concentrations in plasma were 3- to 10-fold and 2- to 4-fold higher than those simultaneously determined in cyst fluid and CSF, respectively. Limited in vitro and clinical data suggest that albendazole sulfoxide may be eliminated from cysts at a slower rate than observed in plasma.
- Albendazole is rapidly converted in the liver to the primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites that have been identified in human urine. Following oral administration, albendazole has not been detected in human urine. Urinary excretion of albendazole sulfoxide is a minor elimination pathway with less than 1% of the dose recovered in the urine. Biliary elimination presumably accounts for a portion of the elimination as evidenced by biliary concentrations of albendazole sulfoxide similar to those achieved in plasma.
## Nonclinical Toxicology
There is limited information regarding nonclinical toxicology of Estradiol valerate and estradiol valerate/dienogest in the drug label.
# Clinical Studies
There is limited information regarding Albendazole Clinical Studies in the drug label.
# How Supplied
- Albendazole is supplied as 200 mg, white to off-white, circular, biconvex, bevel-edged, film coated TILTAB tablet embossed "ap" and "550". They are supplied as follows:
- Bottles of 2 NDC 52054-550-22
- Bottles of 28 NDC 52054-550-28
- ALBENZA and TILTAB are registered trademarks of GlaxoSmithKline, used with permission.
- Manufactured by:
- GlaxoSmithKline
- Mississauga, Ontario
- L5N 6L4 Canada
- Distributed by:
- Amedra Pharmaceuticals, LLC
- Horsham, PA 19044
- LB# 799-03 Rev. February, 2013
## Storage
- Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that:
- Some people, particularly young children, may experience difficulties swallowing the tablets whole. In young children, the tablets should be crushed or chewed and swallowed with a drink of water.
- Albendazole may cause fetal harm, therefore, women of childbearing age should begin treatment after a negative pregnancy test.
- Women of childbearing age should be cautioned against becoming pregnant while on albendazole or within 1 month of completing treatment.
- During albendazole therapy, because of the possibility of harm to the liver or bone marrow, routine (every 2 weeks) monitoring of blood counts and liver function tests should take place.
- Albendazole should be taken with food.
# Precautions with Alcohol
Alcohol-Albendazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Albenza®
# Look-Alike Drug Names
There is limited information regarding Albendazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Albendazole | |
bb5b6a3cf3f228ed9eeb2c78d3b57859792d49a8 | wikidoc | Albiglutide | Albiglutide
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Albiglutide is an antidiabetic drug that is FDA approved for the treatment of type 2 diabetes mellitus in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infection, diarrhea, nausea, and injection site reaction..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
# Limitations of Use
- Albiglutide is not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans. Prescribe albiglutide only to patients for whom the potential benefits are considered to outweigh the potential risk.
- Albiglutide has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Albiglutide is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. Albiglutide is not a substitute for insulin in these patients.
- Albiglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of albiglutide is not recommended in patients with pre-existing severe gastrointestinal disease.
- Albiglutide has not been studied in combination with prandial insulin.
# Dosage
- The recommended dosage of albiglutide is 30 mg once weekly given as a subcutaneous injection in the abdomen, thigh, or upper arm region. The dosage may be increased to 50 mg once weekly if the glycemic response is inadequate.
- Albiglutide may be administered at any time of day without regard to meals. Instruct patients to administer albiglutide once a week on the same day each week. The day of weekly administration may be changed if necessary as long as the last dose was administered 4 or more days before.
- If a dose is missed, instruct patients to administer as soon as possible within 3 days after the missed dose. Thereafter, patients can resume dosing on their usual day of administration. If it is more than 3 days after the missed dose, instruct patients to wait until their next regularly scheduled weekly dose.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
- When initiating albiglutide, consider reducing the dosage of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia.
Dosage in Patients with Renal Impairment
- No dose adjustment is needed in patients with mild, moderate, or severe renal impairment (eGFR 15 to 89 mL/min/1.73 m2). Use caution when initiating or escalating doses of albiglutide in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
Reconstitution of the Lyophilized Powder
- The lyophilized powder contained within the Pen must be reconstituted prior to administration. See Patient Instructions for Use for complete administration instructions with illustrations. The instructions may also be found at www.Albiglutide.com. Instruct patients as follows:
Pen Reconstitution
- Hold the Pen body with the clear cartridge pointing up to see the in the number window.
- To reconstitute the lyophilized powder with the diluent in the Pen, twist the clear cartridge on the Pen in the direction of the arrow until the Pen is felt/heard to “click” into place and the is seen in the number window. This mixes the diluent with the lyophilized powder.
- Slowly and gently rock the Pen side-to-side 5 times to mix the reconstituted solution of albiglutide. Advise the patient to not shake the Pen hard to avoid foaming.
Wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen to ensure that the reconstituted solution is mixed.
Preparing Pen for Injection
- Slowly and gently rock the Pen side-to-side 5 additional times to mix the reconstituted solution.
- Visually inspect the reconstituted solution in the viewing window for particulate matter. The reconstituted solution will be yellow in color. After reconstitution, use Albiglutide within 8 hours.
- Holding the Pen upright, attach the needle to the Pen. Gently tap the clear cartridge to bring large bubbles to the top.
Alternate Method of Reconstitution
- The Patient Instructions for Use provide directions for the patient to wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen after the lyophilized powder and diluent are mixed to ensure reconstitution.
- Healthcare professionals may utilize the following alternate method of reconstitution. Because this method relies on appropriate swirling and visual inspection of the solution, it should only be performed by healthcare professionals.
- Follow Step A (Inspect Your Pen and Mix Your Medication) in the Instructions for Use. Make sure you have:
- Inspected the Pen for in the number window and expiration date.
- Twisted the clear cartridge until appears in the number window and a “click” is heard. This combines the medicine powder and liquid in the clear cartridge.
- Hold the Pen with the clear cartridge pointing up and maintain this orientation throughout the reconstitution.
- Gently swirl the Pen in small circular motions for at least one minute. Avoid shaking as this can result in foaming, which may affect the dose.
- Inspect the solution, and if needed, continue to gently swirl the Pen until all the powder is dissolved and you see a clear yellow solution that is free of particles. A small amount of foam, on top of the solution at the end of reconstitution, is normal.
For 30-mg Pen: Complete dissolution usually occurs within 2 minutes but may take up to 5 minutes, as confirmed by visual inspection for a clear yellow solution free of particles.
- For 50-mg Pen: Complete dissolution usually occurs within 7 minutes but may take up to 10 minutes.
- After reconstitution, continue to follow the steps in the Instructions for Use, starting at Step B: Attach the Needle.
# DOSAGE FORMS AND STRENGTHS
- Albiglutide is supplied as follows:
- For injection: 30-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution.
- For injection: 50-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Albiglutide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Albiglutide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Albiglutide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Albiglutide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Albiglutide in pediatric patients.
# Contraindications
Medullary Thyroid Carcinoma
- Albiglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Hypersensitivity
- Albiglutide is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components.
# Warnings
Risk of Thyroid C-cell Tumors
- Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies. Other GLP-1 receptor agonists have caused dose-related and treatment-duration-dependent thyroid C-cell tumors (adenomas or carcinomas) in rodents. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether albiglutide causes thyroid C-cell tumors, including MTC, in humans.
- Across 8 Phase III clinical trials, MTC was diagnosed in 1 patient receiving albiglutide and 1 patient receiving placebo. Both patients had markedly elevated serum calcitonin levels at baseline. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.
- Albiglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of albiglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or persistent hoarseness).
- Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with albiglutide. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Acute Pancreatitis
- In clinical trials, acute pancreatitis has been reported in association with albiglutide.
- Across 8 Phase III clinical trials, pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving albiglutide (6 of 2,365 ) than in patients receiving placebo (0 of 468 ) or active comparators (2 of 2,065 ).
- After initiation of albiglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue albiglutide. If pancreatitis is confirmed, albiglutide should not be restarted.
- Albiglutide has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- The risk of hypoglycemia is increased when albiglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting.
Hypersensitivity Reactions
Across 8 Phase III clinical trials, a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with albiglutide. If hypersensitivity reactions occur, discontinue use of albiglutide; treat promptly per standard of care and monitor until signs and symptoms resolve.
Renal Impairment
- In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of albiglutide in patients with renal impairment, the frequency of such gastrointestinal reactions increased as renal function declined. Because these reactions may worsen renal function, use caution when initiating or escalating doses of albiglutide in patients with renal impairment.
Macrovascular Outcomes
- There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with albiglutide or any other antidiabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- The following serious reactions are described below or elsewhere in the prescribing information:
- Risk of Thyroid C-cell Tumors
- Acute Pancreatitis
- Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- Hypersensitivity Reactions
- Renal Impairment
# Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Pool of Placebo-Controlled Trials
- The data in Table 1 are derived from 4 placebo-controlled trials. Albiglutide was used as monotherapy in 1 trial and as add-on therapy in 3 trials. These data reflect exposure of 923 patients to albiglutide and a mean duration of exposure to albiglutide of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 9%.
- Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of albiglutide in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on albiglutide than on placebo, and occurred in at least 5% of patients treated with albiglutide.
Gastrointestinal Adverse Reactions
- In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving albiglutide (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving albiglutide: vomiting (2.6% versus 4.2% for placebo versus albiglutide), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus albiglutide), and dyspepsia (2.8% versus 3.4% for placebo versus albiglutide). Constipation also contributed to the frequently reported reactions. In the group treated with albiglutide, investigators graded the severity of GI reactions as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on albiglutide or placebo.
Injection Site Reactions
- In the pool of placebo-controlled trials, injection site reactions occurred more frequently on albiglutide (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on albiglutide: injection site hematoma (1.9% versus 2.1% for placebo versus albiglutide ), injection site erythema (0.4% versus 1.7% for placebo versus albiglutide), injection site rash (0% versus 1.4% for placebo versus albiglutide), injection site hypersensitivity (0% versus 0.8% for placebo versus albiglutide), and injection site hemorrhage (0.6% versus 0.7% for placebo versus albiglutide). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as “mild” by investigators in both groups (73% for albiglutide versus 94% for placebo). More patients on albiglutide than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be “moderate” or “severe” (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%).
Pool of Placebo- and Active-controlled Trials
- The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of albiglutide as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin. In this pool, a total of 2,116 patients with type 2 diabetes were treated with albiglutide for a mean duration of 75 weeks. The mean age of patients treated with albiglutide was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 8% of the population.
- In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1.
Other Adverse Reactions
Hypoglycemia
- The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on albiglutide and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin.
Pneumonia
- In the pool of 7 placebo- and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving albiglutide were serious (0.4% for albiglutide versus 0.1% for all comparators).
Atrial Fibrillation/Flutter
- In the pool of 7 placebo- and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for albiglutide than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.).
Appendicitis
- In the pool of placebo- and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with albiglutide compared with 0% among all comparators.
Immunogenicity
- In the pool of 7 placebo- and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to albiglutide tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions.
- Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products.
Liver Enzyme Abnormalities
- In the pool of placebo- and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus albiglutide). Three subjects on albiglutide and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal. In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of albiglutide. The etiology of hepatocellular injury was possibly related to albiglutide but direct attribution to albiglutide was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event.
Gamma Glutamyltransferase (GGT) Increase
- In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM).
Heart Rate Increase
- In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Albiglutide in the drug label.
# Drug Interactions
- TANZEUM did not affect the absorption of orally administered medications tested in clinical pharmacology studies to any clinically relevant degree. However, TANZEUM causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies of TANZEUM in pregnant women. Nonclinical studies have shown reproductive toxicity, but not teratogenicity, in mice treated with albiglutide at up to 39 times human exposure resulting from the maximum recommended dose of 50 mg/week, based on AUC . TANZEUM should not be used during pregnancy unless the expected benefit outweighs the potential risks.
- Due to the long washout period for TANZEUM, consider stopping TANZEUM at least 1 month before a planned pregnancy.
- There are no data on the effects of TANZEUM on human fertility. Studies in mice showed no effects on fertility. The potential risk to human fertility is unknown.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Albiglutide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Albiglutide during labor and delivery.
### Nursing Mothers
- There are no adequate data to support the use of TANZEUM during lactation in humans.
- It is not known if TANZEUM is excreted into human milk during lactation. Given that TANZEUM is an albumin-based protein therapeutic, it is likely to be present in human milk. Decreased body weight in offspring was observed in mice treated with TANZEUM during gestation and lactation. A decision should be made whether to discontinue nursing or to discontinue TANZEUM, taking into account the importance of the drug to the mother and the potential risks to the infant.
### Pediatric Use
- Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years).
### Geriatic Use
- Of the total number of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 19% (N = 444) were 65 years and older, and <3% (N = 52) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Albiglutide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Albiglutide with respect to specific racial populations.
### Renal Impairment
- Of the total number of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 54% (N = 1,267) had mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2), 12% (N = 275) had moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) and 1% (N = 19) had severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2).
- No dosage adjustment is required in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment.
- Efficacy of TANZEUM in patients with type 2 diabetes and renal impairment is described elsewhere. There is limited clinical experience in patients with severe renal impairment (19 subjects). The frequency of GI events increased as renal function declined. For patients with mild, moderate, or severe impairment, the respective event rates were: diarrhea (6%, 13%, 21%), nausea (3%, 5%, 16%), and vomiting (1%, 2%, 5%). Therefore, caution is recommended when initiating or escalating doses of TANZEUM in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Albiglutide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Albiglutide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Albiglutide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
Instruct patients as follows:
- The pen should be used within 8 hours of reconstitution prior to attaching the needle.
- After attaching the supplied needle, remove air bubbles by slowly twisting the Pen until you see the in the number window. At the same time, the injection button will be automatically released from the bottom of the Pen.
- Use immediately after the needle is attached and primed. The product can clog the needle if allowed to dry in the primed needle.
- After subcutaneously inserting the needle into the skin in the abdomen, thigh, or upper arm region, press the injection button. Hold the injection button until you hear a “click” and then hold the button for 5 additional seconds to deliver the full dose.
- When using TANZEUM with insulin, instruct patients to administer as separate injections and to never mix the products. It is acceptable to inject TANZEUM and insulin in the same body region but the injections should not be adjacent to each other.
- When injecting in the same body region, advise patients to use a different injection site each week. TANZEUM must not be administered intravenously or intramuscularly.
### Monitoring
There is limited information regarding Monitoring of Albiglutide in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Albiglutide in the drug label.
# Overdosage
- No data are available with regard to overdosage in humans. Anticipated symptoms of an overdose may be severe nausea and vomiting.
- In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the half-life of TANZEUM (5 days).
# Pharmacology
## Mechanism of Action
- TANZEUM is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. TANZEUM also slows gastric emptying.
## Structure
There is limited information regarding Albiglutide Structure in the drug label.
## Pharmacodynamics
- TANZEUM lowers fasting glucose and reduces postprandial glucose excursions in patients with type 2 diabetes mellitus. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide. In a Phase II trial in Japanese patients with type 2 diabetes mellitus who received TANZEUM 30 mg, a reduction (22%) in postprandial glucose AUC(0-3 h) was observed at steady state (Week 16) compared with placebo following a mixed meal.
- A single dose of TANZEUM 50 mg subcutaneous (SC) did not impair glucagon response to low glucose concentrations.
Gastric Motility
- TANZEUM slowed gastric emptying compared with placebo for both solids and liquids when albiglutide 100 mg (2 times the maximum approved dosage) was administered as a single dose in healthy subjects.
Cardiac Electrophysiology
- At doses up to the maximum recommended dose (50 mg), TANZEUM does not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
Absorption
- Following SC administration of a single 30-mg dose to subjects with type 2 diabetes mellitus, maximum concentrations of albiglutide were reached at 3 to 5 days post-dosing. The mean peak concentration (Cmax) and mean area under the time-concentration curve (AUC) of albiglutide were 1.74 mcg/mL and 465 mcg.h/mL, respectively, following a single dose of 30 mg albiglutide in type 2 diabetes mellitus subjects. Steady-state exposures are achieved following 4 to 5 weeks of once-weekly administration. Exposures at the 30-mg and 50-mg dose levels were consistent with a dose-proportional increase. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of albiglutide following SC administration has not been evaluated.
Distribution
- The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 L. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed.
Metabolism
- Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed. Because albiglutide is an albumin fusion protein, it likely follows a metabolic pathway similar to native human serum albumin which is catabolized primarily in the vascular endothelium.
Elimination
- The mean apparent clearance of albiglutide is 67 mL/h with an elimination half-life of approximately 5 days, making albiglutide suitable for once-weekly administration.
Specific Patient Populations
- Age, Gender, Race, and Body Weight: Based on the population pharmacokinetic analysis with data collected from 1,113 subjects, age, gender, race, and body weight had no clinically relevant effect on the pharmacokinetics of albiglutide.
- Pediatric: No pharmacokinetic data are available in pediatric patients.
- Renal: In a population pharmacokinetic analysis including a Phase III trial in patients with mild, moderate, and severe renal impairment, exposures were increased by approximately 30% to 40% in severe renal impairment compared with those observed in type 2 diabetic patients with normal renal function.
- Hepatic: No clinical trials were conducted to examine the effects of mild, moderate, or severe hepatic impairment on the pharmacokinetics of albiglutide. Therapeutic proteins such as albiglutide are catabolized by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of albiglutide.
Drug Interactions
- In multiple-dose, drug-drug interaction trials no significant change in systemic exposures of the co-administered drugs were observed, except simvastatin (see Table 3). When albiglutide was co-administered with simvastatin, Cmax of simvastatin and its active metabolite simvastatin acid was increased by approximately 18% and 98%, respectively. In the same trial, AUC of simvastatin decreased by 40% and AUC of simvastatin acid increased by 36%. Clinical relevance of these changes has not been established (see Table 3).
- Additionally, no clinically relevant pharmacodynamic effects on luteinizing hormone, follicle-stimulating hormone, or progesterone were observed when albiglutide and a combination oral contraceptive were co-administered. Albiglutide did not significantly alter the pharmacodynamic effects of warfarin as measured by the international normalized ratio (INR).
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- As albiglutide is a recombinant protein, no genotoxicity studies have been conducted.
- Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies. Other GLP-1 receptor agonists have caused thyroid C-cell tumors in rodent carcinogenicity studies. Human relevance of GLP-1 receptor agonist induced rodent thyroid C-cell tumors has not been determined.
- In a mouse fertility study, males were treated with SC doses of 5, 15, or 50 mg/kg/day for 7 days prior to cohabitation with females, and continuing through mating. In a separate fertility study, females were treated with SC doses of 1, 5, or 50 mg/kg/day for 7 days prior to cohabitation with males, and continuing through mating. Reductions in estrous cycles were observed at 50 mg/kg/day, a dose associated with maternal toxicity (body weight loss and reduced food consumption). There were no effects on mating or fertility in either sex at doses up to 50 mg/kg/day (up to 39 times clinical exposure based on AUC).
Reproductive and Developmental Toxicity
- In order to minimize the impact of the drug-clearing, anti-drug antibody response, reproductive and developmental toxicity assessments in the mouse were partitioned to limit the dosing period to no more than approximately 15 days in each study.
- In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 1 to 6, there were no adverse effects on early embryonic development through implantation at 50 mg/kg/day (39 times clinical exposure based on AUC).
- In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 through 15 (organogenesis), embryo-fetal lethality (post-implantation loss) and bent (wavy) ribs were observed at 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity (body weight loss and reduced food consumption).
- Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 to 17. Offspring of pregnant mice given 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity, had reduced body weight pre-weaning, dehydration and coldness, and a delay in balanopreputial separation.
- Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 15 to lactation Day 10. Increased mortality and morbidity were seen at all doses (≥1 mg/kg/day) in lactating females in mouse pre- and postnatal development studies. Mortalities have not been observed in previous toxicology studies in non-lactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are of questionable relevance to humans. The offspring had decreased pre-weaning body weight which reversed post-weaning in males but not females at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Low levels of albiglutide were detected in plasma of offspring.
- Lactating mice were given SC doses of 1, 5, or 50 mg/kg/day from lactation Day 7 to 21 (weaning) under conditions that limit the impact of lactational ileus (increased caloric intake and culling of litters). Doses ≥1 mg/kg/day (exposures below clinical AUC) caused reduced weight gain in the pups during the treatment period.
# Clinical Studies
- TANZEUM has been studied as monotherapy and in combination with metformin, metformin and a sulfonylurea, a thiazolidinedione (with and without metformin), and insulin glargine (with or without oral anti-diabetic drugs). The efficacy of TANZEUM was compared with placebo, glimepiride, pioglitazone, liraglutide, sitagliptin, insulin lispro, and insulin glargine.
- Trials evaluated the use of TANZEUM 30 mg and 50 mg. Five of the 8 trials allowed optional uptitration of TANZEUM from 30 mg to 50 mg if glycemic response with 30 mg was inadequate.
- In patients with type 2 diabetes mellitus, TANZEUM produced clinically relevant reduction from baseline in HbA1c compared with placebo. No overall differences in glycemic effectiveness or body weight were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).
Monotherapy
- The efficacy of TANZEUM as monotherapy was evaluated in a 52-week, randomized, double-blind, placebo-controlled, multicenter trial. In this trial, 296 patients with type 2 diabetes inadequately controlled on diet and exercise were randomized (1:1:1) to TANZEUM 30 mg SC once weekly, TANZEUM 30 mg SC once weekly uptitrated to 50 mg once weekly at Week 12, or placebo. The mean age of participants was 53 years, 55% of patients were men, the mean duration of diabetes was 4 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. Primary and secondary efficacy results are presented in Table 4. Figure 1 shows the mean adjusted changes in HbA1c from baseline across study visits.
- Compared with placebo, treatment with TANZEUM 30 mg or 50 mg resulted in statistically significant reductions in HbA1c from baseline at Week 52 (see Table 4). The adjusted mean change in weight from baseline did not differ significantly between TANZEUM (-0.4 to -0.9 kg) and placebo (-0.7 kg) at Week 52.
Combination Therapy
Add-on to Metformin
- The efficacy of TANZEUM was evaluated in a 104-week randomized, double-blind, multicenter trial in 999 patients with type 2 diabetes mellitus inadequately controlled on background metformin therapy (≥1,500 mg daily). In this trial, TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared with placebo, sitagliptin 100 mg daily, or glimepiride 2 mg daily (with optional titration to 4 mg daily). The mean age of participants was 55 years, 48% of patients were men, the mean duration of type 2 diabetes was 6 years, and the mean baseline eGFR was 86 mL/min/1.73 m2. Results of the primary and secondary analyses are presented in Table 5. Figure 2 shows the mean adjusted changes in HbA1c across study visits.
- Reduction in HbA1c from baseline achieved with TANZEUM was significantly greater than HbA1c reduction achieved with placebo, sitagliptin, and glimepiride at Week 104 (see Table 5). The difference in body weight change from baseline between TANZEUM and glimepiride was significant at Week 104.
Add-on to Pioglitazone
- The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 299 patients with type 2 diabetes mellitus inadequately controlled on pioglitazone ≥30 mg daily (with or without metformin ≥1,500 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly or placebo. The mean age of participants was 55 years, 60% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 83 mL/min/1.73 m2. Results of the primary and secondary analyses are presented in Table 6.
- Compared with placebo, treatment with TANZEUM resulted in a statistically significant reduction in HbA1c from baseline at Week 52 (see Table 6). The adjusted mean change from baseline in weight did not differ significantly between TANZEUM (+0.3 kg) and placebo (+0.5 kg) at Week 52.
Add-on to Metformin Plus Sulfonylurea
- The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 657 patients with type 2 diabetes mellitus inadequately controlled on metformin (≥1,500 mg daily) and glimepiride (4 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks), placebo, or pioglitazone 30 mg daily (with optional titration to 45 mg/day). The mean age of participants was 55 years, 53% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 7.
- Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline compared with placebo (see Table 7). Treatment with TANZEUM did not meet the pre-specified, non-inferiority margin (0.3%) against pioglitazone. In this trial, TANZEUM provided less HbA1c reduction than pioglitazone and the treatment difference was statistically significant (see Table 7). The change from baseline in body weight for TANZEUM did not differ significantly from placebo but was significantly different compared with pioglitazone (see Table 7).
Combination Therapy: Active-controlled Trial versus Liraglutide
- The efficacy of TANZEUM was evaluated in a 32-week, randomized, open-label, liraglutide-controlled, non-inferiority trial in 805 patients with type 2 diabetes mellitus inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, sulfonylurea, or a combination of these). Patients were randomized to TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly at Week 6) or liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1, and 1.2 mg at Week 1 to Week 2). The mean age of participants was 56 years, 50% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 95 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 8.
- The between-treatment difference of 0.2% with 95% confidence interval (0.08, 0.34) between TANZEUM and liraglutide did not meet the pre-specified, non-inferiority margin (0.3%). In this trial, TANZEUM provided less HbA1c reduction than liraglutide and the treatment difference was statistically significant (see Table 8).
Combination Therapy: Active-controlled Trial versus Basal Insulin
- The efficacy of TANZEUM was evaluated in a 52-week, randomized (2:1), open-label, insulin glargine-controlled, non-inferiority trial in 735 patients with type 2 diabetes mellitus inadequately controlled on metformin ≥1,500 mg daily (with or without sulfonylurea). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly) or insulin glargine (started at 10 units and titrated weekly per prescribing information). The primary endpoint was change in HbA1c from baseline compared with insulin glargine. The starting total daily dose of insulin glargine ranged between 2 and 40 units (median daily dose of 10 units) and ranged between 3 and 230 units (median daily dose of 30 units) at Week 52. Seventy-seven percent of patients treated with TANZEUM were uptitrated to 50 mg SC weekly. The mean age of participants was 56 years, 56% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 85 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 9.
- The between-treatment difference of 0.1% with 95% confidence interval (-0.04%, 0.27%) for TANZEUM and insulin glargine met the pre-specified, non-inferiority margin (0.3%). A mean decrease in body weight was observed for TANZEUM compared with a mean increase in body weight for insulin glargine, and the difference in weight change was statistically significant (see Table 9).
Combination Therapy: Active-controlled Trial versus Prandial Insulin
- The efficacy of TANZEUM was evaluated in a 26-week, randomized, open-label, multicenter, non-inferiority trial in 563 patients with type 2 diabetes mellitus inadequately controlled on insulin glargine (started at 10 units and titrated to ≥20 units per day). Patients were randomized to receive TANZEUM 30 mg SC once weekly (with uptitration to 50 mg if inadequately controlled after Week 8) or insulin lispro (administered daily at meal times, started according to standard of care and titrated to effect). At Week 26, the mean daily dose of insulin glargine was 53 IU for TANZEUM and 51 IU for insulin lispro. The mean daily dose of insulin lispro at Week 26 was 31 IU, and 69% of patients treated with TANZEUM were on 50 mg weekly. The mean age of participants was 56 years, 47% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 91 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 10. Figure 4 shows the mean adjusted changes in HbA1c from baseline across study visits.
- The between-treatment difference of -0.2% with 95% confidence interval (-0.32%, 0.00%) between albiglutide and insulin lispro met the pre-specified non-inferiority margin (0.4%). Treatment with TANZEUM resulted in a mean weight loss for TANZEUM compared with a mean weight gain for insulin lispro, and the difference between treatment groups was statistically significant (see Table 10).
Type 2 Diabetes Mellitus Patients with Renal Impairment
- The efficacy of TANZEUM was evaluated in a 26-week, randomized, double-blind, active-controlled trial in 486 patients with mild (n = 250), moderate (n = 200), and severe renal impairment (n = 36) inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy. Patients were randomized to receive TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly if needed as early as Week 4) or sitagliptin. Sitagliptin was dosed according to renal function (100 mg, 50 mg, and 25 mg daily in mild, moderate, and severe renal impairment, respectively). The mean age of participants was 63 years, 54% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 60 mL/min/1.73 m2.
- Results of the primary and main secondary analyses are presented in Table 11. Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline at Week 26 compared with sitagliptin (see Table 11).
# How Supplied
- TANZEUM is available in the following strengths and package size:
- 30 mg single-dose Pen (NDC 0173-0866-01):
- carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0866-35
50 mg single-dose Pen (NDC 0173-0867-01):
- carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0867-35
## Storage
- Prior to dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Pens may be stored refrigerated until the expiration date.
- Following dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Patients may store Pens at room temperature not to exceed 86°F (30°C) for up to 4 weeks prior to use. Store Pens in the original carton until use.
- Do not freeze.
- Do not use past the expiration date.
- Use within 8 hours after reconstitution.
# Images
## Drug Images
## Package and Label Display Panel
[File:Albiglutide medication guide.png[
# Patient Counseling Information
- See FDA-approved patient labeling (Medication Guide and Instructions for Use). The Medication Guide is contained in a separate leaflet that accompanies the product.
- Inform patients about self-management practices, including the importance of proper storage of TANZEUM, injection technique, timing of dosage of TANZEUM and concomitant oral drugs, and recognition and management of hypoglycemia.
- Inform patients that thyroid C-cell tumors have been observed in rodents treated with some GLP-1 receptor agonists, and the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, dysphagia, dyspnea, or persistent hoarseness) to their physician.
- Advise patients that persistent, severe abdominal pain that may radiate to the back and which may (or may not) be accompanied by vomiting is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TANZEUM promptly and to contact their physician if persistent, severe abdominal pain occurs.
- The risk of hypoglycemia is increased when TANZEUM is used in combination with an agent that induces hypoglycemia, such as sulfonylurea or insulin. Instructions for hypoglycemia should be reviewed with patients and reinforced when initiating therapy with TANZEUM, particularly when concomitantly administered with a sulfonylurea or insulin.
- Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TANZEUM and seek medical advice promptly if such symptoms occur.
- Instruct patients to read the Instructions for Use before starting therapy.
- Instruct patients on proper use, storage, and disposal of the pen.
- Instruct patients to read the Medication Guide before starting TANZEUM and to read again each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- Inform patients not to take an extra dose of TANZEUM to make up for a missed dose.
- If a dose is missed, instruct patients to take a dose as soon as possible within 3 days after the missed dose. Instruct patients to then take their next dose at their usual weekly time. If it has been longer than 3 days after the missed dose, instruct patients to wait and take TANZEUM at the next usual weekly time.
# Precautions with Alcohol
- Alcohol-Albiglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TANZEUM ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Albiglutide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Black Box Warning
# Overview
Albiglutide is an antidiabetic drug that is FDA approved for the treatment of type 2 diabetes mellitus in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infection, diarrhea, nausea, and injection site reaction..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
# Limitations of Use
- Albiglutide is not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans. Prescribe albiglutide only to patients for whom the potential benefits are considered to outweigh the potential risk.
- Albiglutide has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
- Albiglutide is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. Albiglutide is not a substitute for insulin in these patients.
- Albiglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of albiglutide is not recommended in patients with pre-existing severe gastrointestinal disease.
- Albiglutide has not been studied in combination with prandial insulin.
# Dosage
- The recommended dosage of albiglutide is 30 mg once weekly given as a subcutaneous injection in the abdomen, thigh, or upper arm region. The dosage may be increased to 50 mg once weekly if the glycemic response is inadequate.
- Albiglutide may be administered at any time of day without regard to meals. Instruct patients to administer albiglutide once a week on the same day each week. The day of weekly administration may be changed if necessary as long as the last dose was administered 4 or more days before.
- If a dose is missed, instruct patients to administer as soon as possible within 3 days after the missed dose. Thereafter, patients can resume dosing on their usual day of administration. If it is more than 3 days after the missed dose, instruct patients to wait until their next regularly scheduled weekly dose.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
- When initiating albiglutide, consider reducing the dosage of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia.
Dosage in Patients with Renal Impairment
- No dose adjustment is needed in patients with mild, moderate, or severe renal impairment (eGFR 15 to 89 mL/min/1.73 m2). Use caution when initiating or escalating doses of albiglutide in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.
Reconstitution of the Lyophilized Powder
- The lyophilized powder contained within the Pen must be reconstituted prior to administration. See Patient Instructions for Use for complete administration instructions with illustrations. The instructions may also be found at www.Albiglutide.com. Instruct patients as follows:
Pen Reconstitution
- Hold the Pen body with the clear cartridge pointing up to see the [1] in the number window.
- To reconstitute the lyophilized powder with the diluent in the Pen, twist the clear cartridge on the Pen in the direction of the arrow until the Pen is felt/heard to “click” into place and the [2] is seen in the number window. This mixes the diluent with the lyophilized powder.
- Slowly and gently rock the Pen side-to-side 5 times to mix the reconstituted solution of albiglutide. Advise the patient to not shake the Pen hard to avoid foaming.
Wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen to ensure that the reconstituted solution is mixed.
Preparing Pen for Injection
- Slowly and gently rock the Pen side-to-side 5 additional times to mix the reconstituted solution.
- Visually inspect the reconstituted solution in the viewing window for particulate matter. The reconstituted solution will be yellow in color. After reconstitution, use Albiglutide within 8 hours.
- Holding the Pen upright, attach the needle to the Pen. Gently tap the clear cartridge to bring large bubbles to the top.
Alternate Method of Reconstitution
- The Patient Instructions for Use provide directions for the patient to wait 15 minutes for the 30-mg Pen and 30 minutes for the 50-mg Pen after the lyophilized powder and diluent are mixed to ensure reconstitution.
- Healthcare professionals may utilize the following alternate method of reconstitution. Because this method relies on appropriate swirling and visual inspection of the solution, it should only be performed by healthcare professionals.
- Follow Step A (Inspect Your Pen and Mix Your Medication) in the Instructions for Use. Make sure you have:
- Inspected the Pen for [1] in the number window and expiration date.
- Twisted the clear cartridge until [2] appears in the number window and a “click” is heard. This combines the medicine powder and liquid in the clear cartridge.
- Hold the Pen with the clear cartridge pointing up and maintain this orientation throughout the reconstitution.
- Gently swirl the Pen in small circular motions for at least one minute. Avoid shaking as this can result in foaming, which may affect the dose.
- Inspect the solution, and if needed, continue to gently swirl the Pen until all the powder is dissolved and you see a clear yellow solution that is free of particles. A small amount of foam, on top of the solution at the end of reconstitution, is normal.
For 30-mg Pen: Complete dissolution usually occurs within 2 minutes but may take up to 5 minutes, as confirmed by visual inspection for a clear yellow solution free of particles.
- For 50-mg Pen: Complete dissolution usually occurs within 7 minutes but may take up to 10 minutes.
- After reconstitution, continue to follow the steps in the Instructions for Use, starting at Step B: Attach the Needle.
# DOSAGE FORMS AND STRENGTHS
- Albiglutide is supplied as follows:
- For injection: 30-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution.
- For injection: 50-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Albiglutide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Albiglutide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Albiglutide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Albiglutide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Albiglutide in pediatric patients.
# Contraindications
Medullary Thyroid Carcinoma
- Albiglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Hypersensitivity
- Albiglutide is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components.
# Warnings
Risk of Thyroid C-cell Tumors
- Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies. Other GLP-1 receptor agonists have caused dose-related and treatment-duration-dependent thyroid C-cell tumors (adenomas or carcinomas) in rodents. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether albiglutide causes thyroid C-cell tumors, including MTC, in humans.
- Across 8 Phase III clinical trials, MTC was diagnosed in 1 patient receiving albiglutide and 1 patient receiving placebo. Both patients had markedly elevated serum calcitonin levels at baseline. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.
- Albiglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of albiglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or persistent hoarseness).
- Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with albiglutide. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Acute Pancreatitis
- In clinical trials, acute pancreatitis has been reported in association with albiglutide.
- Across 8 Phase III clinical trials, pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving albiglutide (6 of 2,365 [0.3%]) than in patients receiving placebo (0 of 468 [0%]) or active comparators (2 of 2,065 [0.1%]).
- After initiation of albiglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue albiglutide. If pancreatitis is confirmed, albiglutide should not be restarted.
- Albiglutide has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- The risk of hypoglycemia is increased when albiglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting.
Hypersensitivity Reactions
Across 8 Phase III clinical trials, a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with albiglutide. If hypersensitivity reactions occur, discontinue use of albiglutide; treat promptly per standard of care and monitor until signs and symptoms resolve.
Renal Impairment
- In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of albiglutide in patients with renal impairment, the frequency of such gastrointestinal reactions increased as renal function declined. Because these reactions may worsen renal function, use caution when initiating or escalating doses of albiglutide in patients with renal impairment.
Macrovascular Outcomes
- There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with albiglutide or any other antidiabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- The following serious reactions are described below or elsewhere in the prescribing information:
- Risk of Thyroid C-cell Tumors
- Acute Pancreatitis
- Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
- Hypersensitivity Reactions
- Renal Impairment
# Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Pool of Placebo-Controlled Trials
- The data in Table 1 are derived from 4 placebo-controlled trials. Albiglutide was used as monotherapy in 1 trial and as add-on therapy in 3 trials. These data reflect exposure of 923 patients to albiglutide and a mean duration of exposure to albiglutide of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 9%.
- Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of albiglutide in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on albiglutide than on placebo, and occurred in at least 5% of patients treated with albiglutide.
Gastrointestinal Adverse Reactions
- In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving albiglutide (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving albiglutide: vomiting (2.6% versus 4.2% for placebo versus albiglutide), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus albiglutide), and dyspepsia (2.8% versus 3.4% for placebo versus albiglutide). Constipation also contributed to the frequently reported reactions. In the group treated with albiglutide, investigators graded the severity of GI reactions as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on albiglutide or placebo.
Injection Site Reactions
- In the pool of placebo-controlled trials, injection site reactions occurred more frequently on albiglutide (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on albiglutide: injection site hematoma (1.9% versus 2.1% for placebo versus albiglutide ), injection site erythema (0.4% versus 1.7% for placebo versus albiglutide), injection site rash (0% versus 1.4% for placebo versus albiglutide), injection site hypersensitivity (0% versus 0.8% for placebo versus albiglutide), and injection site hemorrhage (0.6% versus 0.7% for placebo versus albiglutide). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as “mild” by investigators in both groups (73% for albiglutide versus 94% for placebo). More patients on albiglutide than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be “moderate” or “severe” (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%).
Pool of Placebo- and Active-controlled Trials
- The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of albiglutide as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin. In this pool, a total of 2,116 patients with type 2 diabetes were treated with albiglutide for a mean duration of 75 weeks. The mean age of patients treated with albiglutide was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 8% of the population.
- In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1.
Other Adverse Reactions
Hypoglycemia
- The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on albiglutide and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin.
Pneumonia
- In the pool of 7 placebo- and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving albiglutide were serious (0.4% for albiglutide versus 0.1% for all comparators).
Atrial Fibrillation/Flutter
- In the pool of 7 placebo- and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for albiglutide than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.).
Appendicitis
- In the pool of placebo- and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with albiglutide compared with 0% among all comparators.
Immunogenicity
- In the pool of 7 placebo- and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to albiglutide tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions.
- Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products.
Liver Enzyme Abnormalities
- In the pool of placebo- and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus albiglutide). Three subjects on albiglutide and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal. In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of albiglutide. The etiology of hepatocellular injury was possibly related to albiglutide but direct attribution to albiglutide was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event.
Gamma Glutamyltransferase (GGT) Increase
- In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM).
Heart Rate Increase
- In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Albiglutide in the drug label.
# Drug Interactions
- TANZEUM did not affect the absorption of orally administered medications tested in clinical pharmacology studies to any clinically relevant degree. However, TANZEUM causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies of TANZEUM in pregnant women. Nonclinical studies have shown reproductive toxicity, but not teratogenicity, in mice treated with albiglutide at up to 39 times human exposure resulting from the maximum recommended dose of 50 mg/week, based on AUC . TANZEUM should not be used during pregnancy unless the expected benefit outweighs the potential risks.
- Due to the long washout period for TANZEUM, consider stopping TANZEUM at least 1 month before a planned pregnancy.
- There are no data on the effects of TANZEUM on human fertility. Studies in mice showed no effects on fertility. The potential risk to human fertility is unknown.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Albiglutide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Albiglutide during labor and delivery.
### Nursing Mothers
- There are no adequate data to support the use of TANZEUM during lactation in humans.
- It is not known if TANZEUM is excreted into human milk during lactation. Given that TANZEUM is an albumin-based protein therapeutic, it is likely to be present in human milk. Decreased body weight in offspring was observed in mice treated with TANZEUM during gestation and lactation. A decision should be made whether to discontinue nursing or to discontinue TANZEUM, taking into account the importance of the drug to the mother and the potential risks to the infant.
### Pediatric Use
- Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years).
### Geriatic Use
- Of the total number of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 19% (N = 444) were 65 years and older, and <3% (N = 52) were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Albiglutide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Albiglutide with respect to specific racial populations.
### Renal Impairment
- Of the total number of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 54% (N = 1,267) had mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2), 12% (N = 275) had moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) and 1% (N = 19) had severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2).
- No dosage adjustment is required in patients with mild (eGFR 60 to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), or severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment.
- Efficacy of TANZEUM in patients with type 2 diabetes and renal impairment is described elsewhere. There is limited clinical experience in patients with severe renal impairment (19 subjects). The frequency of GI events increased as renal function declined. For patients with mild, moderate, or severe impairment, the respective event rates were: diarrhea (6%, 13%, 21%), nausea (3%, 5%, 16%), and vomiting (1%, 2%, 5%). Therefore, caution is recommended when initiating or escalating doses of TANZEUM in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Albiglutide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Albiglutide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Albiglutide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
Instruct patients as follows:
- The pen should be used within 8 hours of reconstitution prior to attaching the needle.
- After attaching the supplied needle, remove air bubbles by slowly twisting the Pen until you see the [3] in the number window. At the same time, the injection button will be automatically released from the bottom of the Pen.
- Use immediately after the needle is attached and primed. The product can clog the needle if allowed to dry in the primed needle.
- After subcutaneously inserting the needle into the skin in the abdomen, thigh, or upper arm region, press the injection button. Hold the injection button until you hear a “click” and then hold the button for 5 additional seconds to deliver the full dose.
- When using TANZEUM with insulin, instruct patients to administer as separate injections and to never mix the products. It is acceptable to inject TANZEUM and insulin in the same body region but the injections should not be adjacent to each other.
- When injecting in the same body region, advise patients to use a different injection site each week. TANZEUM must not be administered intravenously or intramuscularly.
### Monitoring
There is limited information regarding Monitoring of Albiglutide in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Albiglutide in the drug label.
# Overdosage
- No data are available with regard to overdosage in humans. Anticipated symptoms of an overdose may be severe nausea and vomiting.
- In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the half-life of TANZEUM (5 days).
# Pharmacology
## Mechanism of Action
- TANZEUM is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. TANZEUM also slows gastric emptying.
## Structure
There is limited information regarding Albiglutide Structure in the drug label.
## Pharmacodynamics
- TANZEUM lowers fasting glucose and reduces postprandial glucose excursions in patients with type 2 diabetes mellitus. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide. In a Phase II trial in Japanese patients with type 2 diabetes mellitus who received TANZEUM 30 mg, a reduction (22%) in postprandial glucose AUC(0-3 h) was observed at steady state (Week 16) compared with placebo following a mixed meal.
- A single dose of TANZEUM 50 mg subcutaneous (SC) did not impair glucagon response to low glucose concentrations.
Gastric Motility
- TANZEUM slowed gastric emptying compared with placebo for both solids and liquids when albiglutide 100 mg (2 times the maximum approved dosage) was administered as a single dose in healthy subjects.
Cardiac Electrophysiology
- At doses up to the maximum recommended dose (50 mg), TANZEUM does not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
Absorption
- Following SC administration of a single 30-mg dose to subjects with type 2 diabetes mellitus, maximum concentrations of albiglutide were reached at 3 to 5 days post-dosing. The mean peak concentration (Cmax) and mean area under the time-concentration curve (AUC) of albiglutide were 1.74 mcg/mL and 465 mcg.h/mL, respectively, following a single dose of 30 mg albiglutide in type 2 diabetes mellitus subjects. Steady-state exposures are achieved following 4 to 5 weeks of once-weekly administration. Exposures at the 30-mg and 50-mg dose levels were consistent with a dose-proportional increase. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of albiglutide following SC administration has not been evaluated.
Distribution
- The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 L. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed.
Metabolism
- Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed. Because albiglutide is an albumin fusion protein, it likely follows a metabolic pathway similar to native human serum albumin which is catabolized primarily in the vascular endothelium.
Elimination
- The mean apparent clearance of albiglutide is 67 mL/h with an elimination half-life of approximately 5 days, making albiglutide suitable for once-weekly administration.
Specific Patient Populations
- Age, Gender, Race, and Body Weight: Based on the population pharmacokinetic analysis with data collected from 1,113 subjects, age, gender, race, and body weight had no clinically relevant effect on the pharmacokinetics of albiglutide.
- Pediatric: No pharmacokinetic data are available in pediatric patients.
- Renal: In a population pharmacokinetic analysis including a Phase III trial in patients with mild, moderate, and severe renal impairment, exposures were increased by approximately 30% to 40% in severe renal impairment compared with those observed in type 2 diabetic patients with normal renal function.
- Hepatic: No clinical trials were conducted to examine the effects of mild, moderate, or severe hepatic impairment on the pharmacokinetics of albiglutide. Therapeutic proteins such as albiglutide are catabolized by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of albiglutide.
Drug Interactions
- In multiple-dose, drug-drug interaction trials no significant change in systemic exposures of the co-administered drugs were observed, except simvastatin (see Table 3). When albiglutide was co-administered with simvastatin, Cmax of simvastatin and its active metabolite simvastatin acid was increased by approximately 18% and 98%, respectively. In the same trial, AUC of simvastatin decreased by 40% and AUC of simvastatin acid increased by 36%. Clinical relevance of these changes has not been established (see Table 3).
- Additionally, no clinically relevant pharmacodynamic effects on luteinizing hormone, follicle-stimulating hormone, or progesterone were observed when albiglutide and a combination oral contraceptive were co-administered. Albiglutide did not significantly alter the pharmacodynamic effects of warfarin as measured by the international normalized ratio (INR).
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- As albiglutide is a recombinant protein, no genotoxicity studies have been conducted.
- Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies. Other GLP-1 receptor agonists have caused thyroid C-cell tumors in rodent carcinogenicity studies. Human relevance of GLP-1 receptor agonist induced rodent thyroid C-cell tumors has not been determined.
- In a mouse fertility study, males were treated with SC doses of 5, 15, or 50 mg/kg/day for 7 days prior to cohabitation with females, and continuing through mating. In a separate fertility study, females were treated with SC doses of 1, 5, or 50 mg/kg/day for 7 days prior to cohabitation with males, and continuing through mating. Reductions in estrous cycles were observed at 50 mg/kg/day, a dose associated with maternal toxicity (body weight loss and reduced food consumption). There were no effects on mating or fertility in either sex at doses up to 50 mg/kg/day (up to 39 times clinical exposure based on AUC).
Reproductive and Developmental Toxicity
- In order to minimize the impact of the drug-clearing, anti-drug antibody response, reproductive and developmental toxicity assessments in the mouse were partitioned to limit the dosing period to no more than approximately 15 days in each study.
- In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 1 to 6, there were no adverse effects on early embryonic development through implantation at 50 mg/kg/day (39 times clinical exposure based on AUC).
- In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 through 15 (organogenesis), embryo-fetal lethality (post-implantation loss) and bent (wavy) ribs were observed at 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity (body weight loss and reduced food consumption).
- Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 to 17. Offspring of pregnant mice given 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity, had reduced body weight pre-weaning, dehydration and coldness, and a delay in balanopreputial separation.
- Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 15 to lactation Day 10. Increased mortality and morbidity were seen at all doses (≥1 mg/kg/day) in lactating females in mouse pre- and postnatal development studies. Mortalities have not been observed in previous toxicology studies in non-lactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are of questionable relevance to humans. The offspring had decreased pre-weaning body weight which reversed post-weaning in males but not females at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Low levels of albiglutide were detected in plasma of offspring.
- Lactating mice were given SC doses of 1, 5, or 50 mg/kg/day from lactation Day 7 to 21 (weaning) under conditions that limit the impact of lactational ileus (increased caloric intake and culling of litters). Doses ≥1 mg/kg/day (exposures below clinical AUC) caused reduced weight gain in the pups during the treatment period.
# Clinical Studies
- TANZEUM has been studied as monotherapy and in combination with metformin, metformin and a sulfonylurea, a thiazolidinedione (with and without metformin), and insulin glargine (with or without oral anti-diabetic drugs). The efficacy of TANZEUM was compared with placebo, glimepiride, pioglitazone, liraglutide, sitagliptin, insulin lispro, and insulin glargine.
- Trials evaluated the use of TANZEUM 30 mg and 50 mg. Five of the 8 trials allowed optional uptitration of TANZEUM from 30 mg to 50 mg if glycemic response with 30 mg was inadequate.
- In patients with type 2 diabetes mellitus, TANZEUM produced clinically relevant reduction from baseline in HbA1c compared with placebo. No overall differences in glycemic effectiveness or body weight were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).
Monotherapy
- The efficacy of TANZEUM as monotherapy was evaluated in a 52-week, randomized, double-blind, placebo-controlled, multicenter trial. In this trial, 296 patients with type 2 diabetes inadequately controlled on diet and exercise were randomized (1:1:1) to TANZEUM 30 mg SC once weekly, TANZEUM 30 mg SC once weekly uptitrated to 50 mg once weekly at Week 12, or placebo. The mean age of participants was 53 years, 55% of patients were men, the mean duration of diabetes was 4 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. Primary and secondary efficacy results are presented in Table 4. Figure 1 shows the mean adjusted changes in HbA1c from baseline across study visits.
- Compared with placebo, treatment with TANZEUM 30 mg or 50 mg resulted in statistically significant reductions in HbA1c from baseline at Week 52 (see Table 4). The adjusted mean change in weight from baseline did not differ significantly between TANZEUM (-0.4 to -0.9 kg) and placebo (-0.7 kg) at Week 52.
Combination Therapy
Add-on to Metformin
- The efficacy of TANZEUM was evaluated in a 104-week randomized, double-blind, multicenter trial in 999 patients with type 2 diabetes mellitus inadequately controlled on background metformin therapy (≥1,500 mg daily). In this trial, TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared with placebo, sitagliptin 100 mg daily, or glimepiride 2 mg daily (with optional titration to 4 mg daily). The mean age of participants was 55 years, 48% of patients were men, the mean duration of type 2 diabetes was 6 years, and the mean baseline eGFR was 86 mL/min/1.73 m2. Results of the primary and secondary analyses are presented in Table 5. Figure 2 shows the mean adjusted changes in HbA1c across study visits.
- Reduction in HbA1c from baseline achieved with TANZEUM was significantly greater than HbA1c reduction achieved with placebo, sitagliptin, and glimepiride at Week 104 (see Table 5). The difference in body weight change from baseline between TANZEUM and glimepiride was significant at Week 104.
Add-on to Pioglitazone
- The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 299 patients with type 2 diabetes mellitus inadequately controlled on pioglitazone ≥30 mg daily (with or without metformin ≥1,500 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly or placebo. The mean age of participants was 55 years, 60% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 83 mL/min/1.73 m2. Results of the primary and secondary analyses are presented in Table 6.
- Compared with placebo, treatment with TANZEUM resulted in a statistically significant reduction in HbA1c from baseline at Week 52 (see Table 6). The adjusted mean change from baseline in weight did not differ significantly between TANZEUM (+0.3 kg) and placebo (+0.5 kg) at Week 52.
Add-on to Metformin Plus Sulfonylurea
- The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 657 patients with type 2 diabetes mellitus inadequately controlled on metformin (≥1,500 mg daily) and glimepiride (4 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks), placebo, or pioglitazone 30 mg daily (with optional titration to 45 mg/day). The mean age of participants was 55 years, 53% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 7.
- Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline compared with placebo (see Table 7). Treatment with TANZEUM did not meet the pre-specified, non-inferiority margin (0.3%) against pioglitazone. In this trial, TANZEUM provided less HbA1c reduction than pioglitazone and the treatment difference was statistically significant (see Table 7). The change from baseline in body weight for TANZEUM did not differ significantly from placebo but was significantly different compared with pioglitazone (see Table 7).
Combination Therapy: Active-controlled Trial versus Liraglutide
- The efficacy of TANZEUM was evaluated in a 32-week, randomized, open-label, liraglutide-controlled, non-inferiority trial in 805 patients with type 2 diabetes mellitus inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, sulfonylurea, or a combination of these). Patients were randomized to TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly at Week 6) or liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1, and 1.2 mg at Week 1 to Week 2). The mean age of participants was 56 years, 50% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 95 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 8.
- The between-treatment difference of 0.2% with 95% confidence interval (0.08, 0.34) between TANZEUM and liraglutide did not meet the pre-specified, non-inferiority margin (0.3%). In this trial, TANZEUM provided less HbA1c reduction than liraglutide and the treatment difference was statistically significant (see Table 8).
Combination Therapy: Active-controlled Trial versus Basal Insulin
- The efficacy of TANZEUM was evaluated in a 52-week, randomized (2:1), open-label, insulin glargine-controlled, non-inferiority trial in 735 patients with type 2 diabetes mellitus inadequately controlled on metformin ≥1,500 mg daily (with or without sulfonylurea). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly) or insulin glargine (started at 10 units and titrated weekly per prescribing information). The primary endpoint was change in HbA1c from baseline compared with insulin glargine. The starting total daily dose of insulin glargine ranged between 2 and 40 units (median daily dose of 10 units) and ranged between 3 and 230 units (median daily dose of 30 units) at Week 52. Seventy-seven percent of patients treated with TANZEUM were uptitrated to 50 mg SC weekly. The mean age of participants was 56 years, 56% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 85 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 9.
- The between-treatment difference of 0.1% with 95% confidence interval (-0.04%, 0.27%) for TANZEUM and insulin glargine met the pre-specified, non-inferiority margin (0.3%). A mean decrease in body weight was observed for TANZEUM compared with a mean increase in body weight for insulin glargine, and the difference in weight change was statistically significant (see Table 9).
Combination Therapy: Active-controlled Trial versus Prandial Insulin
- The efficacy of TANZEUM was evaluated in a 26-week, randomized, open-label, multicenter, non-inferiority trial in 563 patients with type 2 diabetes mellitus inadequately controlled on insulin glargine (started at 10 units and titrated to ≥20 units per day). Patients were randomized to receive TANZEUM 30 mg SC once weekly (with uptitration to 50 mg if inadequately controlled after Week 8) or insulin lispro (administered daily at meal times, started according to standard of care and titrated to effect). At Week 26, the mean daily dose of insulin glargine was 53 IU for TANZEUM and 51 IU for insulin lispro. The mean daily dose of insulin lispro at Week 26 was 31 IU, and 69% of patients treated with TANZEUM were on 50 mg weekly. The mean age of participants was 56 years, 47% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 91 mL/min/1.73 m2. Results of the primary and main secondary analyses are presented in Table 10. Figure 4 shows the mean adjusted changes in HbA1c from baseline across study visits.
- The between-treatment difference of -0.2% with 95% confidence interval (-0.32%, 0.00%) between albiglutide and insulin lispro met the pre-specified non-inferiority margin (0.4%). Treatment with TANZEUM resulted in a mean weight loss for TANZEUM compared with a mean weight gain for insulin lispro, and the difference between treatment groups was statistically significant (see Table 10).
Type 2 Diabetes Mellitus Patients with Renal Impairment
- The efficacy of TANZEUM was evaluated in a 26-week, randomized, double-blind, active-controlled trial in 486 patients with mild (n = 250), moderate (n = 200), and severe renal impairment (n = 36) inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy. Patients were randomized to receive TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly if needed as early as Week 4) or sitagliptin. Sitagliptin was dosed according to renal function (100 mg, 50 mg, and 25 mg daily in mild, moderate, and severe renal impairment, respectively). The mean age of participants was 63 years, 54% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 60 mL/min/1.73 m2.
- Results of the primary and main secondary analyses are presented in Table 11. Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline at Week 26 compared with sitagliptin (see Table 11).
# How Supplied
- TANZEUM is available in the following strengths and package size:
- 30 mg single-dose Pen (NDC 0173-0866-01):
- carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0866-35
50 mg single-dose Pen (NDC 0173-0867-01):
- carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0867-35
## Storage
- Prior to dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Pens may be stored refrigerated until the expiration date.
- Following dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Patients may store Pens at room temperature not to exceed 86°F (30°C) for up to 4 weeks prior to use. Store Pens in the original carton until use.
- Do not freeze.
- Do not use past the expiration date.
- Use within 8 hours after reconstitution.
# Images
## Drug Images
## Package and Label Display Panel
[File:Albiglutide medication guide.png[
# Patient Counseling Information
- See FDA-approved patient labeling (Medication Guide and Instructions for Use). The Medication Guide is contained in a separate leaflet that accompanies the product.
- Inform patients about self-management practices, including the importance of proper storage of TANZEUM, injection technique, timing of dosage of TANZEUM and concomitant oral drugs, and recognition and management of hypoglycemia.
- Inform patients that thyroid C-cell tumors have been observed in rodents treated with some GLP-1 receptor agonists, and the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, dysphagia, dyspnea, or persistent hoarseness) to their physician.
- Advise patients that persistent, severe abdominal pain that may radiate to the back and which may (or may not) be accompanied by vomiting is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TANZEUM promptly and to contact their physician if persistent, severe abdominal pain occurs.
- The risk of hypoglycemia is increased when TANZEUM is used in combination with an agent that induces hypoglycemia, such as sulfonylurea or insulin. Instructions for hypoglycemia should be reviewed with patients and reinforced when initiating therapy with TANZEUM, particularly when concomitantly administered with a sulfonylurea or insulin.
- Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TANZEUM and seek medical advice promptly if such symptoms occur.
- Instruct patients to read the Instructions for Use before starting therapy.
- Instruct patients on proper use, storage, and disposal of the pen.
- Instruct patients to read the Medication Guide before starting TANZEUM and to read again each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- Inform patients not to take an extra dose of TANZEUM to make up for a missed dose.
- If a dose is missed, instruct patients to take a dose as soon as possible within 3 days after the missed dose. Instruct patients to then take their next dose at their usual weekly time. If it has been longer than 3 days after the missed dose, instruct patients to wait and take TANZEUM at the next usual weekly time.
# Precautions with Alcohol
- Alcohol-Albiglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TANZEUM ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Albiglutide | |
2cabd52fb40a225779adf1c6fe0b08fc4469cc32 | wikidoc | Albuminuria | Albuminuria
# Overview
Albuminuria is a pathological condition where albumin is present in the urine. It is a type of proteinuria.
# Causes
## Life Threatening Causes
## Common Causes
The kidneys normally filter out large molecules from the urine, so albuminuria can be an indicator of damage to the kidneys. It can also occur in patients with long-standing diabetes especially type 1 diabetes.
Causes of albuminuria can be discriminated between by the amount of protein excreted.
- The nephrotic syndrome usually results in the excretion of about 3.0 to 3.5 grams per 24 hours.
- Nephritic syndrome results in far less albuminuria.
- Microalbuminuria (less than 300mg) can be a forerunner of diabetic nephropathy.
## Causes by Organ System
## Causes in Alphabetical Order
# Diagnosis
## Laboratory Findings
The amount of protein being lost in the urine can be quantified by collecting the urine for 24 hours, measuring a sample of the pooled urine, and extrapolating to the volume collected. | Albuminuria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Albuminuria is a pathological condition where albumin is present in the urine. It is a type of proteinuria.
# Causes
## Life Threatening Causes
## Common Causes
The kidneys normally filter out large molecules from the urine, so albuminuria can be an indicator of damage to the kidneys. It can also occur in patients with long-standing diabetes especially type 1 diabetes.
Causes of albuminuria can be discriminated between by the amount of protein excreted.
- The nephrotic syndrome usually results in the excretion of about 3.0 to 3.5 grams per 24 hours.
- Nephritic syndrome results in far less albuminuria.
- Microalbuminuria (less than 300mg) can be a forerunner of diabetic nephropathy.
## Causes by Organ System
## Causes in Alphabetical Order
# Diagnosis
## Laboratory Findings
The amount of protein being lost in the urine can be quantified by collecting the urine for 24 hours, measuring a sample of the pooled urine, and extrapolating to the volume collected. | https://www.wikidoc.org/index.php/Albuminuria | |
c2bb204f74003755f99b290202b2349081830ffb | wikidoc | Alcaftadine | Alcaftadine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Alcaftadine is an antihistamine that is FDA approved for the prophylaxis of allergic conjunctivitis. Common adverse reactions include eye irritation, burning and/or stinging upon instillation, eye redness and eye pruritus, nasopharyngitis, headache, eye discharge, eye swelling, erythema of eyelid, eyelid edema, hypersensitivity, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- LASTACAFT® is an H1 histamine receptor antagonist indicated for the prevention of itching associated with allergic conjunctivitis.
- Instill one drop in each eye once daily. If more than 1 topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alcaftadine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alcaftadine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Alcaftadine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alcaftadine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alcaftadine in pediatric patients.
# Contraindications
Alcaftadine is contraindicated in patients with hypersensitivity to any component in the product.
# Warnings
- To minimize eye injury and contamination of the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use.
- Patients should be advised not to wear a contact lens if their eye is red.
- Alcaftadine should not be used to treat contact lens-related irritation.
- Alcaftadine should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of alcaftadine. The preservative in alcaftadine, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of alcaftadine.
- Alcaftadine is for topical ophthalmic use only.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The most frequent ocular adverse reactions, occurring in less than 4% of eyes treated with alcaftadine, were eye irritation, burning and/or stinging upon instillation, eye redness and eye pruritus.
- The most frequent non-ocular adverse reactions, occurring in less than 3% of subjects with eyes treated with alcaftadine, were nasopharyngitis and headache. Some of these events were similar to the underlying disease being studied.
## Postmarketing Experience
- The following adverse reactions have been identified during postmarketing use of alcaftadine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions include: eye discharge, eye swelling, erythema of eyelid, eyelid edema, hypersensitivity, and somnolence.
# Drug Interactions
There is limited information regarding Alcaftadine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Pregnancy Category B. Reproduction studies performed in rats and rabbits revealed no evidence of impaired female reproduction or harm to the fetus due to alcaftadine. Oral doses in rats and rabbits of 20 and 80 mg/kg/day, respectively, produced plasma exposure levels approximately 200 and 9000 times the plasma exposure at the recommended human ocular dose. There are however, no adequate and well controlled studies in pregnant] women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alcaftadine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alcaftadine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alcaftadine is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness were observed between elderly and younger subjects.
### Gender
There is no FDA guidance on the use of Alcaftadine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alcaftadine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alcaftadine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alcaftadine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alcaftadine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alcaftadine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Alcaftadine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Alcaftadine and IV administrations.
# Overdosage
There is limited information regarding Alcaftadine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Alcaftadine is a sterile, topically administered H1 receptor antagonist containing alcaftadine for ophthalmic use.
- Alcaftadine is a white to yellow powder with an empirical formula of C19H21N3O and a molecular weight of 307.39.
- Active: alcaftadine 0.25% (2.5 mg/mL)
- Inactives: benzalkonium chloride 0.005% as a preservative; edetate disodium; sodium phosphate, monobasic; purified water; sodium chloride; sodium hydroxide and/or hydrochloric acid (to adjust pH)
## Structure
- Alcaftadine is a sterile, topically administered H1 receptor antagonist containing alcaftadine for ophthalmic use.
- Alcaftadine is a white to yellow powder with an empirical formula of C19H21N3O and a molecular weight of 307.39.
- Active: alcaftadine 0.25% (2.5 mg/mL)
- Inactives: benzalkonium chloride 0.005% as a preservative; edetate disodium; sodium phosphate, monobasic; purified water; sodium chloride; sodium hydroxide and/or hydrochloric acid (to adjust pH)
## Pharmacodynamics
There is limited information regarding Alcaftadine Pharmacodynamics in the drug label.
## Pharmacokinetics
- Following bilateral topical ocular administration of alcaftadine ophthalmic solution, 0.25%, the mean plasma Cmax of alcaftadine was approximately 60 pg/mL and the median Tmax occurred at 15 minutes. Plasma concentrations of alcaftadine were below the lower limit of quantification (10 pg/mL) by 3 hours after dosing. The mean Cmax of the active carboxylic acid metabolite was approximately 3 ng/mL and occurred at 1 hour after dosing. Plasma concentrations of the carboxylic acid metabolite were below the lower limit of quantification (100 pg/mL) by 12 hours after dosing. There was no indication of systemic accumulation or changes in plasma exposure of alcaftadine or the active metabolite following daily topical ocular administration.
- The protein binding of alcaftadine and the active metabolite are 39.2% and 62.7%, respectively.
- The metabolism of alcaftadine is mediated by non-CYP450 cytosolic enzymes to the active carboxylic acid metabolite.
- The elimination half-life of the carboxylic acid metabolite is approximately 2 hours following topical ocular administration. Based on data following oral administration of alcaftadine, the carboxylic acid metabolite is primarily eliminated unchanged in the urine.
- In vitro studies showed that neither alcaftadine nor the carboxylic acid metabolite substantially inhibited reactions catalyzed by major CYP450 enzymes.
## Nonclinical Toxicology
- Alcaftadine was not mutagenic or genotoxic in the Ames test, the mouse lymphoma assay or the mouse micronucleus assay.
- Alcaftadine was found to have no effect on fertility of male and female rats at oral doses up to 20 mg/kg/day (approximately 200 times the plasma exposure at the recommended human ocular dose)
# Clinical Studies
- Alcaftadine was not mutagenic or genotoxic in the Ames test, the mouse lymphoma assay or the mouse micronucleus assay.
- Alcaftadine was found to have no effect on fertility of male and female rats at oral doses up to 20 mg/kg/day (approximately 200 times the plasma exposure at the recommended human ocular dose).
# How Supplied
- Alcaftadine ophthalmic solution) 0.25% is supplied in an opaque, white low-density polyethylene bottle with a white polypropylene cap.
- 3 mL fill in 5 mL bottle NDC 0023-4290-03
## Storage
- Store at 15°-25°C (59°-77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To minimize eye injury and contamination of the dropper tip and solution, patients should be advised to not touch the eyelids or surrounding areas with the dropper tip, as this may contaminate the contents.
- If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.
- Patients should be advised not to wear a contact lens if their eye is red. Patients should be advised that LASTACAFT® should not be used to treat contact lens-related irritation. Patients should also be advised to remove contact lenses prior to instillation of LASTACAFT®. The preservative in LASTACAFT®, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of LASTACAFT®.
- For topical ophthalmic administration only.
# Precautions with Alcohol
Alcohol-Alcaftadine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LASTACAFT ®
# Look-Alike Drug Names
There is limited information regarding Alcaftadine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Alcaftadine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Alcaftadine is an antihistamine that is FDA approved for the prophylaxis of allergic conjunctivitis. Common adverse reactions include eye irritation, burning and/or stinging upon instillation, eye redness and eye pruritus, nasopharyngitis, headache, eye discharge, eye swelling, erythema of eyelid, eyelid edema, hypersensitivity, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- LASTACAFT® is an H1 histamine receptor antagonist indicated for the prevention of itching associated with allergic conjunctivitis.
- Instill one drop in each eye once daily. If more than 1 topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alcaftadine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alcaftadine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Alcaftadine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alcaftadine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alcaftadine in pediatric patients.
# Contraindications
Alcaftadine is contraindicated in patients with hypersensitivity to any component in the product.
# Warnings
- To minimize eye injury and contamination of the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use.
- Patients should be advised not to wear a contact lens if their eye is red.
- Alcaftadine should not be used to treat contact lens-related irritation.
- Alcaftadine should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of alcaftadine. The preservative in alcaftadine, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of alcaftadine.
- Alcaftadine is for topical ophthalmic use only.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The most frequent ocular adverse reactions, occurring in less than 4% of eyes treated with alcaftadine, were eye irritation, burning and/or stinging upon instillation, eye redness and eye pruritus.
- The most frequent non-ocular adverse reactions, occurring in less than 3% of subjects with eyes treated with alcaftadine, were nasopharyngitis and headache. Some of these events were similar to the underlying disease being studied.
## Postmarketing Experience
- The following adverse reactions have been identified during postmarketing use of alcaftadine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions include: eye discharge, eye swelling, erythema of eyelid, eyelid edema, hypersensitivity, and somnolence.
# Drug Interactions
There is limited information regarding Alcaftadine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Pregnancy Category B. Reproduction studies performed in rats and rabbits revealed no evidence of impaired female reproduction or harm to the fetus due to alcaftadine. Oral doses in rats and rabbits of 20 and 80 mg/kg/day, respectively, produced plasma exposure levels approximately 200 and 9000 times the plasma exposure at the recommended human ocular dose. There are however, no adequate and well controlled studies in pregnant] women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alcaftadine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alcaftadine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alcaftadine is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness were observed between elderly and younger subjects.
### Gender
There is no FDA guidance on the use of Alcaftadine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alcaftadine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alcaftadine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alcaftadine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alcaftadine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alcaftadine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Alcaftadine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Alcaftadine and IV administrations.
# Overdosage
There is limited information regarding Alcaftadine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Alcaftadine is a sterile, topically administered H1 receptor antagonist containing alcaftadine for ophthalmic use.
- Alcaftadine is a white to yellow powder with an empirical formula of C19H21N3O and a molecular weight of 307.39.
- Active: alcaftadine 0.25% (2.5 mg/mL)
- Inactives: benzalkonium chloride 0.005% as a preservative; edetate disodium; sodium phosphate, monobasic; purified water; sodium chloride; sodium hydroxide and/or hydrochloric acid (to adjust pH)
## Structure
- Alcaftadine is a sterile, topically administered H1 receptor antagonist containing alcaftadine for ophthalmic use.
- Alcaftadine is a white to yellow powder with an empirical formula of C19H21N3O and a molecular weight of 307.39.
- Active: alcaftadine 0.25% (2.5 mg/mL)
- Inactives: benzalkonium chloride 0.005% as a preservative; edetate disodium; sodium phosphate, monobasic; purified water; sodium chloride; sodium hydroxide and/or hydrochloric acid (to adjust pH)
## Pharmacodynamics
There is limited information regarding Alcaftadine Pharmacodynamics in the drug label.
## Pharmacokinetics
- Following bilateral topical ocular administration of alcaftadine ophthalmic solution, 0.25%, the mean plasma Cmax of alcaftadine was approximately 60 pg/mL and the median Tmax occurred at 15 minutes. Plasma concentrations of alcaftadine were below the lower limit of quantification (10 pg/mL) by 3 hours after dosing. The mean Cmax of the active carboxylic acid metabolite was approximately 3 ng/mL and occurred at 1 hour after dosing. Plasma concentrations of the carboxylic acid metabolite were below the lower limit of quantification (100 pg/mL) by 12 hours after dosing. There was no indication of systemic accumulation or changes in plasma exposure of alcaftadine or the active metabolite following daily topical ocular administration.
- The protein binding of alcaftadine and the active metabolite are 39.2% and 62.7%, respectively.
- The metabolism of alcaftadine is mediated by non-CYP450 cytosolic enzymes to the active carboxylic acid metabolite.
- The elimination half-life of the carboxylic acid metabolite is approximately 2 hours following topical ocular administration. Based on data following oral administration of alcaftadine, the carboxylic acid metabolite is primarily eliminated unchanged in the urine.
- In vitro studies showed that neither alcaftadine nor the carboxylic acid metabolite substantially inhibited reactions catalyzed by major CYP450 enzymes.
## Nonclinical Toxicology
- Alcaftadine was not mutagenic or genotoxic in the Ames test, the mouse lymphoma assay or the mouse micronucleus assay.
- Alcaftadine was found to have no effect on fertility of male and female rats at oral doses up to 20 mg/kg/day (approximately 200 times the plasma exposure at the recommended human ocular dose)
# Clinical Studies
- Alcaftadine was not mutagenic or genotoxic in the Ames test, the mouse lymphoma assay or the mouse micronucleus assay.
- Alcaftadine was found to have no effect on fertility of male and female rats at oral doses up to 20 mg/kg/day (approximately 200 times the plasma exposure at the recommended human ocular dose).
# How Supplied
- Alcaftadine ophthalmic solution) 0.25% is supplied in an opaque, white low-density polyethylene bottle with a white polypropylene cap.
- 3 mL fill in 5 mL bottle NDC 0023-4290-03
## Storage
- Store at 15°-25°C (59°-77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- To minimize eye injury and contamination of the dropper tip and solution, patients should be advised to not touch the eyelids or surrounding areas with the dropper tip, as this may contaminate the contents.
- If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.
- Patients should be advised not to wear a contact lens if their eye is red. Patients should be advised that LASTACAFT® should not be used to treat contact lens-related irritation. Patients should also be advised to remove contact lenses prior to instillation of LASTACAFT®. The preservative in LASTACAFT®, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of LASTACAFT®.
- For topical ophthalmic administration only.
# Precautions with Alcohol
Alcohol-Alcaftadine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LASTACAFT ®[1]
# Look-Alike Drug Names
There is limited information regarding Alcaftadine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Alcaftadine | |
b3ce91b106a34090e47aeafd90fd5d74a7217e11 | wikidoc | Alcohol rub | Alcohol rub
# Overview
An alcohol rub, also known as a hand sanitizer or healthcare personnel hand wash is used as a supplement or alternative to hand washing with soap and water. The active ingredient in alcohol rubs may be isopropanol, ethanol, or (in Europe) propanol. A variety of preparations are available, including gels, foam and liquid solutions. Hand sanitizers containing alcohol are more effective at killing germs than soaps and do not dry out hands as much as soaps.
# Uses
When hands are not visibly dirty, the Centers for Disease Control and Prevention considers alcohol hand sanitizers as an acceptable alternative to soap and water for hand hygiene.
Alcohol concentration must be above 60% for alcohol rubs to be effective in killing microbes. Researchers at East Tennessee State University found that products with alcohol concentrations as low as 40% are available in American stores.
The optimum alcohol concentration to kill germs is 70 to 95 %. Alcohol gels containing 62 v/v % alcohol are less effective germ killers than alcohol rubs containing at least 70 wt/wt % alcohol.
Alcohol rubs containing two different germ killers (i.e. alcohol and benzalkonium chloride) are significantly more effective than alcohol alone.
Most alcohol rub formulations include a moisturizer to keep hands from drying out.
# Efficacy
Alcohol rubs kill many different kinds of bacteria, including antibiotic resistant bacteria and TB bacteria. Alcohol rubs inactivate many different kinds of viruses, including the flu virus and the common cold virus. Alcohol rubs also kill fungus.
Not all pathogens are equally susceptible. Certain bacteria, especially the spore-forming gram positives (e.g. Clostridium difficile) are relatively resistant and remain biologically viable. During the Anthrax attacks on the United States Postal Service, authorities warned that alcohol hand rubs would not kill anthrax spores. In environments with high lipids or protein waste (such as food processing), the use of alcohol hand rubs alone may not be sufficient to ensure proper hand hygiene.
# Safety
Alcohol gel can catch fire, producing a dim blue flame. This is due to the flammable alcohol in the gel. Some hand sanitizer gels may not produce this effect due to a high concentration of water or moisturizing agents.
There have been numerous, but rare, instances where alcohol hand gels have been implicated in starting fires, including a case where static electricity ignited the gel. To minimize the risk of fire, users are instructed to rub their hands until dry, which indicates that the flammable alcohol has evaporated.
It has been also noted that if ingested it can cause alcohol poisoning in small children. In the US alone, there have been more than 12,000 cases of child-related alcohol-poisoning directly attributed to hand sanitizer products.
# Sources
- ↑ "Alcohol Hand Rub and Hand Hygiene" (PDF). Clinical Excellence Commission, Health, New South Wales, Austrialia. Retrieved 2007-05-18..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Hand Hygiene FAQ". Centers for Disease Control and Prevention. Retrieved 2007-02-01.
Reynolds, Scott A. (March 2006). "Hand Sanitizer Alert". Emerging Infectious Diseases. Centers for Disease Control and Prevention. 12 (3). Retrieved 2007-02-02. Unknown parameter |coauthors= ignored (help)
- ↑ "Hand Hygiene for Healthcare Workers". LearnWell Resources, Inc, a California nonprofit public benefit 501(c)(3) corporation. Retrieved 2007-04-27.
Kramer, Axel (2002). "Limited efficacy of alcohol-based hand gels". Lancet. THE LANCET. 359 (April 27): 1489–1490. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
Pietsch, Hanns (2001). "Hand Antiseptics: Rubs Versus Scrubs, Alcoholic Solutions Versus Alcoholic Gels". J. Hospital Infection. Hospital Infection Society. 48 (Supl A): S33–S36. |access-date= requires |url= (help)
Hibbard, John S. (May/June 2005). "Analyses Comparing the Antimicrobial Activity and Safety of Current Antiseptic Agents". J. Infusion Nursing. Infusion Nurses Society. 28 (3): 194–207. Check date values in: |date= (help); |access-date= requires |url= (help)
- ↑ "Alcohol-Based Hand-Rubs and Fire Safety". Centers for Disease Control and Prevention. Retrieved 2007-04-26.
- ↑ "Hand Sanitizers Could Be A Dangerous Poison To Unsupervised Children". NBC News Channel. Retrieved 2007-07-15. | Alcohol rub
# Overview
An alcohol rub, also known as a hand sanitizer or healthcare personnel hand wash is used as a supplement or alternative to hand washing with soap and water. The active ingredient in alcohol rubs may be isopropanol, ethanol, or (in Europe) propanol. A variety of preparations are available, including gels, foam and liquid solutions. Hand sanitizers containing alcohol are more effective at killing germs than soaps and do not dry out hands as much as soaps.[1]
# Uses
When hands are not visibly dirty, the Centers for Disease Control and Prevention considers alcohol hand sanitizers as an acceptable alternative to soap and water for hand hygiene.[2]
Alcohol concentration must be above 60% for alcohol rubs to be effective in killing microbes. Researchers at East Tennessee State University found that products with alcohol concentrations as low as 40% are available in American stores.
[3] The optimum alcohol concentration to kill germs is 70 to 95 %. Alcohol gels containing 62 v/v % alcohol are less effective germ killers than alcohol rubs containing at least 70 wt/wt % alcohol. [4]
[5]
[6]
Alcohol rubs containing two different germ killers (i.e. alcohol and benzalkonium chloride) are significantly more effective than alcohol alone.
[7] Most alcohol rub formulations include a moisturizer to keep hands from drying out.
# Efficacy
Alcohol rubs kill many different kinds of bacteria, including antibiotic resistant bacteria and TB bacteria. Alcohol rubs inactivate many different kinds of viruses, including the flu virus and the common cold virus. Alcohol rubs also kill fungus.
Not all pathogens are equally susceptible. Certain bacteria, especially the spore-forming gram positives (e.g. Clostridium difficile) are relatively resistant and remain biologically viable. During the Anthrax attacks on the United States Postal Service, authorities warned that alcohol hand rubs would not kill anthrax spores. In environments with high lipids or protein waste (such as food processing), the use of alcohol hand rubs alone may not be sufficient to ensure proper hand hygiene.
# Safety
Alcohol gel can catch fire, producing a dim blue flame. This is due to the flammable alcohol in the gel. Some hand sanitizer gels may not produce this effect due to a high concentration of water or moisturizing agents.
There have been numerous, but rare, instances where alcohol hand gels have been implicated in starting fires, including a case where static electricity ignited the gel. To minimize the risk of fire, users are instructed to rub their hands until dry, which indicates that the flammable alcohol has evaporated. [8]
It has been also noted that if ingested it can cause alcohol poisoning in small children. [9]In the US alone, there have been more than 12,000 cases of child-related alcohol-poisoning directly attributed to hand sanitizer products. [1]
# Sources
Template:FootnotesSmall
Template:WS
- ↑ "Alcohol Hand Rub and Hand Hygiene" (PDF). Clinical Excellence Commission, Health, New South Wales, Austrialia. Retrieved 2007-05-18..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Hand Hygiene FAQ". Centers for Disease Control and Prevention. Retrieved 2007-02-01.
- ↑
Reynolds, Scott A. (March 2006). "Hand Sanitizer Alert". Emerging Infectious Diseases. Centers for Disease Control and Prevention. 12 (3). Retrieved 2007-02-02. Unknown parameter |coauthors= ignored (help)
- ↑ "Hand Hygiene for Healthcare Workers". LearnWell Resources, Inc, a California nonprofit public benefit 501(c)(3) corporation. Retrieved 2007-04-27.
- ↑
Kramer, Axel (2002). "Limited efficacy of alcohol-based hand gels". Lancet. THE LANCET. 359 (April 27): 1489–1490. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
- ↑
Pietsch, Hanns (2001). "Hand Antiseptics: Rubs Versus Scrubs, Alcoholic Solutions Versus Alcoholic Gels". J. Hospital Infection. Hospital Infection Society. 48 (Supl A): S33–S36. |access-date= requires |url= (help)
- ↑
Hibbard, John S. (May/June 2005). "Analyses Comparing the Antimicrobial Activity and Safety of Current Antiseptic Agents". J. Infusion Nursing. Infusion Nurses Society. 28 (3): 194–207. Check date values in: |date= (help); |access-date= requires |url= (help)
- ↑ "Alcohol-Based Hand-Rubs and Fire Safety". Centers for Disease Control and Prevention. Retrieved 2007-04-26.
- ↑ "Hand Sanitizers Could Be A Dangerous Poison To Unsupervised Children". NBC News Channel. Retrieved 2007-07-15. | https://www.wikidoc.org/index.php/Alcohol_rub | |
38d529026519668599cc959bcc7c496d212adaea | wikidoc | Aldesleukin | Aldesleukin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Aldesleukin is an interleukin-2 that is FDA approved for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC) and metastatic melanoma.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anaphylaxis, cellulitis, injection site necrosis, retroperitoneal hemorrhage, cardiomyopathy, cerebral hemorrhage, fatal endocarditis , hypertension, cholecystitis, colitis, gastritis, hepatitis, hepatosplenomegaly, intestinal obstruction, hyperthyroidism, neutropenia, myopathy, myositis, rhabdomyolysis, cerebral lesions, encephalopathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Aldesleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).
- Aldesleukin is indicated for the treatment of adults with metastatic melanoma.
- Careful patient selection is mandatory prior to the administration of Aldesleukin.
- Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at treatment initiation respond better to Aldesleukin, with a higher response rate and lower toxicity . Therefore, selection of patients for treatment should include assessment of performance status.
- Experience in patients with ECOG PS >1 is extremely limited.
- The recommended PROLEUKIN® (aldesleukin) for injection treatment regimen is administered by a 15-minute IV infusion every 8 hours. The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period.
- 400,000 IU/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute IV infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated.
- During clinical trials, doses were frequently withheld for toxicity. Metastatic RCC patients treated with this schedule received a median of 20 of the 28 doses during the first course of therapy. Metastatic melanoma patients received a median of 18 doses during the first course of therapy.
- Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last (course and retreatment is not contraindicated ). Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
- Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be given. Decisions to stop, hold, or restart Aldesleukin therapy must be made after a global assessment of the patient. With this in mind, the following guidelines should be used:
Reconstitution and Dilution Directions: Reconstitution and dilution procedures other than those recommended may alter the delivery and/or pharmacology of Aldesleukin and thus should be avoided.
- Aldesleukin is a sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution. EACH VIAL CONTAINS 22 MILLION IU (1.3 MG) OF Aldesleukin AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML OF STERILE WATER FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) OF PROLEUKIN. The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use only and any unused portion should be discarded.
- During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled to avoid excess foaming. DO NOT SHAKE.
- The dose of Aldesleukin, reconstituted with Sterile Water for Injection, USP (without preservative) should be diluted aseptically in 50 mL of 5% Dextrose Injection, USP (D5W) and infused over a 15-minute period.
- In cases where the total dose of Aldesleukin is 1.5 mg or less (e.g., a patient with a body weight of less than 40 kilograms), the dose of Aldesleukin should be diluted in a smaller volume of D5W. Concentrations of Aldesleukin below 30 µg/mL and above 70 µg/mL have shown increased variability in drug delivery. Dilution and delivery of Aldesleukin outside of this concentration range should be avoided.
- Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results. It is recommended that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results in more consistent drug delivery. In-line filters should not be used when administering Aldesleukin.
- Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 46°F). Do not freeze. Administer Aldesleukin within 48 hours of reconstitution. The solution should be brought to room temperature prior to infusion in the patient.
- Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP should be avoided because of increased aggregation. Aldesleukin should not be coadministered with other drugs in the same container.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aldesleukin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aldesleukin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children under 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness in children under 18 years of age have not been established..
### Non–Guideline-Supported Use
Safety and effectiveness in children under 18 years of age have not been established.
# Contraindications
- Aldesleukin is contraindicated in patients with a known history of hypersensitivity to interleukin-2 or any component of the Aldesleukin formulation.
- Aldesleukin is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts. Retreatment with Aldesleukin is contraindicated in patients who have experienced the following drug-related toxicities while receiving an earlier course of therapy:
- Sustained ventricular tachycardia (≥5 beats)
- Cardiac arrhythmias not controlled or unresponsive to management
- Chest pain with ECG changes, consistent with angina or myocardial infarction
- Cardiac tamponade
- Intubation for >72 hours
- Renal failure requiring dialysis >72 hours
- Coma or toxic psychosis lasting >48 hours
- Repetitive or difficult to control seizures
- Bowel ischemia/perforation
- GI bleeding requiring surgery
# Warnings
- Because of the severe adverse events which generally accompany Aldesleukin therapy at the recommended dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment in whom Aldesleukin is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal adverse events. Adverse events are frequent, often serious, and sometimes fatal.
- Should adverse events, which require dose modification occur, dosage should be withheld rather than reduced .
- Aldesleukin has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid, has been reported following treatment with IL-2.
- All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving Aldesleukin therapy. New neurologic signs, symptoms, and anatomic lesions following Aldesleukin therapy have been reported in patients without evidence of CNS metastases. Clinical manifestations included changes in mental status, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms associated with Aldesleukin therapy usually improve after discontinuation of Aldesleukin therapy, however, there are reports of permanent neurologic defects. One case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In patients with known seizure disorders, extreme caution should be exercised as Aldesleukin may cause seizures.
### PRECAUTIONS
- Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy . Capillary leak syndrome (CLS) begins immediately after aldesleukin treatment starts and is marked by increased capillary permeability to protein and fluids and reduced vascular tone. In most patients, this results in a concomitant drop in mean arterial blood pressure within 2 to 12 hours after the start of treatment. With continued therapy, clinically significant hypotension (defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids into the extravascular space will lead to the formation of edema and creation of new effusions.
- Medical management of CLS begins with careful monitoring of the patient’s fluid and organ perfusion status. This is achieved by frequent determination of blood pressure and pulse, and by monitoring organ function, which includes assessment of mental status and urine output. Hypovolemia is assessed by catheterization and central pressure monitoring.
- Flexibility in fluid and pressor management is essential for maintaining organ perfusion and blood pressure. Consequently, extreme caution should be used in treating patients with fixed requirements for large volumes of fluid (e.g., patients with hypercalcemia). Administration of IV fluids, either colloids or crystalloids is recommended for treatment of hypovolemia. Correction of hypovolemia may require large volumes of IV fluids but caution is required because unrestrained fluid administration may exacerbate problems associated with edema formation or effusions. With extravascular fluid accumulation, edema is common and ascites, pleural or pericardial effusions may develop. Management of these events depends on a careful balancing of the effects of fluid shifts so that neither the consequences of hypovolemia (e.g., impaired organ perfusion) nor the consequences of fluid accumulations (e.g., pulmonary edema) exceed the patient’s tolerance.
- Clinical experience has shown that early administration of dopamine (1 to 5 µg/kg/min) to patients manifesting capillary leak syndrome, before the onset of hypotension, can help to maintain organ perfusion particularly to the kidney and thus preserve urine output. Weight and urine output should be carefully monitored. If organ perfusion and blood pressure are not sustained by dopamine therapy, clinical investigators have increased the dose of dopamine to 6 to 10 µg/kg/min or have added phenylephrine hydrochloride (1 to 5 µg/kg/min) to low dose dopamine . Prolonged use of pressors, either in combination or as individual agents, at relatively high doses, may be associated with cardiac rhythm disturbances. If there has been excessive weight gain or edema formation, particularly if associated with shortness of breath from pulmonary congestion, use of diuretics, once blood pressure has normalized, has been shown to hasten recovery. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product.
- Aldesleukin treatment should be withheld for failure to maintain organ perfusion as demonstrated by altered mental status, reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac arrhythmias . Recovery from CLS begins soon after cessation of Aldesleukin therapy. Usually, within a few hours, the blood pressure rises, organ perfusion is restored and reabsorption of extravasated fluid and protein begins.
- Kidney and liver function are impaired during Aldesleukin treatment. Use of concomitant nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver.
- Mental status changes including irritability, confusion, or depression which occur while receiving Aldesleukin may be indicators of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct Aldesleukin-induced CNS toxicity. Alterations in mental status due solely to Aldesleukin therapy may progress for several days before recovery begins. Rarely, patients have sustained permanent neurologic deficits .
- Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following Aldesleukin alone or in combination with interferon . Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following Aldesleukin treatment. Some of these patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of autoimmunity. Onset of symptomatic hyperglycemia and/or diabetes mellitus has been reported during Aldesleukin therapy.
- Aldesleukin enhancement of cellular immune function may increase the risk of allograft rejection in transplant patients.
- The following clinical evaluations are recommended for all patients, prior to beginning treatment and then daily during drug administration.
- Standard hematologic tests-including CBC, differential and platelet counts
- Blood chemistries-including electrolytes, renal and hepatic function tests
- Chest x-rays
- Serum creatinine should be ≤1.5 mg/dL prior to initiation of Aldesleukin treatment.
- All patients should have baseline pulmonary function tests with arterial blood gases. Adequate pulmonary function should be documented (FEV1 >2 liters or ≥75% of predicted for height and age) prior to initiating therapy.
- All patients should be screened with a stress thallium study. Normal ejection fraction and unimpaired wall motion should be documented. If a thallium stress test suggests minor wall motion abnormalities further testing is suggested to exclude significant coronary artery disease.
- Daily monitoring during therapy with Aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should be performed. Vital signs in these hypotensive patients should be taken hourly.
- During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry. Patients with dyspnea or clinical signs of respiratory impairment (tachypnea or rales) should be further assessed with arterial blood gas determination. These tests are to be repeated as often as clinically indicated.
- Cardiac function should be assessed daily by clinical examination and assessment of vital signs. Patients with signs or symptoms of chest pain, murmurs, gallops, irregular rhythm or palpitations should be further assessed with an ECG examination and cardiac enzyme evaluation. Evidence of myocardial injury, including findings compatible with myocardial infarction or myocarditis, has been reported. Ventricular hypokinesia due to myocarditis may be persistent for several months. If there is evidence of cardiac ischemia or congestive heart failure, Aldesleukin therapy should be held, and a repeat thallium study should be done.
- A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with various interleukin-2 containing regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1 to 4 hours) following the administration of contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some clinicians have noted that these reactions resemble the immediate side effects caused by interleukin-2 administration, however the cause of contrast reactions after interleukin-2 therapy is unknown. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin-2. These events were also reported to occur when contrast media was given several months after interleukin-2 treatment.13
# Adverse Reactions
## Clinical Trials Experience
- The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent aldesleukin was 4% (11/255), the rate of drug-related deaths in the 270 metastatic melanoma patients who received single-agent Aldesleukin was 2% (6/270).
- The following data on common adverse events (reported in greater than 10% of patients, any grade), presented by body system, decreasing frequency and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen.
- The following life-threatening (grade 4) events were reported by <1% of the 525 patients: hypothermia, shock, bradycardia, ventricular extrasystoles, myocardial ischemia, syncope, hemorrhage, atrial arrhythmia, phlebitis, AV block second degree, endocarditis, pericardial effusion, peripheral gangrene, thrombosis, coronary artery disorder, stomatitis, nausea and vomiting, liver function tests abnormal, gastrointestinal hemorrhage, hematemesis, bloody diarrhea, gastrointestinal disorder, intestinal perforation, pancreatitis, anemia, leukopenia, leukocytosis, hypocalcemia, alkaline phosphatase increase, BUN increase, hyperuricemia, NPN increase, respiratory acidosis, somnolence, agitation, neuropathy, paranoid reaction, convulsion, grand mal convulsion, delirium, asthma, lung edema, hyperventilation, hypoxia, hemoptysis, hypoventilation, pneumothorax, mydriasis, pupillary disorder, kidney function abnormal, kidney failure, acute tubular necrosis.
- In an additional population of greater than 1,800 patients treated with Aldesleukin-based regimens using a variety of doses and schedules (e.g., subcutaneous, continuous infusion, administration with LAK cells) the following serious adverse events were reported: duodenal ulceration, bowel necrosis, myocarditis, supraventricular tachycardia, permanent or transient blindness secondary to optic neuritis, transient ischemic attacks, meningitis, cerebral edema, pericarditis, allergic interstitial nephritis, tracheo-esophageal fistula.
- In the same clinical population, the following fatal events each occurred with a frequency of <1%: malignant hyperthermia, cardiac arrest, myocardial infarction, pulmonary emboli, stroke, intestinal perforation, liver or renal failure, severe depression leading to suicide, pulmonary edema, respiratory arrest, respiratory failure. In patients with both metastatic RCC and metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events.
- Most adverse reactions are self-limiting and, usually, but not invariably, reverse or improve within 2 or 3 days of discontinuation of therapy. Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/infarction, and gangrene.
## Postmarketing Experience
- In post-marketing experience, the following serious adverse events have been reported in a variety of treatment regimens that include interleukin-2: anaphylaxis, cellulitis, injection site necrosis, retroperitoneal hemorrhage, cardiomyopathy, cerebral hemorrhage, fatal endocarditis , hypertension, cholecystitis, colitis, gastritis, hepatitis, hepatosplenomegaly, intestinal obstruction, hyperthyroidism, neutropenia, myopathy, myositis, rhabdomyolysis, cerebral lesions, encephalopathy, extrapyramidal syndrome, insomnia, neuralgia, neuritis, neuropathy (demyelination), urticaria, pneumonia (bacterial, fungal, viral).
- Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported. Persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin-2. Synergistic, additive and novel toxicities have been reported with Aldesleukin used in combination with other drugs. Novel toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents.
- Experience has shown the following concomitant medications to be useful in the management of patients on Aldesleukin therapy: a) standard antipyretic therapy, including nonsteroidal anti-inflammatories (NSAIDs), started immediately prior to Aldesleukin to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity, b) meperidine used to control the rigors associated with fever, c) H2 antagonists given for prophylaxis of gastrointestinal irritation and bleeding, d) antiemetics and antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last dose of PROLEUKIN.
- Patients with indwelling central lines have a higher risk of infection with gram positive organism]s.9-11 A reduced incidence of staphylococcal infections in Aldesleukin studies has been associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used to control symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and ointments should be applied as needed for skin manifestations. Preparations containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product.
# Drug Interactions
- Aldesleukin may affect central nervous function. Therefore, interactions could occur following concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, sedatives, tranquilizers).
- Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides, indomethacin), myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or hepatotoxic (e.g., methotrexate, asparaginase) effects with Aldesleukin may increase toxicity in these organ systems. The safety and efficacy of Aldesleukin in combination with any antineoplastic agents have not been established.
- In addition, reduced kidney and liver function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
- Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose Aldesleukin and antineoplastic agents, specifically, dacarbazine, cis-platinum, tamoxifen and interferon-alfa. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients.
- Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to be increased in patients receiving Aldesleukin and interferon-alfa concurrently.
- Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following concurrent use of interferon-alfa and PROLEUKIN, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome.
- Although glucocorticoids have been shown to reduce PROLEUKIN-induced side effects including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with Aldesleukin may reduce the antitumor effectiveness of Aldesleukin and thus should be avoided.
- Beta-blockers and other antihypertensives may potentiate the hypotension seen with Aldesleukin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Aldesleukin has been shown to have embryolethal effects in rats when given in doses at 27 to 36 times the human dose (scaled by body weight). Significant maternal toxicities were observed in pregnant rats administered Aldesleukin by IV injection at doses 2.1 to 36 times higher than the human dose during critical period of organogenesis. No evidence of teratogenicity was observed other than that attributed to maternal toxicity. There are no adequate well-controlled studies of Aldesleukin in pregnant women. Aldesleukin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aldesleukin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aldesleukin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Aldesleukin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in children under 18 years of age have not been established.
### Geriatic Use
- There were a small number of patients aged 65 and over in clinical trials of Aldesleukin, experience is limited to 27 patients, eight with metastatic melanoma and nineteen with metastatic renal cell carcinoma. The response rates were similar in patients 65 years and over as compared to those less than 65 years of age. The median number of courses and the median number of doses per course were similar between older and younger patients.
- Aldesleukin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The pattern of organ system toxicity and the proportion of patients with severe toxicities by organ system were generally similar in patients 65 and older and younger patients. There was a trend, however, towards an increased incidence of severe urogenital toxicities and dyspnea in the older patients.
### Gender
There is no FDA guidance on the use of Aldesleukin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aldesleukin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Aldesleukin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Aldesleukin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aldesleukin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aldesleukin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Daily monitoring during therapy with Aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should be performed. Vital signs in these hypotensive patients should be taken hourly.
- During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry.
# IV Compatibility
There is limited information regarding the compatibility of Aldesleukin and IV administrations.
# Overdosage
- Side effects following the use of aldesleukin appear to be dose-related. Exceeding the recommended dose has been associated with a more rapid onset of expected dose-limiting toxicities. Symptoms which persist after cessation of Aldesleukin should be monitored and treated supportively. Life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone, which may also result in loss of the therapeutic effects of Aldesleukin.
NOTE: Prior to the use of dexamethasone, the physician should refer to the package insert for this product.
# Pharmacology
## Mechanism of Action
- Aldesleukin has been shown to possess the biological activities of human native interleukin-2.1,2 In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of Aldesleukin , including: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, b) enhancement of lymphocyte cytotoxicity, c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity, and d) induction of interferon-gamma production.
- The in vivo administration of Aldesleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. 3 In vivo experiments in murine tumor models have shown inhibition of tumor growth.4 The exact mechanism by which Aldesleukin mediates its antitumor activity in animals and humans is unknown.
## Structure
- Aldesleukin for injection, a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight of approximately 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. Aldesleukin , a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) Aldesleukin is not glycosylated because it is derived from E. coli , b) the molecule has no N-terminal alanine, the codon for this amino acid was deleted during the genetic engineering procedure, c) the molecule has serine substituted for cysteine at amino acid position 125, this was accomplished by site specific manipulation during the genetic engineering procedure, and d) the aggregation state of Aldesleukin is likely to be different from that of native interleukin-2.
- The in vitro biological activities of the native nonrecombinant molecule have been reproduced with Aldesleukin .
- Aldesleukin is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous (IV) administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million IU (1.1 mg) Aldesleukin , 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The manufacturing process for Aldesleukin involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. Aldesleukin contains no preservatives in the final product.
- Aldesleukin biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units (IU) as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is as follows:
- 18 million (18 x 106) IU Aldesleukin = 1.1 mg protein
## Pharmacodynamics
There is limited information regarding Aldesleukin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Aldesleukin exists as biologically active, non-covalently bound microaggregates with an average size of 27 recombinant interleukin-2 molecules. The solubilizing agent, sodium dodecyl sulfate, may have an effect on the kinetic properties of this product.
- The pharmacokinetic profile of Aldesleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Studies of IV Aldesleukin in sheep and humans indicate that upon completion of infusion, approximately 30% of the administered dose is detectable in plasma. This finding is consistent with studies in rats using radiolabeled Aldesleukin , which demonstrate a rapid (<1 min) uptake of the majority of the label into the lungs, liver, kidney, and spleen.
- The serum half-life (T 1/2) curves of Aldesleukin remaining in the plasma are derived from studies done in 52 cancer patients following a 5-minute IV infusion. These patients were shown to have a distribution and elimination T 1/2 of 13 and 85 minutes, respectively.
- Following the initial rapid organ distribution, the primary route of clearance of circulating Aldesleukin is the kidney. In humans and animals, Aldesleukin is cleared from the circulation by both glomerular filtration and peritubular extraction in the kidney.5-8 This dual mechanism for delivery of Aldesleukin to the proximal tubule may account for the preservation of clearance in patients with rising serum creatinine values. Greater than 80% of the amount of Aldesleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. In humans, the mean clearance rate in cancer patients is 268 mL/min.
- The relatively rapid clearance of Aldesleukin has led to dosage schedules characterized by frequent, short infusions. Observed serum levels are proportional to the dose of aldesleukin.
- Fifty-seven of 77 (74%) metastatic renal cell carcinoma patients treated with an every 8-hour Aldesleukin regimen and 33 of 50 (66%) metastatic melanoma patients treated with a variety of IV regimens developed low titers of non-neutralizing anti-Aldesleukin antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/106 (<1%) patients treated with IV Aldesleukin using a wide variety of schedules and doses. The clinical significance of anti-Aldesleukin antibodies is unknown.
- Two hundred fifty-five patients with metastatic renal cell cancer (metastatic RCC) were treated with single agent Aldesleukin in 7 clinical studies conducted at 21 institutions. Two hundred seventy patients with metastatic melanoma were treated with single agent Aldesleukin in 8 clinical studies conducted at 22 institutions. Patients enrolled in trials of single agent Aldesleukin were required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 and normal organ function as determined by cardiac stress test, pulmonary function tests, and creatinine ≤1.5 mg/dL. Patients with brain metastases, active infections, organ allografts and diseases requiring steroid treatment were excluded.
- Aldesleukin was given by 15 min IV infusion every 8 hours for up to 5 days (maximum of 14 doses). No treatment was given on days 6 to 14 and then dosing was repeated for up to 5 days on days 15 to 19 (maximum of 14 doses). These 2 cycles constituted 1 course of therapy. Patients could receive a maximum of 28 doses during a course of therapy. In practice >90% of patients had doses withheld. Metastatic RCC patients received a median of 20 of 28 scheduled doses of aldesleukin. Metastatic melanoma patients received a median of 18 of 28 scheduled doses of Aldesleukin during the first course of therapy. Doses were withheld for specific toxicities.
- In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients, with 17 (7%) complete and 20 (8%) partial responders (see Table I). The 95% confidence interval for objective response was 11% to 20%. Onset of tumor regression was observed as early as 4 weeks after completion of the first course of treatment, and in some cases, tumor regression continued for up to 12 months after the start of treatment. Responses were observed in both lung and non-lung sites (e.g., liver, lymph node, renal bed occurrences, soft tissue). Responses were also observed in patients with individual bulky lesions and high tumor burden.
- In the metastatic melanoma studies (n=270), objective response was seen in 43 (16%) patients, with 17 (6%) complete and 26 (10%) partial responders (see Table I). The 95% confidence interval for objective response was 12% to 21%. Responses in metastatic melanoma patients were observed in both visceral and non-visceral sites (e.g., lung, liver, lymph node, soft tissue, adrenal, subcutaneous). Responses were also observed in patients with individual bulky lesions and large cumulative tumor burden.
## Nonclinical Toxicology
- There have been no studies conducted assessing the carcinogenic or mutagenic potential of Aldesleukin .
- There have been no studies conducted assessing the effect of Aldesleukin on fertility. It is recommended that this drug not be administered to fertile persons of either gender not practicing effective contraception.
# Clinical Studies
There is limited information regarding Aldesleukin Clinical Studies in the drug label.
# How Supplied
- aldesleukin for injection is supplied in individually boxed single-use vials. Each vial contains 22 x 106 IU of Aldesleukin . Discard unused portion.
- NDC 0078-0495-61 Individually boxed single-use vial
## Storage
- Store vials of lyophilized Aldesleukin in a refrigerator at 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT. Store in carton until time of use.
- Reconstituted or diluted Aldesleukin is stable for up to 48 hours at refrigerated and room temperatures, 2° to 25°C (36° to 77°F). However, since this product contains no preservative, the reconstituted and diluted solutions should be stored in the refrigerator.
- Do not use beyond the expiration date printed on the vial. NOTE: This product contains no preservative.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Aldesleukin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Aldesleukin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Proleukin
# Look-Alike Drug Names
There is limited information regarding Aldesleukin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Aldesleukin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Aldesleukin is an interleukin-2 that is FDA approved for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC) and metastatic melanoma.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anaphylaxis, cellulitis, injection site necrosis, retroperitoneal hemorrhage, cardiomyopathy, cerebral hemorrhage, fatal endocarditis , hypertension, cholecystitis, colitis, gastritis, hepatitis, hepatosplenomegaly, intestinal obstruction, hyperthyroidism, neutropenia, myopathy, myositis, rhabdomyolysis, cerebral lesions, encephalopathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Aldesleukin is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).
- Aldesleukin is indicated for the treatment of adults with metastatic melanoma.
- Careful patient selection is mandatory prior to the administration of Aldesleukin.
- Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at treatment initiation respond better to Aldesleukin, with a higher response rate and lower toxicity . Therefore, selection of patients for treatment should include assessment of performance status.
- Experience in patients with ECOG PS >1 is extremely limited.
- The recommended PROLEUKIN® (aldesleukin) for injection treatment regimen is administered by a 15-minute IV infusion every 8 hours. The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period.
- 400,000 IU/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute IV infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated.
- During clinical trials, doses were frequently withheld for toxicity. Metastatic RCC patients treated with this schedule received a median of 20 of the 28 doses during the first course of therapy. Metastatic melanoma patients received a median of 18 doses during the first course of therapy.
- Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last (course and retreatment is not contraindicated ). Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
- Dose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be given. Decisions to stop, hold, or restart Aldesleukin therapy must be made after a global assessment of the patient. With this in mind, the following guidelines should be used:
Reconstitution and Dilution Directions: Reconstitution and dilution procedures other than those recommended may alter the delivery and/or pharmacology of Aldesleukin and thus should be avoided.
- Aldesleukin is a sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution. EACH VIAL CONTAINS 22 MILLION IU (1.3 MG) OF Aldesleukin AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML OF STERILE WATER FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) OF PROLEUKIN. The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use only and any unused portion should be discarded.
- During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled to avoid excess foaming. DO NOT SHAKE.
- The dose of Aldesleukin, reconstituted with Sterile Water for Injection, USP (without preservative) should be diluted aseptically in 50 mL of 5% Dextrose Injection, USP (D5W) and infused over a 15-minute period.
- In cases where the total dose of Aldesleukin is 1.5 mg or less (e.g., a patient with a body weight of less than 40 kilograms), the dose of Aldesleukin should be diluted in a smaller volume of D5W. Concentrations of Aldesleukin below 30 µg/mL and above 70 µg/mL have shown increased variability in drug delivery. Dilution and delivery of Aldesleukin outside of this concentration range should be avoided.
- Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results. It is recommended that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results in more consistent drug delivery. In-line filters should not be used when administering Aldesleukin.
- Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 46°F). Do not freeze. Administer Aldesleukin within 48 hours of reconstitution. The solution should be brought to room temperature prior to infusion in the patient.
- Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP should be avoided because of increased aggregation. Aldesleukin should not be coadministered with other drugs in the same container.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aldesleukin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aldesleukin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children under 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness in children under 18 years of age have not been established..
### Non–Guideline-Supported Use
Safety and effectiveness in children under 18 years of age have not been established.
# Contraindications
- Aldesleukin is contraindicated in patients with a known history of hypersensitivity to interleukin-2 or any component of the Aldesleukin formulation.
- Aldesleukin is contraindicated in patients with an abnormal thallium stress test or abnormal pulmonary function tests and those with organ allografts. Retreatment with Aldesleukin is contraindicated in patients who have experienced the following drug-related toxicities while receiving an earlier course of therapy:
- Sustained ventricular tachycardia (≥5 beats)
- Cardiac arrhythmias not controlled or unresponsive to management
- Chest pain with ECG changes, consistent with angina or myocardial infarction
- Cardiac tamponade
- Intubation for >72 hours
- Renal failure requiring dialysis >72 hours
- Coma or toxic psychosis lasting >48 hours
- Repetitive or difficult to control seizures
- Bowel ischemia/perforation
- GI bleeding requiring surgery
# Warnings
- Because of the severe adverse events which generally accompany Aldesleukin therapy at the recommended dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment in whom Aldesleukin is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal adverse events. Adverse events are frequent, often serious, and sometimes fatal.
- Should adverse events, which require dose modification occur, dosage should be withheld rather than reduced .
- Aldesleukin has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid, has been reported following treatment with IL-2.
- All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving Aldesleukin therapy. New neurologic signs, symptoms, and anatomic lesions following Aldesleukin therapy have been reported in patients without evidence of CNS metastases. Clinical manifestations included changes in mental status, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms associated with Aldesleukin therapy usually improve after discontinuation of Aldesleukin therapy, however, there are reports of permanent neurologic defects. One case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In patients with known seizure disorders, extreme caution should be exercised as Aldesleukin may cause seizures.
### PRECAUTIONS
- Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy . Capillary leak syndrome (CLS) begins immediately after aldesleukin treatment starts and is marked by increased capillary permeability to protein and fluids and reduced vascular tone. In most patients, this results in a concomitant drop in mean arterial blood pressure within 2 to 12 hours after the start of treatment. With continued therapy, clinically significant hypotension (defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids into the extravascular space will lead to the formation of edema and creation of new effusions.
- Medical management of CLS begins with careful monitoring of the patient’s fluid and organ perfusion status. This is achieved by frequent determination of blood pressure and pulse, and by monitoring organ function, which includes assessment of mental status and urine output. Hypovolemia is assessed by catheterization and central pressure monitoring.
- Flexibility in fluid and pressor management is essential for maintaining organ perfusion and blood pressure. Consequently, extreme caution should be used in treating patients with fixed requirements for large volumes of fluid (e.g., patients with hypercalcemia). Administration of IV fluids, either colloids or crystalloids is recommended for treatment of hypovolemia. Correction of hypovolemia may require large volumes of IV fluids but caution is required because unrestrained fluid administration may exacerbate problems associated with edema formation or effusions. With extravascular fluid accumulation, edema is common and ascites, pleural or pericardial effusions may develop. Management of these events depends on a careful balancing of the effects of fluid shifts so that neither the consequences of hypovolemia (e.g., impaired organ perfusion) nor the consequences of fluid accumulations (e.g., pulmonary edema) exceed the patient’s tolerance.
- Clinical experience has shown that early administration of dopamine (1 to 5 µg/kg/min) to patients manifesting capillary leak syndrome, before the onset of hypotension, can help to maintain organ perfusion particularly to the kidney and thus preserve urine output. Weight and urine output should be carefully monitored. If organ perfusion and blood pressure are not sustained by dopamine therapy, clinical investigators have increased the dose of dopamine to 6 to 10 µg/kg/min or have added phenylephrine hydrochloride (1 to 5 µg/kg/min) to low dose dopamine . Prolonged use of pressors, either in combination or as individual agents, at relatively high doses, may be associated with cardiac rhythm disturbances. If there has been excessive weight gain or edema formation, particularly if associated with shortness of breath from pulmonary congestion, use of diuretics, once blood pressure has normalized, has been shown to hasten recovery. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product.
- Aldesleukin treatment should be withheld for failure to maintain organ perfusion as demonstrated by altered mental status, reduced urine output, a fall in the systolic blood pressure below 90 mm Hg or onset of cardiac arrhythmias . Recovery from CLS begins soon after cessation of Aldesleukin therapy. Usually, within a few hours, the blood pressure rises, organ perfusion is restored and reabsorption of extravasated fluid and protein begins.
- Kidney and liver function are impaired during Aldesleukin treatment. Use of concomitant nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver.
- Mental status changes including irritability, confusion, or depression which occur while receiving Aldesleukin may be indicators of bacteremia or early bacterial sepsis, hypoperfusion, occult CNS malignancy, or direct Aldesleukin-induced CNS toxicity. Alterations in mental status due solely to Aldesleukin therapy may progress for several days before recovery begins. Rarely, patients have sustained permanent neurologic deficits .
- Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following Aldesleukin alone or in combination with interferon . Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following Aldesleukin treatment. Some of these patients required thyroid replacement therapy. Changes in thyroid function may be a manifestation of autoimmunity. Onset of symptomatic hyperglycemia and/or diabetes mellitus has been reported during Aldesleukin therapy.
- Aldesleukin enhancement of cellular immune function may increase the risk of allograft rejection in transplant patients.
- The following clinical evaluations are recommended for all patients, prior to beginning treatment and then daily during drug administration.
- Standard hematologic tests-including CBC, differential and platelet counts
- Blood chemistries-including electrolytes, renal and hepatic function tests
- Chest x-rays
- Serum creatinine should be ≤1.5 mg/dL prior to initiation of Aldesleukin treatment.
- All patients should have baseline pulmonary function tests with arterial blood gases. Adequate pulmonary function should be documented (FEV1 >2 liters or ≥75% of predicted for height and age) prior to initiating therapy.
- All patients should be screened with a stress thallium study. Normal ejection fraction and unimpaired wall motion should be documented. If a thallium stress test suggests minor wall motion abnormalities further testing is suggested to exclude significant coronary artery disease.
- Daily monitoring during therapy with Aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should be performed. Vital signs in these hypotensive patients should be taken hourly.
- During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry. Patients with dyspnea or clinical signs of respiratory impairment (tachypnea or rales) should be further assessed with arterial blood gas determination. These tests are to be repeated as often as clinically indicated.
- Cardiac function should be assessed daily by clinical examination and assessment of vital signs. Patients with signs or symptoms of chest pain, murmurs, gallops, irregular rhythm or palpitations should be further assessed with an ECG examination and cardiac enzyme evaluation. Evidence of myocardial injury, including findings compatible with myocardial infarction or myocarditis, has been reported. Ventricular hypokinesia due to myocarditis may be persistent for several months. If there is evidence of cardiac ischemia or congestive heart failure, Aldesleukin therapy should be held, and a repeat thallium study should be done.
- A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with various interleukin-2 containing regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1 to 4 hours) following the administration of contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some clinicians have noted that these reactions resemble the immediate side effects caused by interleukin-2 administration, however the cause of contrast reactions after interleukin-2 therapy is unknown. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin-2. These events were also reported to occur when contrast media was given several months after interleukin-2 treatment.13
# Adverse Reactions
## Clinical Trials Experience
- The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent aldesleukin was 4% (11/255), the rate of drug-related deaths in the 270 metastatic melanoma patients who received single-agent Aldesleukin was 2% (6/270).
- The following data on common adverse events (reported in greater than 10% of patients, any grade), presented by body system, decreasing frequency and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen.
- The following life-threatening (grade 4) events were reported by <1% of the 525 patients: hypothermia, shock, bradycardia, ventricular extrasystoles, myocardial ischemia, syncope, hemorrhage, atrial arrhythmia, phlebitis, AV block second degree, endocarditis, pericardial effusion, peripheral gangrene, thrombosis, coronary artery disorder, stomatitis, nausea and vomiting, liver function tests abnormal, gastrointestinal hemorrhage, hematemesis, bloody diarrhea, gastrointestinal disorder, intestinal perforation, pancreatitis, anemia, leukopenia, leukocytosis, hypocalcemia, alkaline phosphatase increase, BUN increase, hyperuricemia, NPN increase, respiratory acidosis, somnolence, agitation, neuropathy, paranoid reaction, convulsion, grand mal convulsion, delirium, asthma, lung edema, hyperventilation, hypoxia, hemoptysis, hypoventilation, pneumothorax, mydriasis, pupillary disorder, kidney function abnormal, kidney failure, acute tubular necrosis.
- In an additional population of greater than 1,800 patients treated with Aldesleukin-based regimens using a variety of doses and schedules (e.g., subcutaneous, continuous infusion, administration with LAK cells) the following serious adverse events were reported: duodenal ulceration, bowel necrosis, myocarditis, supraventricular tachycardia, permanent or transient blindness secondary to optic neuritis, transient ischemic attacks, meningitis, cerebral edema, pericarditis, allergic interstitial nephritis, tracheo-esophageal fistula.
- In the same clinical population, the following fatal events each occurred with a frequency of <1%: malignant hyperthermia, cardiac arrest, myocardial infarction, pulmonary emboli, stroke, intestinal perforation, liver or renal failure, severe depression leading to suicide, pulmonary edema, respiratory arrest, respiratory failure. In patients with both metastatic RCC and metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events.
- Most adverse reactions are self-limiting and, usually, but not invariably, reverse or improve within 2 or 3 days of discontinuation of therapy. Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/infarction, and gangrene.
## Postmarketing Experience
- In post-marketing experience, the following serious adverse events have been reported in a variety of treatment regimens that include interleukin-2: anaphylaxis, cellulitis, injection site necrosis, retroperitoneal hemorrhage, cardiomyopathy, cerebral hemorrhage, fatal endocarditis , hypertension, cholecystitis, colitis, gastritis, hepatitis, hepatosplenomegaly, intestinal obstruction, hyperthyroidism, neutropenia, myopathy, myositis, rhabdomyolysis, cerebral lesions, encephalopathy, extrapyramidal syndrome, insomnia, neuralgia, neuritis, neuropathy (demyelination), urticaria, pneumonia (bacterial, fungal, viral).
- Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported. Persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin-2. Synergistic, additive and novel toxicities have been reported with Aldesleukin used in combination with other drugs. Novel toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents.
- Experience has shown the following concomitant medications to be useful in the management of patients on Aldesleukin therapy: a) standard antipyretic therapy, including nonsteroidal anti-inflammatories (NSAIDs), started immediately prior to Aldesleukin to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity, b) meperidine used to control the rigors associated with fever, c) H2 antagonists given for prophylaxis of gastrointestinal irritation and bleeding, d) antiemetics and antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last dose of PROLEUKIN.
- Patients with indwelling central lines have a higher risk of infection with gram positive organism]s.9-11 A reduced incidence of staphylococcal infections in Aldesleukin studies has been associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used to control symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and ointments should be applied as needed for skin manifestations. Preparations containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product.
# Drug Interactions
- Aldesleukin may affect central nervous function. Therefore, interactions could occur following concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, sedatives, tranquilizers).
- Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides, indomethacin), myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or hepatotoxic (e.g., methotrexate, asparaginase) effects with Aldesleukin may increase toxicity in these organ systems. The safety and efficacy of Aldesleukin in combination with any antineoplastic agents have not been established.
- In addition, reduced kidney and liver function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
- Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose Aldesleukin and antineoplastic agents, specifically, dacarbazine, cis-platinum, tamoxifen and interferon-alfa. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients.
- Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to be increased in patients receiving Aldesleukin and interferon-alfa concurrently.
- Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following concurrent use of interferon-alfa and PROLEUKIN, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome.
- Although glucocorticoids have been shown to reduce PROLEUKIN-induced side effects including fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant administration of these agents with Aldesleukin may reduce the antitumor effectiveness of Aldesleukin and thus should be avoided.
- Beta-blockers and other antihypertensives may potentiate the hypotension seen with Aldesleukin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Aldesleukin has been shown to have embryolethal effects in rats when given in doses at 27 to 36 times the human dose (scaled by body weight). Significant maternal toxicities were observed in pregnant rats administered Aldesleukin by IV injection at doses 2.1 to 36 times higher than the human dose during critical period of organogenesis. No evidence of teratogenicity was observed other than that attributed to maternal toxicity. There are no adequate well-controlled studies of Aldesleukin in pregnant women. Aldesleukin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aldesleukin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aldesleukin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Aldesleukin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in children under 18 years of age have not been established.
### Geriatic Use
- There were a small number of patients aged 65 and over in clinical trials of Aldesleukin, experience is limited to 27 patients, eight with metastatic melanoma and nineteen with metastatic renal cell carcinoma. The response rates were similar in patients 65 years and over as compared to those less than 65 years of age. The median number of courses and the median number of doses per course were similar between older and younger patients.
- Aldesleukin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The pattern of organ system toxicity and the proportion of patients with severe toxicities by organ system were generally similar in patients 65 and older and younger patients. There was a trend, however, towards an increased incidence of severe urogenital toxicities and dyspnea in the older patients.
### Gender
There is no FDA guidance on the use of Aldesleukin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aldesleukin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Aldesleukin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Aldesleukin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aldesleukin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aldesleukin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Daily monitoring during therapy with Aldesleukin should include vital signs (temperature, pulse, blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should be performed. Vital signs in these hypotensive patients should be taken hourly.
- During treatment, pulmonary function should be monitored on a regular basis by clinical examination, assessment of vital signs and pulse oximetry.
# IV Compatibility
There is limited information regarding the compatibility of Aldesleukin and IV administrations.
# Overdosage
- Side effects following the use of aldesleukin appear to be dose-related. Exceeding the recommended dose has been associated with a more rapid onset of expected dose-limiting toxicities. Symptoms which persist after cessation of Aldesleukin should be monitored and treated supportively. Life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone, which may also result in loss of the therapeutic effects of Aldesleukin.
NOTE: Prior to the use of dexamethasone, the physician should refer to the package insert for this product.
# Pharmacology
## Mechanism of Action
- Aldesleukin has been shown to possess the biological activities of human native interleukin-2.1,2 In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of Aldesleukin , including: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, b) enhancement of lymphocyte cytotoxicity, c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity, and d) induction of interferon-gamma production.
- The in vivo administration of Aldesleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. 3 In vivo experiments in murine tumor models have shown inhibition of tumor growth.4 The exact mechanism by which Aldesleukin mediates its antitumor activity in animals and humans is unknown.
## Structure
- Aldesleukin for injection, a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight of approximately 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. Aldesleukin , a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) Aldesleukin is not glycosylated because it is derived from E. coli , b) the molecule has no N-terminal alanine, the codon for this amino acid was deleted during the genetic engineering procedure, c) the molecule has serine substituted for cysteine at amino acid position 125, this was accomplished by site specific manipulation during the genetic engineering procedure, and d) the aggregation state of Aldesleukin is likely to be different from that of native interleukin-2.
- The in vitro biological activities of the native nonrecombinant molecule have been reproduced with Aldesleukin .
- Aldesleukin is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous (IV) administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million IU (1.1 mg) Aldesleukin , 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The manufacturing process for Aldesleukin involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. Aldesleukin contains no preservatives in the final product.
- Aldesleukin biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units (IU) as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is as follows:
- 18 million (18 x 106) IU Aldesleukin = 1.1 mg protein
## Pharmacodynamics
There is limited information regarding Aldesleukin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Aldesleukin exists as biologically active, non-covalently bound microaggregates with an average size of 27 recombinant interleukin-2 molecules. The solubilizing agent, sodium dodecyl sulfate, may have an effect on the kinetic properties of this product.
- The pharmacokinetic profile of Aldesleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Studies of IV Aldesleukin in sheep and humans indicate that upon completion of infusion, approximately 30% of the administered dose is detectable in plasma. This finding is consistent with studies in rats using radiolabeled Aldesleukin , which demonstrate a rapid (<1 min) uptake of the majority of the label into the lungs, liver, kidney, and spleen.
- The serum half-life (T 1/2) curves of Aldesleukin remaining in the plasma are derived from studies done in 52 cancer patients following a 5-minute IV infusion. These patients were shown to have a distribution and elimination T 1/2 of 13 and 85 minutes, respectively.
- Following the initial rapid organ distribution, the primary route of clearance of circulating Aldesleukin is the kidney. In humans and animals, Aldesleukin is cleared from the circulation by both glomerular filtration and peritubular extraction in the kidney.5-8 This dual mechanism for delivery of Aldesleukin to the proximal tubule may account for the preservation of clearance in patients with rising serum creatinine values. Greater than 80% of the amount of Aldesleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. In humans, the mean clearance rate in cancer patients is 268 mL/min.
- The relatively rapid clearance of Aldesleukin has led to dosage schedules characterized by frequent, short infusions. Observed serum levels are proportional to the dose of aldesleukin.
- Fifty-seven of 77 (74%) metastatic renal cell carcinoma patients treated with an every 8-hour Aldesleukin regimen and 33 of 50 (66%) metastatic melanoma patients treated with a variety of IV regimens developed low titers of non-neutralizing anti-Aldesleukin antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/106 (<1%) patients treated with IV Aldesleukin using a wide variety of schedules and doses. The clinical significance of anti-Aldesleukin antibodies is unknown.
- Two hundred fifty-five patients with metastatic renal cell cancer (metastatic RCC) were treated with single agent Aldesleukin in 7 clinical studies conducted at 21 institutions. Two hundred seventy patients with metastatic melanoma were treated with single agent Aldesleukin in 8 clinical studies conducted at 22 institutions. Patients enrolled in trials of single agent Aldesleukin were required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 and normal organ function as determined by cardiac stress test, pulmonary function tests, and creatinine ≤1.5 mg/dL. Patients with brain metastases, active infections, organ allografts and diseases requiring steroid treatment were excluded.
- Aldesleukin was given by 15 min IV infusion every 8 hours for up to 5 days (maximum of 14 doses). No treatment was given on days 6 to 14 and then dosing was repeated for up to 5 days on days 15 to 19 (maximum of 14 doses). These 2 cycles constituted 1 course of therapy. Patients could receive a maximum of 28 doses during a course of therapy. In practice >90% of patients had doses withheld. Metastatic RCC patients received a median of 20 of 28 scheduled doses of aldesleukin. Metastatic melanoma patients received a median of 18 of 28 scheduled doses of Aldesleukin during the first course of therapy. Doses were withheld for specific toxicities.
- In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients, with 17 (7%) complete and 20 (8%) partial responders (see Table I). The 95% confidence interval for objective response was 11% to 20%. Onset of tumor regression was observed as early as 4 weeks after completion of the first course of treatment, and in some cases, tumor regression continued for up to 12 months after the start of treatment. Responses were observed in both lung and non-lung sites (e.g., liver, lymph node, renal bed occurrences, soft tissue). Responses were also observed in patients with individual bulky lesions and high tumor burden.
- In the metastatic melanoma studies (n=270), objective response was seen in 43 (16%) patients, with 17 (6%) complete and 26 (10%) partial responders (see Table I). The 95% confidence interval for objective response was 12% to 21%. Responses in metastatic melanoma patients were observed in both visceral and non-visceral sites (e.g., lung, liver, lymph node, soft tissue, adrenal, subcutaneous). Responses were also observed in patients with individual bulky lesions and large cumulative tumor burden.
## Nonclinical Toxicology
- There have been no studies conducted assessing the carcinogenic or mutagenic potential of Aldesleukin .
- There have been no studies conducted assessing the effect of Aldesleukin on fertility. It is recommended that this drug not be administered to fertile persons of either gender not practicing effective contraception.
# Clinical Studies
There is limited information regarding Aldesleukin Clinical Studies in the drug label.
# How Supplied
- aldesleukin for injection is supplied in individually boxed single-use vials. Each vial contains 22 x 106 IU of Aldesleukin . Discard unused portion.
- NDC 0078-0495-61 Individually boxed single-use vial
## Storage
- Store vials of lyophilized Aldesleukin in a refrigerator at 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT. Store in carton until time of use.
- Reconstituted or diluted Aldesleukin is stable for up to 48 hours at refrigerated and room temperatures, 2° to 25°C (36° to 77°F). However, since this product contains no preservative, the reconstituted and diluted solutions should be stored in the refrigerator.
- Do not use beyond the expiration date printed on the vial. NOTE: This product contains no preservative.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Aldesleukin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Aldesleukin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Proleukin
# Look-Alike Drug Names
There is limited information regarding Aldesleukin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aldesleukin | |
f8d5bcd8fdf55268b8cb905dde25dc1c9627475c | wikidoc | Aldosterone | Aldosterone
# Overview
Aldosterone is a steroid hormone (mineralocorticoid family) produced by the outer-section (zona glomerulosa) of the adrenal cortex in the adrenal gland to regulate sodium and potassium balance in the blood.
It was first isolated by Simpson and Tait in 1953.
# Synthesis
The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).
Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions). But aldosterone synthase is also able to perform a 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and reticularis.
Note: aldosterone synthase is absent in other sections of the adrenal gland.
# Function
Aldosterone is the primary of several endogenous members of the class of mineralocorticoids in human. Deoxycorticosterone is another important member of this class. At the late distal tubule & collecting duct, aldosterone has two main actions:
- Acting on mineralocorticoid receptors (MR) on principal cells in the distal tubule of the kidney nephron, it increases the permeability of their apical (luminal) membrane to potassium and sodium and activates their basolateral Na+/K+ pumps, stimulating ATP hydrolysis leading to phosphorylation of the pump and a conformational change in the pump exposes the Na+ ions to the outside. The phosphorylated form of the pump has a low affinity for Na+ ions, hence reabsorbing sodium (Na+) ions and water into the blood, and secreting potassium (K+) ions into the urine. (Chlorine anions are also reabsorbed in conjunction with sodium cations to maintain the system's electrochemical balance.)
- Aldosterone stimulates H+ secretion by intercalated cells in the collecting duct, regulating plasma bicarbonate (HCO3−) levels and its acid/base balance.
- Aldosterone may act on the central nervous system via the posterior pituitary gland to release vasopressin (ADH) which serves to conserve water by direct actions on renal tubular resorption.
Aldosterone is responsible for the reabsorption of about 2% of filtered sodium in the kidneys, which is nearly equal to the entire sodium content in human blood under normal GFR (glomerular filtration rate).
# Location of receptors
Unlike neuroreceptors, classic steroid receptors are intracellularly located. The aldosterone/MR receptor complex binds on the DNA to specific hormone response element, which leads to gene specific transcription.
Some of the transcribed genes are crucial for transepithelial sodium transport, including the three subunits of the epithelial sodium channel, the Na+/K+ pumps and their regulatory proteins serum and glucocorticoid-induced kinase, and channel-inducing factor respectively.
# Stimulation of synthesis
Aldosterone synthesis is stimulated by several factors:
- by increased plasma angiotensin II, ACTH, or potassium levels, which are present in proportion to plasma sodium deficiencies. (The increased potassium level works to regulate aldosterone synthesis by depolarizing the cells in the zona glomerulosa, which opens the voltage-dependent calcium channels.) The level of angiotensin II is regulated by angiotensin I, which is in turn regulated by the hormone renin.
- by plasma acidosis.
- by the stretch receptors located in the atria of the heart. If decreased blood pressure is detected, the adrenal gland is stimulated by these stretch receptors to release aldosterone, which increases sodium reabsorption from the urine, sweat and the gut. This causes increased osmolarity in the extracellular fluid which will eventually return blood pressure toward normal.
The secretion of aldosterone has a diurnal rhythm.
# Control of aldosterone release from the Adrenal Cortex
- The role of the renin-angiotensin system
- The role of sympathetic nerves
- The role of baroreceptors
- The role of the juxtaglomerular apparatus
- The plasma concentration of potassium
# Additional images
- Corticosteroid biosynthetic pathway in rat
- Steroidogenesis
- Corticosterone | Aldosterone
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Aldosterone is a steroid hormone (mineralocorticoid family) produced by the outer-section (zona glomerulosa) of the adrenal cortex in the adrenal gland to regulate sodium and potassium balance in the blood.
It was first isolated by Simpson and Tait in 1953.[1]
# Synthesis
The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).
Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions). But aldosterone synthase is also able to perform a 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and reticularis.
Note: aldosterone synthase is absent in other sections of the adrenal gland.
# Function
Aldosterone is the primary of several endogenous members of the class of mineralocorticoids in human. Deoxycorticosterone is another important member of this class. At the late distal tubule & collecting duct, aldosterone has two main actions:
- Acting on mineralocorticoid receptors (MR) on principal cells in the distal tubule of the kidney nephron, it increases the permeability of their apical (luminal) membrane to potassium and sodium and activates their basolateral Na+/K+ pumps, stimulating ATP hydrolysis leading to phosphorylation of the pump and a conformational change in the pump exposes the Na+ ions to the outside. The phosphorylated form of the pump has a low affinity for Na+ ions, hence reabsorbing sodium (Na+) ions and water into the blood, and secreting potassium (K+) ions into the urine. (Chlorine anions are also reabsorbed in conjunction with sodium cations to maintain the system's electrochemical balance.)
- Aldosterone stimulates H+ secretion by intercalated cells in the collecting duct, regulating plasma bicarbonate (HCO3−) levels and its acid/base balance.[2]
- Aldosterone may act on the central nervous system via the posterior pituitary gland to release vasopressin (ADH) which serves to conserve water by direct actions on renal tubular resorption.
Aldosterone is responsible for the reabsorption of about 2% of filtered sodium in the kidneys, which is nearly equal to the entire sodium content in human blood under normal GFR (glomerular filtration rate).[3]
# Location of receptors
Unlike neuroreceptors, classic steroid receptors are intracellularly located. The aldosterone/MR receptor complex binds on the DNA to specific hormone response element, which leads to gene specific transcription.
Some of the transcribed genes are crucial for transepithelial sodium transport, including the three subunits of the epithelial sodium channel, the Na+/K+ pumps and their regulatory proteins serum and glucocorticoid-induced kinase, and channel-inducing factor respectively.
# Stimulation of synthesis
Aldosterone synthesis is stimulated by several factors:
- by increased plasma angiotensin II, ACTH, or potassium levels, which are present in proportion to plasma sodium deficiencies. (The increased potassium level works to regulate aldosterone synthesis by depolarizing the cells in the zona glomerulosa, which opens the voltage-dependent calcium channels.) The level of angiotensin II is regulated by angiotensin I, which is in turn regulated by the hormone renin.
- by plasma acidosis.
- by the stretch receptors located in the atria of the heart. If decreased blood pressure is detected, the adrenal gland is stimulated by these stretch receptors to release aldosterone, which increases sodium reabsorption from the urine, sweat and the gut. This causes increased osmolarity in the extracellular fluid which will eventually return blood pressure toward normal.
The secretion of aldosterone has a diurnal rhythm.[4]
# Control of aldosterone release from the Adrenal Cortex
- The role of the renin-angiotensin system
- The role of sympathetic nerves
- The role of baroreceptors
- The role of the juxtaglomerular apparatus
- The plasma concentration of potassium
# Additional images
- Corticosteroid biosynthetic pathway in rat
- Steroidogenesis
- Corticosterone | https://www.wikidoc.org/index.php/Aldosterone | |
89fb93cb1a96dc69d4899ee56b7734c72e862e52 | wikidoc | Mees' lines | Mees' lines
Synonyms and keywords: Mee's lines; Aldrich-Mees' lines
# Overview
Mees' lines are lines of discoloration across the nails of the fingers and toes after an episode of poisoning with arsenic or thallium or other heavy metals. They are typically white bands traversing the width of the nail. As the nail grows they move towards the end, and finally disappear when trimmed.
# Historical Perspective
Although the phenomenon is named after the Dutch physician R.A. Mees, earlier descriptions of the same abnormality were made by the Englishman E.S. Reynolds and the American C.J. Aldrich in 1901 and 1904, respectively.
# Pathophysiology
## Associated Conditions
- Fluorosis
- Occasionally occurs in leprosy
# Causes
## Common Causes
- Drugs/Toxins
- Poisoning with:
Arsenic
Heavy metal
Thallium
- Arsenic
- Heavy metal
- Thallium
- Renal failure
# Diagnosis
## Physical Examination
The following image shows an example of the white bands present on the nails of a person with Mees' lines.
Image shown below is courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
- Nail disease; white banding | Mees' lines
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Mee's lines; Aldrich-Mees' lines
# Overview
Mees' lines are lines of discoloration across the nails of the fingers and toes after an episode of poisoning with arsenic or thallium or other heavy metals.[1] They are typically white bands traversing the width of the nail. As the nail grows they move towards the end, and finally disappear when trimmed.
# Historical Perspective
Although the phenomenon is named after the Dutch physician R.A. Mees, earlier descriptions of the same abnormality were made by the Englishman E.S. Reynolds and the American C.J. Aldrich in 1901 and 1904, respectively.[2]
# Pathophysiology
## Associated Conditions
- Fluorosis
- Occasionally occurs in leprosy
# Causes
## Common Causes
- Drugs/Toxins
- Poisoning with:
Arsenic
Heavy metal
Thallium
- Arsenic
- Heavy metal
- Thallium
- Renal failure
# Diagnosis
## Physical Examination
The following image shows an example of the white bands present on the nails of a person with Mees' lines.
Image shown below is courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
- Nail disease; white banding | https://www.wikidoc.org/index.php/Aldrich-Mees%27_lines | |
e3b29c2d555a1bf158f6fac32fa39a106ec5330f | wikidoc | Alemtuzumab | Alemtuzumab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Alemtuzumab is a monoclonal antibody that is FDA approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include cytopenias, infusion reactions, cytomegalovirus (CMV) and other infections, nausea, diarrhea and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Alemtuzumab is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).
### Dosage
- Gradually escalate to the maximum recommended single dose of 30 mg.
- Escalation Strategy:
- Administer 3 mg daily until infusion reactions are ≤ grade 2.
- Then administer 10 mg daily until infusion reactions are ≤ grade 2.
- Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri).
- The total duration of therapy, including dose escalation, is 12 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alemtuzumab in adult patients.
### Non–Guideline-Supported Use
- Autoimmune disease - Cytopenia
- Malignant tumor of lymphoid hemopoietic and related tissue
- Relapsed or refractory primary cutaneous T-cell lymphoma
- Prophylaxis of renal transplant rejection
- T-cell prolymphocytic leukemia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alemtuzumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alemtuzumab in pediatric patients.
# Contraindications
None
# Warnings
### Cytopenias
Severe, including fatal, autoimmune anemia and thrombocytopenia, and prolonged myelosuppression have been reported in patients receiving alemtuzumab.
In addition, hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia have been reported after treatment with alemtuzumab at the recommended dose. Single doses of alemtuzumab greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.
Withhold alemtuzumab for severe cytopenias (except lymphopenia). Discontinue for autoimmune cytopenias or recurrent/persistent severe cytopenias (except lymphopenia). No data exist on the safety of alemtuzumab resumption in patients with autoimmune cytopenias or marrow aplasia.
### Infusion Reactions
Adverse reactions occurring during or shortly after alemtuzumab infusion include pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm. In clinical trials, the frequency of infusion reactions was highest in the first week of treatment. Monitor for the signs and symptoms listed above and withhold infusion for Grade 3 or 4 infusion reactions.
The following serious, including fatal, infusion reactions have been identified in post-marketing reports: syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock.
Initiate alemtuzumab according to the recommended dose-escalation scheme. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion reactions as needed. If therapy is interrupted for 7 or more days, reinstitute alemtuzumab with gradual dose escalation.
### Immunosuppression/Infections
Alemtuzumab treatment results in severe and prolonged lymphopenia with a concomitant increased incidence of opportunistic infections. Administer PCP and herpes viral prophylaxis during alemtuzumab therapy and for a minimum of 2 months after completion of alemtuzumab or until the CD4+ count is ≥ 200 cells/µL, whichever occurs later. Prophylaxis does not eliminate these infections.
Routinely monitor patients for CMV infection during alemtuzumab treatment and for at least 2 months following completion of treatment. Withhold alemtuzumab for serious infections and during antiviral treatment for CMV infection or confirmed CMV viremia (defined as polymerase chain reaction (PCR) positive CMV in ≥ 2 consecutive samples obtained 1 week apart). Initiate therapeutic ganciclovir (or equivalent) for CMV infection or confirmed CMV viremia.
Administer only irradiated blood products to avoid transfusion associated Graft versus Host Disease (TAGVHD), unless emergent circumstances dictate immediate transfusion.
In patients receiving alemtuzumab as initial therapy, recovery of CD4+ counts to ≥ 200 cells/µL occurred by 6 months post-treatment; however at 2 months post-treatment, the median was 183 cells/µL. In previously treated patients receiving alemtuzumab, the median time to recovery of CD4+ counts to ≥ 200 cells/µL was 2 months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months.
### Laboratory Monitoring
Obtain complete blood counts (CBC) at weekly intervals during alemtuzumab therapy and more frequently if worsening anemia, neutropenia, or thrombocytopenia occurs. Assess CD4+ counts after treatment until recovery to ≥ 200 cells/µL.
### Immunization
The safety of immunization with live viral vaccines following alemtuzumab therapy has not been studied. Do not administer live viral vaccines to patients who have recently received alemtuzumab. The ability to generate an immune response to any vaccine following alemtuzumab therapy has not been studied.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data below reflect exposure to alemtuzumab in 296 patients with CLL of whom 147 were previously untreated and 149 received at least 2 prior chemotherapy regimens. The median duration of exposure was 11.7 weeks for previously untreated patients and 8 weeks for previously treated patients.
Lymphopenia: Severe lymphopenia and a rapid and sustained decrease in lymphocyte subsets occurred in previously untreated and previously treated patients following administration of alemtuzumab. In previously untreated patients, the median CD4+ was 0 cells/μL at one month after treatment and 238 cells/μL 25-75% interquartile range 115 to 418 cells/μL at 6 months post-treatment.
Neutropenia: In previously untreated patients, the incidence of Grade 3 or 4 neutropenia was 42% with a median time to onset of 31 days and a median duration of 37 days. In previously treated patients, the incidence of Grade 3 or 4 neutropenia was 64% with a median duration of 28 days. Ten percent of previously untreated patients and 17% of previously treated patients received granulocyte colony stimulating factors.
Anemia: In previously untreated patients, the incidence of Grade 3 or 4 anemia was 12% with a median time to onset of 31 days and a median duration of 8 days. In previously treated patients, the incidence of Grade 3 or 4 anemia was 38%. Seventeen percent of previously untreated patients and 66% of previously treated patients received either erythropoiesis stimulating agents, transfusions or both.
Thrombocytopenia: In previously untreated patients, the incidence of Grade 3 or 4 thrombocytopenia was 14% with a median time to onset of 9 days and a median duration of 14 days. In previously treated patients, the incidence of Grade 3 or 4 thrombocytopenia was 52% with a median duration of 21 days. Autoimmune thrombocytopenia was reported in 2% of previously treated patients with one fatality.
Infusion reactions: Infusion reactions, which included pyrexia, chills, hypotension, urticaria, and dyspnea, were common. Grade 3 and 4 pyrexia and/or chills occurred in approximately 10% of previously untreated patients and in approximately 35% of previously treated patients. The occurrence of infusion reactions was greatest during the initial week of treatment and decreased with subsequent doses of alemtuzumab. All patients were pretreated with antipyretics and antihistamines; additionally, 43% of previously untreated patients received glucocorticoid pre-treatment.
Infections: In the study of previously untreated patients, patients were tested weekly for CMV using a PCR assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. CMV infection occurred in 16% (23/147) of previously untreated patients; approximately one-third of these infections were serious or life threatening. In studies of previously treated patients in which routine CMV surveillance was not required, CMV infection was documented in 6% (9/149) of patients; nearly all of these infections were serious or life threatening.
Other infections were reported in approximately 50% of patients across all studies. Grade 3 - 5 sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade 3 - 4 febrile neutropenia ranged from 5 to 10% across studies and was higher in previously treated patients. Infection-related fatalities occurred in 2% of previously untreated patients and 16% of previously treated patients. There were 198 episodes of other infection in 109 previously untreated patients; 16% were bacterial, 7% were fungal, 4% were other viral, and in 73%, the organism was not identified.
Cardiac: Cardiac dysrhythmias occurred in approximately 14% of previously untreated patients. The majority were tachycardias and were temporally associated with infusion; dysrhythmias were Grade 3 or 4 in 1% of patients.
### Previously Untreated Patients
TABLE 1 contains selected adverse reactions observed in 294 patients randomized (1:1) to receive alemtuzumab or chlorambucil as first line therapy for B-CLL. alemtuzumab was administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks. The median duration of therapy was 11.7 weeks with a median weekly dose of 82 mg (25-75% interquartile range: 69 mg – 90 mg).
### Previously Treated Patients
Additional safety information was obtained from 3 single arm studies of 149 previously treated patients with CLL administered 30 mg alemtuzumab intravenously three times weekly for 4 to 12 weeks (median cumulative dose 673 mg ; median duration of therapy 8.0 weeks). Adverse reactions in these studies not listed in TABLE 1 that occurred at an incidence rate of > 5% were fatigue, nausea, emesis, musculoskeletal pain, anorexia, dysesthesia, mucositis, and bronchospasm.
## Postmarketing Experience
The following adverse reactions were identified during post-approval use of alemtuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to alemtuzumab exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:
- Seriousness of the reaction,
- Reported frequency of the reaction, or
- Strength of causal connection to alemtuzumab
### Fatal infusion reactions
syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock.
### Cardiovascular
Congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents).
### Immune disorders
Goodpasture's syndrome, Graves' disease, aplastic anemia, Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, fatal transfusion associated Graft versus Host Disease.
### Infections
Epstein-Barr Virus (EBV) including EBV-associated lymphoproliferative disorder, progressive multifocal leukoencephalopathy (PML), re-activation of latent viruses.
### Metabolic
Tumor lysis syndrome
### Neurologic
Optic neuropathy
# Drug Interactions
No formal drug interaction studies have been performed with alemtuzumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with alemtuzumab. IgG antibodies, such as alemtuzumab, can cross the placental barrier. It is not known whether alemtuzumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. alemtuzumab should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): B2
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alemtuzumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alemtuzumab during labor and delivery.
### Nursing Mothers
Excretion of alemtuzumab in human breast milk has not been studied; it is not known whether this drug is excreted in human milk. IgG antibodies, such as alemtuzumab, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from alemtuzumab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the elimination half-life of alemtuzumab and the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
Of 147 previously untreated B-CLL patients treated with alemtuzumab, 35% were ≥ age 65 and 4% were ≥ age 75. Of 149 previously treated patients with B-CLL, 44% were ≥ 65 years of age and 10% were ≥ 75 years of age. Clinical studies of alemtuzumab did not include sufficient number of subjects age 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Alemtuzumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alemtuzumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alemtuzumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alemtuzumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No long-term studies in animals have been performed to establish the effects on fertility in males or females.
### Immunocompromised Patients
There is no FDA guidance one the use of Alemtuzumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Alemtuzumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Alemtuzumab and IV administrations.
# Overdosage
Across all clinical experience, the reported maximum single dose received was 90 mg. Bone marrow aplasia, infections, or severe infusions reactions occurred in patients who received a dose higher than recommended.
One patient received an 80 mg dose by IV infusion and experienced acute bronchospasm, cough, and dyspnea, followed by anuria and death. Another patient received two 90 mg doses by IV infusion one day apart during the second week of treatment and experienced a rapid onset of bone marrow aplasia.
There is no known specific antidote for alemtuzumab overdosage. Treatment consists of drug discontinuation and supportive therapy.
# Pharmacology
## Mechanism of Action
alemtuzumab binds to CD52, an antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. A proportion of bone marrow cells, including some CD34+ cells, express variable levels of CD52. The proposed mechanism of action is antibody-dependent cellular-mediated lysis following cell surface binding of alemtuzumab to the leukemic cells.
## Structure
There is limited information regarding Alemtuzumab Structure in the drug label.
## Pharmacodynamics
### Cardiac Electrophysiology
The effect of multiple doses of alemtuzumab (12 mg/day for 5 days) on the QTc interval was evaluated in a single-arm study in 53 patients without malignancy. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study. A mean increase in heart rate of 22 to 26 beats/min was observed for at least 2 hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.
## Pharmacokinetics
Alemtuzumab pharmacokinetics were characterized in a study of 30 previously treated B-CLL patients in whom alemtuzumab was administered at the recommended dose and schedule. alemtuzumab pharmacokinetics displayed nonlinear elimination kinetics. After the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg). Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). After 12 weeks of dosing, patients exhibited a seven-fold increase in mean AUC. Mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6 days (range 1 to 14 days) after the last 30 mg dose.
Comparisons of AUC in patients ≥ 65 years (n=6) versus patients < 65 years (n=15) suggested that no dose adjustments are necessary for age. Comparisons of AUC in female patients (n=4) versus male patients (n=17) suggested that no dose adjustments are necessary for gender.
The pharmacokinetics of alemtuzumab in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alemtuzumab have not been studied.
## Nonclinical Toxicology
No long-term studies in animals have been performed to establish the carcinogenic or mutagenic potential of alemtuzumab.
# Clinical Studies
### Previously Untreated B-CLL Patients
alemtuzumab was evaluated in an open-label, randomized (1:1) active-controlled study in previously untreated patients with B-CLL, Rai Stage I-IV, with evidence of progressive disease requiring therapy. Patients received either alemtuzumab 30 mg IV 3 times/week for a maximum of 12 weeks or chlorambucil 40 mg/m2 PO once every 28 days, for a maximum of 12 cycles.
Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had a WHO performance status 0-1, 23% had maximum lymph node diameter ≥ 5cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.
Patients randomized to receive alemtuzumab experienced longer progression free survival (PFS) compared to those randomized to receive chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively). The overall response rates were 83% and 55% (p < 0.0001) and the complete response rates were 24% and 2% (p < 0.0001) for alemtuzumab and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in FIGURE 1.
### Previously Treated B-CLL Patients
alemtuzumab was evaluated in three multicenter, open-label, single arm studies of 149 patients with B-CLL previously treated with alkylating agents, fludarabine, or other chemotherapies. Patients were treated with the recommended dose of alemtuzumab, 30 mg intravenously, three times per week for up to 12 weeks. Partial response rates of 21 to 31% and complete response rates of 0 to 2% were observed.
# How Supplied
Alemtuzumab is supplied in 30 mg/1 mL single use vial
- Each carton contains three alemtuzumab vials (NDC 58468-0357-3) or one alemtuzumab vial (NDC 58468-0357-1).
## Storage
Store at 2-8°C (36-46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Cytopenias: Advise patients to report any signs or symptoms such as bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue.
- Infusion Reactions: Advise patients of the signs and symptoms of infusion reactions and of the need to take premedications as prescribed.
- Infections: Advise patients to immediately report symptoms of infection (e.g. pyrexia) and to take prophylactic anti-infectives for PCP (trimethoprim/sulfamethoxazole DS or equivalent) and for herpes virus (famciclovir or equivalent) as prescribed.
- Advise patients that irradiation of blood products is required.
- Advise patients that they should not be immunized with live viral vaccines if they have recently been treated with alemtuzumab.
- Advise male and female patients with reproductive potential to use effective contraceptive methods during treatment and for a minimum of 6 months following alemtuzumab therapy.
# Precautions with Alcohol
Alcohol-Alemtuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Campath
- Lemtrada
# Look-Alike Drug Names
There is limited information regarding Alemtuzumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Alemtuzumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]; Sree Teja Yelamanchili, MBBS [3]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Alemtuzumab is a monoclonal antibody that is FDA approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include cytopenias, infusion reactions, cytomegalovirus (CMV) and other infections, nausea, diarrhea and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Alemtuzumab is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).
### Dosage
- Gradually escalate to the maximum recommended single dose of 30 mg.
- Escalation Strategy:
- Administer 3 mg daily until infusion reactions are ≤ grade 2.
- Then administer 10 mg daily until infusion reactions are ≤ grade 2.
- Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri).
- The total duration of therapy, including dose escalation, is 12 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alemtuzumab in adult patients.
### Non–Guideline-Supported Use
- Autoimmune disease - Cytopenia
- Malignant tumor of lymphoid hemopoietic and related tissue
- Relapsed or refractory primary cutaneous T-cell lymphoma
- Prophylaxis of renal transplant rejection
- T-cell prolymphocytic leukemia
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alemtuzumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Alemtuzumab in pediatric patients.
# Contraindications
None
# Warnings
### Cytopenias
Severe, including fatal, autoimmune anemia and thrombocytopenia, and prolonged myelosuppression have been reported in patients receiving alemtuzumab.
In addition, hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia have been reported after treatment with alemtuzumab at the recommended dose. Single doses of alemtuzumab greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.
Withhold alemtuzumab for severe cytopenias (except lymphopenia). Discontinue for autoimmune cytopenias or recurrent/persistent severe cytopenias (except lymphopenia). No data exist on the safety of alemtuzumab resumption in patients with autoimmune cytopenias or marrow aplasia.
### Infusion Reactions
Adverse reactions occurring during or shortly after alemtuzumab infusion include pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm. In clinical trials, the frequency of infusion reactions was highest in the first week of treatment. Monitor for the signs and symptoms listed above and withhold infusion for Grade 3 or 4 infusion reactions.
The following serious, including fatal, infusion reactions have been identified in post-marketing reports: syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock.
Initiate alemtuzumab according to the recommended dose-escalation scheme. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion reactions as needed. If therapy is interrupted for 7 or more days, reinstitute alemtuzumab with gradual dose escalation.
### Immunosuppression/Infections
Alemtuzumab treatment results in severe and prolonged lymphopenia with a concomitant increased incidence of opportunistic infections. Administer PCP and herpes viral prophylaxis during alemtuzumab therapy and for a minimum of 2 months after completion of alemtuzumab or until the CD4+ count is ≥ 200 cells/µL, whichever occurs later. Prophylaxis does not eliminate these infections.
Routinely monitor patients for CMV infection during alemtuzumab treatment and for at least 2 months following completion of treatment. Withhold alemtuzumab for serious infections and during antiviral treatment for CMV infection or confirmed CMV viremia (defined as polymerase chain reaction (PCR) positive CMV in ≥ 2 consecutive samples obtained 1 week apart). Initiate therapeutic ganciclovir (or equivalent) for CMV infection or confirmed CMV viremia.
Administer only irradiated blood products to avoid transfusion associated Graft versus Host Disease (TAGVHD), unless emergent circumstances dictate immediate transfusion.
In patients receiving alemtuzumab as initial therapy, recovery of CD4+ counts to ≥ 200 cells/µL occurred by 6 months post-treatment; however at 2 months post-treatment, the median was 183 cells/µL. In previously treated patients receiving alemtuzumab, the median time to recovery of CD4+ counts to ≥ 200 cells/µL was 2 months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months.
### Laboratory Monitoring
Obtain complete blood counts (CBC) at weekly intervals during alemtuzumab therapy and more frequently if worsening anemia, neutropenia, or thrombocytopenia occurs. Assess CD4+ counts after treatment until recovery to ≥ 200 cells/µL.
### Immunization
The safety of immunization with live viral vaccines following alemtuzumab therapy has not been studied. Do not administer live viral vaccines to patients who have recently received alemtuzumab. The ability to generate an immune response to any vaccine following alemtuzumab therapy has not been studied.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data below reflect exposure to alemtuzumab in 296 patients with CLL of whom 147 were previously untreated and 149 received at least 2 prior chemotherapy regimens. The median duration of exposure was 11.7 weeks for previously untreated patients and 8 weeks for previously treated patients.
Lymphopenia: Severe lymphopenia and a rapid and sustained decrease in lymphocyte subsets occurred in previously untreated and previously treated patients following administration of alemtuzumab. In previously untreated patients, the median CD4+ was 0 cells/μL at one month after treatment and 238 cells/μL 25-75% interquartile range 115 to 418 cells/μL at 6 months post-treatment.
Neutropenia: In previously untreated patients, the incidence of Grade 3 or 4 neutropenia was 42% with a median time to onset of 31 days and a median duration of 37 days. In previously treated patients, the incidence of Grade 3 or 4 neutropenia was 64% with a median duration of 28 days. Ten percent of previously untreated patients and 17% of previously treated patients received granulocyte colony stimulating factors.
Anemia: In previously untreated patients, the incidence of Grade 3 or 4 anemia was 12% with a median time to onset of 31 days and a median duration of 8 days. In previously treated patients, the incidence of Grade 3 or 4 anemia was 38%. Seventeen percent of previously untreated patients and 66% of previously treated patients received either erythropoiesis stimulating agents, transfusions or both.
Thrombocytopenia: In previously untreated patients, the incidence of Grade 3 or 4 thrombocytopenia was 14% with a median time to onset of 9 days and a median duration of 14 days. In previously treated patients, the incidence of Grade 3 or 4 thrombocytopenia was 52% with a median duration of 21 days. Autoimmune thrombocytopenia was reported in 2% of previously treated patients with one fatality.
Infusion reactions: Infusion reactions, which included pyrexia, chills, hypotension, urticaria, and dyspnea, were common. Grade 3 and 4 pyrexia and/or chills occurred in approximately 10% of previously untreated patients and in approximately 35% of previously treated patients. The occurrence of infusion reactions was greatest during the initial week of treatment and decreased with subsequent doses of alemtuzumab. All patients were pretreated with antipyretics and antihistamines; additionally, 43% of previously untreated patients received glucocorticoid pre-treatment.
Infections: In the study of previously untreated patients, patients were tested weekly for CMV using a PCR assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. CMV infection occurred in 16% (23/147) of previously untreated patients; approximately one-third of these infections were serious or life threatening. In studies of previously treated patients in which routine CMV surveillance was not required, CMV infection was documented in 6% (9/149) of patients; nearly all of these infections were serious or life threatening.
Other infections were reported in approximately 50% of patients across all studies. Grade 3 - 5 sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade 3 - 4 febrile neutropenia ranged from 5 to 10% across studies and was higher in previously treated patients. Infection-related fatalities occurred in 2% of previously untreated patients and 16% of previously treated patients. There were 198 episodes of other infection in 109 previously untreated patients; 16% were bacterial, 7% were fungal, 4% were other viral, and in 73%, the organism was not identified.
Cardiac: Cardiac dysrhythmias occurred in approximately 14% of previously untreated patients. The majority were tachycardias and were temporally associated with infusion; dysrhythmias were Grade 3 or 4 in 1% of patients.
### Previously Untreated Patients
TABLE 1 contains selected adverse reactions observed in 294 patients randomized (1:1) to receive alemtuzumab or chlorambucil as first line therapy for B-CLL. alemtuzumab was administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks. The median duration of therapy was 11.7 weeks with a median weekly dose of 82 mg (25-75% interquartile range: 69 mg – 90 mg).
### Previously Treated Patients
Additional safety information was obtained from 3 single arm studies of 149 previously treated patients with CLL administered 30 mg alemtuzumab intravenously three times weekly for 4 to 12 weeks (median cumulative dose 673 mg [range 2 – 1106 mg]; median duration of therapy 8.0 weeks). Adverse reactions in these studies not listed in TABLE 1 that occurred at an incidence rate of > 5% were fatigue, nausea, emesis, musculoskeletal pain, anorexia, dysesthesia, mucositis, and bronchospasm.
## Postmarketing Experience
The following adverse reactions were identified during post-approval use of alemtuzumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to alemtuzumab exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:
- Seriousness of the reaction,
- Reported frequency of the reaction, or
- Strength of causal connection to alemtuzumab
### Fatal infusion reactions
syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock.
### Cardiovascular
Congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents).
### Immune disorders
Goodpasture's syndrome, Graves' disease, aplastic anemia, Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, fatal transfusion associated Graft versus Host Disease.
### Infections
Epstein-Barr Virus (EBV) including EBV-associated lymphoproliferative disorder, progressive multifocal leukoencephalopathy (PML), re-activation of latent viruses.
### Metabolic
Tumor lysis syndrome
### Neurologic
Optic neuropathy
# Drug Interactions
No formal drug interaction studies have been performed with alemtuzumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with alemtuzumab. IgG antibodies, such as alemtuzumab, can cross the placental barrier. It is not known whether alemtuzumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. alemtuzumab should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): B2
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alemtuzumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alemtuzumab during labor and delivery.
### Nursing Mothers
Excretion of alemtuzumab in human breast milk has not been studied; it is not known whether this drug is excreted in human milk. IgG antibodies, such as alemtuzumab, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from alemtuzumab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the elimination half-life of alemtuzumab and the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
Of 147 previously untreated B-CLL patients treated with alemtuzumab, 35% were ≥ age 65 and 4% were ≥ age 75. Of 149 previously treated patients with B-CLL, 44% were ≥ 65 years of age and 10% were ≥ 75 years of age. Clinical studies of alemtuzumab did not include sufficient number of subjects age 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Alemtuzumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alemtuzumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Alemtuzumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Alemtuzumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No long-term studies in animals have been performed to establish the effects on fertility in males or females.
### Immunocompromised Patients
There is no FDA guidance one the use of Alemtuzumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Alemtuzumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Alemtuzumab and IV administrations.
# Overdosage
Across all clinical experience, the reported maximum single dose received was 90 mg. Bone marrow aplasia, infections, or severe infusions reactions occurred in patients who received a dose higher than recommended.
One patient received an 80 mg dose by IV infusion and experienced acute bronchospasm, cough, and dyspnea, followed by anuria and death. Another patient received two 90 mg doses by IV infusion one day apart during the second week of treatment and experienced a rapid onset of bone marrow aplasia.
There is no known specific antidote for alemtuzumab overdosage. Treatment consists of drug discontinuation and supportive therapy.
# Pharmacology
## Mechanism of Action
alemtuzumab binds to CD52, an antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. A proportion of bone marrow cells, including some CD34+ cells, express variable levels of CD52. The proposed mechanism of action is antibody-dependent cellular-mediated lysis following cell surface binding of alemtuzumab to the leukemic cells.
## Structure
There is limited information regarding Alemtuzumab Structure in the drug label.
## Pharmacodynamics
### Cardiac Electrophysiology
The effect of multiple doses of alemtuzumab (12 mg/day for 5 days) on the QTc interval was evaluated in a single-arm study in 53 patients without malignancy. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study. A mean increase in heart rate of 22 to 26 beats/min was observed for at least 2 hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.
## Pharmacokinetics
Alemtuzumab pharmacokinetics were characterized in a study of 30 previously treated B-CLL patients in whom alemtuzumab was administered at the recommended dose and schedule. alemtuzumab pharmacokinetics displayed nonlinear elimination kinetics. After the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg). Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). After 12 weeks of dosing, patients exhibited a seven-fold increase in mean AUC. Mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6 days (range 1 to 14 days) after the last 30 mg dose.
Comparisons of AUC in patients ≥ 65 years (n=6) versus patients < 65 years (n=15) suggested that no dose adjustments are necessary for age. Comparisons of AUC in female patients (n=4) versus male patients (n=17) suggested that no dose adjustments are necessary for gender.
The pharmacokinetics of alemtuzumab in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alemtuzumab have not been studied.
## Nonclinical Toxicology
No long-term studies in animals have been performed to establish the carcinogenic or mutagenic potential of alemtuzumab.
# Clinical Studies
### Previously Untreated B-CLL Patients
alemtuzumab was evaluated in an open-label, randomized (1:1) active-controlled study in previously untreated patients with B-CLL, Rai Stage I-IV, with evidence of progressive disease requiring therapy. Patients received either alemtuzumab 30 mg IV 3 times/week for a maximum of 12 weeks or chlorambucil 40 mg/m2 PO once every 28 days, for a maximum of 12 cycles.
Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had a WHO performance status 0-1, 23% had maximum lymph node diameter ≥ 5cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.
Patients randomized to receive alemtuzumab experienced longer progression free survival (PFS) compared to those randomized to receive chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively). The overall response rates were 83% and 55% (p < 0.0001) and the complete response rates were 24% and 2% (p < 0.0001) for alemtuzumab and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in FIGURE 1.
### Previously Treated B-CLL Patients
alemtuzumab was evaluated in three multicenter, open-label, single arm studies of 149 patients with B-CLL previously treated with alkylating agents, fludarabine, or other chemotherapies. Patients were treated with the recommended dose of alemtuzumab, 30 mg intravenously, three times per week for up to 12 weeks. Partial response rates of 21 to 31% and complete response rates of 0 to 2% were observed.
# How Supplied
Alemtuzumab is supplied in 30 mg/1 mL single use vial
- Each carton contains three alemtuzumab vials (NDC 58468-0357-3) or one alemtuzumab vial (NDC 58468-0357-1).
## Storage
Store at 2-8°C (36-46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Cytopenias: Advise patients to report any signs or symptoms such as bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue.
- Infusion Reactions: Advise patients of the signs and symptoms of infusion reactions and of the need to take premedications as prescribed.
- Infections: Advise patients to immediately report symptoms of infection (e.g. pyrexia) and to take prophylactic anti-infectives for PCP (trimethoprim/sulfamethoxazole DS or equivalent) and for herpes virus (famciclovir or equivalent) as prescribed.
- Advise patients that irradiation of blood products is required.
- Advise patients that they should not be immunized with live viral vaccines if they have recently been treated with alemtuzumab.
- Advise male and female patients with reproductive potential to use effective contraceptive methods during treatment and for a minimum of 6 months following alemtuzumab therapy.
# Precautions with Alcohol
Alcohol-Alemtuzumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Campath [1]
- Lemtrada
# Look-Alike Drug Names
There is limited information regarding Alemtuzumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Alemtuzumab | |
46a7482c158d89a988f3e29267a74f24a3d96a80 | wikidoc | Alendronate | Alendronate
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Alendronate is a bisphosphonate that is FDA approved for the treatment of osteoporosis in postmenopausal women, glucocorticoid-induced osteoporosis, paget's disease of bone, to increase bone mass in men with osteoporosis. Common adverse reactions include abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- one 70 mg tablet once weekly or one 10 mg tablet once daily.
- Dosing Information
- one 35 mg tablet once weekly or one 5 mg tablet once daily.
- Dosing Information
- one 70 mg tablet once weekly or one 10 mg tablet once daily.
- Dosing Information
- The recommended dosage is one 5 mg (alendronate) tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg (alendronate) tablet once daily.
- Dosing Information
- The recommended treatment regimen is 40 mg once a day for six months.
- Re-treatment of Paget’s Disease
- Re-treatment with alendronate sodium tablets may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alendronate in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 70 mg orally once weekly.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Intravenous alendronate 5 mg as a 2-hour infusion.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 10 mg per day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Alendronate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alendronate in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Oral alendronate 10 mg daily.
- Dosing Information
- Oral alendronate 10 mg daily.
# Contraindications
- Alendronate sodium tablets are contraindicated in patients with the following conditions:
- Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
- Inability to stand or sit upright for at least 30 minutes
- Hypocalcemia
- Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported.
# Warnings
### Precautions
- Upper Gastrointestinal Adverse Reactions
- (Alendronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).
- Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
- The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium and/or who fail to swallow oral bisphosphonates including alendronate sodium with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision.
- There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
- Mineral Metabolism
- Hypocalcemia must be corrected before initiating therapy with alendronate sodium. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium.
- Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget’s disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.
- Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget’s disease of bone and in patients receiving glucocorticoids.
- Musculoskeletal Pain
- In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis. This category of drugs includes alendronate. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
- In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.
- Osteonecrosis of the Jaw
- Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
- For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
- Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
- Atypical Subtrochanteric and Diaphyseal Femoral Fractures
- Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
- Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.
- Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
- Renal Impairment
- Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min.
- Glucocorticoid-Induced Osteoporosis
- The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established. Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered.
- A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined alendronate sodium and glucocorticoid treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Treatment of Osteoporosis in Postmenopausal Women
- Daily Dosing
- The safety of alendronate sodium in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44 to 84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n=994); Study 3 was the three year vertebral fracture cohort of the Fracture Intervention Trial (n=2027) and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate sodium. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 international units Vitamin D per day.
- Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate sodium group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate sodium group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate sodium group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate sodium or placebo are presented in Table 1.
- Rash and erythema have occurred.
- Gastrointestinal Adverse Reactions: One patient treated with alendronate (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin, developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49 to 54% had a history of gastrointestinal disorders at baseline and 54 to 89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies.
- Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate sodium versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups.
- Weekly Dosing
- The safety of alendronate 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing alendronate 70 mg once weekly and alendronate 10 mg daily. The overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2.
- Prevention of Osteoporosis in Postmenopausal Women
- Daily Dosing
- The safety of alendronate 5 mg/day in postmenopausal women 40 to 60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to receive alendronate sodium for either two or three years. In these studies the overall safety profiles of alendronate 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse event occurred in 7.5% of 642 patients treated with alendronate 5 mg/day and 5.7% of 648 patients treated with placebo.
- Weekly Dosing
- The safety of alendronate 35 mg once weekly compared to alendronate 5 mg daily was evaluated in a one-year, double-blind, multicenter study of 723 patients. The overall safety and tolerability profiles of once weekly alendronate 35 mg and alendronate 5 mg daily were similar.
- The adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either once weekly alendronate 35 mg, alendronate 5 mg/day or placebo are presented in Table 3.
- Concomitant Use with Estrogen/Hormone Replacement Therapy
- In two studies (of one and two years’ duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with alendronate 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments.
- Osteoporosis in Men
- In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate 10 mg/day and a one-year study of once weekly alendronate 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either alendronate or placebo are presented in Table 4.
- Glucocorticoid-Induced Osteoporosis
- In two, one-year, placebo-controlled, double-blind, multicenter studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of alendronate 5 and 10 mg/day were generally similar to that of placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate 5 or 10 mg/day or placebo are presented in Table 5.
- The overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that continued therapy for the second year of the studies (alendronate sodium: n=147) was consistent with that observed in the first year.
- Paget's Disease of Bone
- In clinical studies (osteoporosis and Paget's disease), adverse events reported in 175 patients taking alendronate 40 mg/day for 3 to 12 months were similar to those in postmenopausal women treated with alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking alendronate 40 mg/day (17.7% alendronate sodium vs. 10.2% placebo). One case of esophagitis and two cases of gastritis resulted in discontinuation of treatment.
- Additionally, musculoskeletal (bone, muscle or joint) pain, which has been described in patients with Paget's disease treated with other bisphosphonates, was considered by the investigators as possibly, probably, or definitely drug related in approximately 6% of patients treated with alendronate 40 mg/day versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy. Discontinuation of therapy due to any clinical adverse events occurred in 6.4% of patients with Paget's disease treated with alendronate 40 mg/day and 2.4% of patients treated with placebo.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of alendronate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.
- Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications, have also been reported.
- Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported.
- Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating; joint swelling; low-energy femoral shaft and subtrochanteric fractures.
- Nervous System: dizziness and vertigo.
- Pulmonary: acute asthma exacerbations.
- Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
- Special Senses: uveitis, scleritis or episcleritis.
# Drug Interactions
- Calcium Supplements/Antacids
- Co-administration of alendronate sodium and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate sodium. Therefore, instruct patients to wait at least one-half hour after taking alendronate sodium before taking any other oral medications.
- Aspirin
- In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate greater than 10 mg and aspirin-containing products.
- Nonsteroidal Anti-Inflammatory Drugs
- Alendronate sodium may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate sodium.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no studies in pregnant women. Alendronate sodium should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
- Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.
- Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose.
- Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; intravenous calcium supplementation prevented maternal, but not fetal deaths.
- Exposure multiples based on surface area, mg/m2, were calculated using a 40-mg human daily dose. Animal dose ranged between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alendronate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alendronate during labor and delivery.
### Nursing Mothers
- It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate sodium is administered to nursing women.
### Pediatric Use
- Alendronate sodium tablets are not indicated for use in pediatric patients.
- The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4 to 18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate daily (weight less than 40 kg) or 10 mg alendronate daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate sodium-treated patients and 0.1 in the placebo-treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate sodium patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate sodium-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults.
- The overall safety profile of alendronate sodium in osteogenesis imperfecta patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in osteogenesis imperfecta patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo.
- In a pharmacokinetic study, 6 of 24 pediatric osteogenesis imperfecta patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium.
### Geriatic Use
- Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women, osteoporosis studies in men, glucocorticoid-induced osteoporosis studies, and Paget’s disease studies, 45%, 54%, 37%, and 70%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Alendronate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alendronate with respect to specific racial populations.
### Renal Impairment
- Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35 to 60 mL/min.
### Hepatic Impairment
- As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alendronate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alendronate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Alendronate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Alendronate in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2).
- Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage.
### Management
- No specific information is available on the treatment of overdosage with alendronate sodium.
- Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.
- Dialysis would not be beneficial.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Alendronate in the drug label.
# Pharmacology
## Mechanism of Action
- Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.
## Structure
- Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.
- Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.
- The empirical formula of alendronate sodium is C4H12NNaO7P23H2O and its formula weight is 325.12. The structural formula is:
- Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.
- Alendronate sodium tablets, USP for oral administration contain 6.53, 13.05, 45.68 or 91.35 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5, 10, 35 and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, mannitol, and magnesium stearate.
## Pharmacodynamics
- Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.
- Osteoporosis in Postmenopausal Women
- Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.
- Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.
- Long-term treatment of osteoporosis with alendronate 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with alendronate sodium. In osteoporosis treatment studies alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. In osteoporosis prevention studies alendronate 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly alendronate 70 mg for the treatment of osteoporosis and once weekly alendronate 35 mg for the prevention of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.
- As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with alendronate sodium. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of alendronate 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. Similar reductions were observed with alendronate 5 mg/day. In one-year studies with once weekly alendronate 35 and 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate sodium but also a decrease in renal phosphate reabsorption.
- Osteoporosis in Men
- Treatment of men with osteoporosis with alendronate 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly alendronate 70 mg.
- Glucocorticoid-Induced Osteoporosis
- Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly inhibiting bone formation.
- In clinical studies of up to two years’ duration, alendronate 5 and 10 mg/day reduced cross-linked N-telopeptides of type I collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 15 to 30% and 8 to 18%, respectively. As a result of inhibition of bone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to 8%).
- Paget's Disease of Bone
- Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
- Clinical manifestations of Paget’s disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
- Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate sodium 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate sodium induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.
## Pharmacokinetics
- Absorption
- Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.
- Alendronate sodium 70 mg oral solution and alendronate sodium 70 mg tablet are equally bioavailable.
- A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
- Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.
- Distribution
- Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.
- Metabolism
- There is no evidence that alendronate is metabolized in animals or humans.
- Excretion
- Following a single intravenous dose of alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval ), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with alendronate (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.
- Specific Populations
- Gender: Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and women.
- Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary in elderly patients.
- Race: Pharmacokinetic differences due to race have not been studied.
- Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.
- No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure.
- Hepatic Impairment: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.
- Drug Interactions
- Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.
- In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).
- Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.
## Nonclinical Toxicology
- Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to approximately 0.1 to 1 times a maximum recommended daily dose of 40 mg (Paget’s disease) based on surface area, mg/m2. The relevance of this finding to humans is unknown.
- Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to approximately 0.3 and 1 times a 40 mg human daily dose based on surface area, mg/m2. The relevance of this finding to humans is unknown.
- Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.
- Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (approximately 1 times a 40 mg human daily dose based on surface area, mg/m2).
- The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.
# Clinical Studies
- Daily Dosing
- The efficacy of alendronate 10 mg daily was assessed in four clinical trials. Study 1, a three-year, multicenter double-blind, placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter double blind placebo controlled Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture.
- Effect on Fracture Incidence
- To assess the effects of alendronate sodium on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of alendronate (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with alendronate sodium experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received alendronate sodium had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm).
- The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion.
- Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 2027-patient study (alendronate sodium, n=1022; placebo, n=1005) demonstrated that treatment with alendronate sodium resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6.
- Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate sodium significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%).
- In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on alendronate sodium, p=0.047. Figure 1 displays the cumulative incidence of hip fractures in this study.
- Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 4432-patient study (alendronate sodium, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to alendronate sodium. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in Table 7 for the patients with osteoporosis.
- Fracture Results Across Studies:
- In the Three-Year Study of FIT, alendronate sodium reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034).
- Alendronate sodium reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, alendronate sodium reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).
- Thus, alendronate sodium reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture.
- Effect on Bone Mineral Density
- The bone mineral density efficacy of alendronate 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years’ duration.
- Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate 10 mg/day relative to placebo-treated patients at three years for each of these studies.
- At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received alendronate 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See Figure 3 for lumbar spine results.) In the two-year extension of these studies, treatment of 147 patients with alendronate 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained. Alendronate sodium was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean).
- In patients with postmenopausal osteoporosis treated with alendronate 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups.
- Bone Histology
- Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate sodium at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with alendronate sodium is of normal quality.
- Effect on Height
- Alendronate sodium, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.
- Weekly Dosing
- The therapeutic equivalence of once weekly alendronate 70 mg (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70-mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in the 10-mg daily group (n=330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.
- Concomitant Use with Estrogen/Hormone Replacement Therapy (HRT)
- The effects on BMD of treatment with alendronate 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or alendronate sodium alone (both 6.0%).
- The effects on BMD when alendronate sodium was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of alendronate 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).
- In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.
- Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with alendronate sodium and HRT, 94% on alendronate sodium alone, and 78% on HRT alone. The long-term effects of combined alendronate sodium and HRT on fracture occurrence and fracture healing have not been studied.
- Daily Dosing
- Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40 to 60 years of age. One thousand six hundred nine patients (alendronate 5 mg/day; n=498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (alendronate 5 mg/day; n=88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, alendronate 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see Figure 4). In addition, alendronate 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. Alendronate 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.
- Bone Histology
- Bone histology was normal in the 28 patients biopsied at the end of three years who received alendronate at doses of up to 10 mg/day.
- Weekly Dosing
- The therapeutic equivalence of once weekly alendronate 35 mg (n=362) and alendronate 5 mg daily (n=361) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women without osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2.9% (2.6, 3.2%; 95% CI) in the 35-mg once-weekly group (n=307) and 3.2% (2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.
- The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.
- Daily Dosing
- A two-year, double-blind, placebo-controlled, multicenter study of alendronate 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving alendronate 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with alendronate sodium also reduced height loss (alendronate sodium, -0.6 mm vs. placebo, -2.4 mm).
- Weekly Dosing
- A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a BMD T-score less than or equal to -2 at the lumbar spine and less than or equal to -1 at the femoral neck, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving alendronate 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study.
- In both studies, BMD responses were similar regardless of age (greater than or equal to 65 years vs. less than 65 years), gonadal function (baseline testosterone less than 9 ng/dL vs. greater than or equal to 9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score less than or equal to -2.5 vs. greater than -2.5).
- The efficacy of alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year, double-blind, randomized, placebo-controlled, multicenter studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational ). These studies enrolled 232 and 328 patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D. Figure 5 shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate 5 mg/day for each study.
- After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in patients who received alendronate 5 mg/day. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck (-1.2%), and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained with alendronate 5 mg/day. The increases in BMD with alendronate 10 mg/day were similar to those with alendronate 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with alendronate 10 mg/day were greater than those with alendronate 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Alendronate sodium was effective regardless of dose or duration of glucocorticoid use. In addition, alendronate sodium was similarly effective regardless of age (less than 65 vs. greater than or equal to 65 years), race (Caucasian vs. other races), gender, underlying disease, baseline BMD, baseline bone turnover, and use with a variety of common medications.
- Bone histology was normal in the 49 patients biopsied at the end of one year who received alendronate at doses of up to 10 mg/day.
- Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/day of prednisone or equivalent continued into a one-year double-blind extension. After two years of treatment, spine BMD increased by 3.7% and 5.0% relative to placebo with alendronate 5 and 10 mg/day, respectively. Significant increases in BMD (relative to placebo) were also observed at the femoral neck, trochanter, and total body.
- After one year, 2.3% of patients treated with alendronate 5 or 10 mg/day (pooled) vs. 3.7% of those treated with placebo experienced a new vertebral fracture (not significant). However, in the population studied for two years, treatment with alendronate (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) significantly reduced the incidence of patients with a new vertebral fracture (alendronate sodium 0.7% vs. placebo 6.8%).
- The efficacy of alendronate 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget's disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled, multinational study and a U.S. comparative study with etidronate disodium 400 mg/day. Figure 6 shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment.
- At six months the suppression in alkaline phosphatase in patients treated with alendronate sodium was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline greater than or equal to 60%)occurred in approximately 85% of patients treated with alendronate sodium in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. Alendronate sodium was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).
- Bone histology was evaluated in 33 patients with Paget's disease treated with alendronate 40 mg/day for 6 months. As in patients treated for osteoporosis , alendronate sodium did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with alendronate sodium, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with alendronate sodium is of normal quality.
# How Supplied
- Alendronate sodium tablets, USP 5 mg, are available for oral administration as white, round, flat-faced, bevelled-edged tablets, engraved “A” on one side and “5” on the other side. They are supplied as follows:
- NDC 60505-2592-3 bottles of 30
- NDC 60505-2592-1 bottles of 100
- NDC 60505-2592-8 bottles of 1000
- NDC 60505-2592-0 unit dose packages of 100 (10x10)
- Alendronate sodium tablets, USP 10 mg, are available for oral administration as white, round, flat-faced, bevelled-edged tablet. Engraved “APO” on one side and “A10” on the other side. They are supplied as follows:
- NDC 60505-2593-3 bottles of 30
- NDC 60505-2593-1 bottles of 100
- NDC 60505-2593-8 bottles of 1000
- NDC 60505-2593-0 unit dose packages of 100 (10x10)
- Alendronate sodium tablets, USP 35 mg, are available for oral administration as white, oval, biconvexed tablet. Engraved “APO” on one side and “ALE35” on the other side. They are supplied as follows:
- NDC 60505-2594-3 bottles of 30
- NDC 60505-2594-1 bottles of 100
- NDC 60505-2594-8 bottles of 1000
- NDC 60505-2594-4 unit of use blister packages of 4
- NDC 60505-2594-7 unit of use blister packages of 12 (3x4)
- NDC 60505-2594-2 unit dose packages of 20
- NDC 60505-2594-0 unit dose packages of 100 (10x10)
- Alendronate sodium tablets, USP 70 mg, are available for oral administration as white, oval, biconvexed tablet. Engraved “APO” on one side and “ALE70” on the other side. They are supplied as follows:
- NDC 60505-2596-3 bottles of 30
- NDC 60505-2596-1 bottles of 100
- NDC 60505-2596-8 bottles of 1000
- NDC 60505-2596-4 unit dose packages of 4
- NDC 60505-2596-7 unit of use blister packages of 12 (3x4)
- NDC 60505-2596-2 unit dose packages of 20
- NDC 60505-2596-0 unit dose packages of 100 (10x10)
- Storage
- Store at 20° to 25°C (68° to 77°F) excursions permitted to 15° to 30°C (59° to 86°F).
- Dispense in a tight, light-resistant container.
## Storage
There is limited information regarding Alendronate Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to read the Medication Guide before starting therapy with alendronate sodium and to reread it each time the prescription is renewed.
- Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation
- Instruct patients to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.
- Dosing Instructions
- Instruct patients that the expected benefits of alendronate sodium may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate sodium.
- Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal ulceration.
- Instruct patients to swallow each tablet of alendronate sodium with a full glass of water (6 to 8 ounces) to facilitate delivery to the stomach and thus reduce the potential for esophageal irritation.
- Instruct patients not to lie down for at least 30 minutes and until after their first food of the day.
- Instruct patients not to take alendronate sodium at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems.
- Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate sodium and consult their physician.
- If patients miss a dose of once weekly alendronate sodium, instruct patients to take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.
# Precautions with Alcohol
- Alcohol-Alendronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alendronate®
# Look-Alike Drug Names
There is limited information regarding Alendronate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Alendronate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Alendronate is a bisphosphonate that is FDA approved for the treatment of osteoporosis in postmenopausal women, glucocorticoid-induced osteoporosis, paget's disease of bone, to increase bone mass in men with osteoporosis. Common adverse reactions include abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- one 70 mg tablet once weekly or one 10 mg tablet once daily.
- Dosing Information
- one 35 mg tablet once weekly or one 5 mg tablet once daily.
- Dosing Information
- one 70 mg tablet once weekly or one 10 mg tablet once daily.
- Dosing Information
- The recommended dosage is one 5 mg (alendronate) tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg (alendronate) tablet once daily.
- Dosing Information
- The recommended treatment regimen is 40 mg once a day for six months.
- Re-treatment of Paget’s Disease
- Re-treatment with alendronate sodium tablets may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alendronate in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 70 mg orally once weekly.[1]
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Intravenous alendronate 5 mg as a 2-hour infusion.
- Dosing Information
- Alendronate 10 mg per day.
- Dosing Information
- Alendronate 10 mg per day.[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Alendronate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Alendronate in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Oral alendronate 10 mg daily.
- Dosing Information
- Oral alendronate 10 mg daily.[3]
# Contraindications
- Alendronate sodium tablets are contraindicated in patients with the following conditions:
- Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
- Inability to stand or sit upright for at least 30 minutes
- Hypocalcemia
- Hypersensitivity to any component of this product. Hypersensitivity reactions including urticaria and angioedema have been reported.
# Warnings
### Precautions
- Upper Gastrointestinal Adverse Reactions
- (Alendronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when alendronate sodium is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).
- Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
- The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium and/or who fail to swallow oral bisphosphonates including alendronate sodium with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision.
- There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.
- Mineral Metabolism
- Hypocalcemia must be corrected before initiating therapy with alendronate sodium. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium.
- Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget’s disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.
- Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget’s disease of bone and in patients receiving glucocorticoids.
- Musculoskeletal Pain
- In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis. This category of drugs includes alendronate. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
- In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups.
- Osteonecrosis of the Jaw
- Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
- For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
- Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.
- Atypical Subtrochanteric and Diaphyseal Femoral Fractures
- Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
- Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.
- Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
- Renal Impairment
- Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min.
- Glucocorticoid-Induced Osteoporosis
- The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established. Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered.
- A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined alendronate sodium and glucocorticoid treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Treatment of Osteoporosis in Postmenopausal Women
- Daily Dosing
- The safety of alendronate sodium in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44 to 84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational n=994); Study 3 was the three year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027) and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to alendronate sodium. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 international units Vitamin D per day.
- Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the alendronate sodium group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the alendronate sodium group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the alendronate sodium group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate sodium or placebo are presented in Table 1.
- Rash and erythema have occurred.
- Gastrointestinal Adverse Reactions: One patient treated with alendronate (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin, developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49 to 54% had a history of gastrointestinal disorders at baseline and 54 to 89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies.
- Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate sodium versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups.
- Weekly Dosing
- The safety of alendronate 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing alendronate 70 mg once weekly and alendronate 10 mg daily. The overall safety and tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2.
- Prevention of Osteoporosis in Postmenopausal Women
- Daily Dosing
- The safety of alendronate 5 mg/day in postmenopausal women 40 to 60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomized to receive alendronate sodium for either two or three years. In these studies the overall safety profiles of alendronate 5 mg/day and placebo were similar. Discontinuation of therapy due to any clinical adverse event occurred in 7.5% of 642 patients treated with alendronate 5 mg/day and 5.7% of 648 patients treated with placebo.
- Weekly Dosing
- The safety of alendronate 35 mg once weekly compared to alendronate 5 mg daily was evaluated in a one-year, double-blind, multicenter study of 723 patients. The overall safety and tolerability profiles of once weekly alendronate 35 mg and alendronate 5 mg daily were similar.
- The adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either once weekly alendronate 35 mg, alendronate 5 mg/day or placebo are presented in Table 3.
- Concomitant Use with Estrogen/Hormone Replacement Therapy
- In two studies (of one and two years’ duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with alendronate 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments.
- Osteoporosis in Men
- In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of alendronate 10 mg/day and a one-year study of once weekly alendronate 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either alendronate or placebo are presented in Table 4.
- Glucocorticoid-Induced Osteoporosis
- In two, one-year, placebo-controlled, double-blind, multicenter studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of alendronate 5 and 10 mg/day were generally similar to that of placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either alendronate 5 or 10 mg/day or placebo are presented in Table 5.
- The overall safety and tolerability profile in the glucocorticoid-induced osteoporosis population that continued therapy for the second year of the studies (alendronate sodium: n=147) was consistent with that observed in the first year.
- Paget's Disease of Bone
- In clinical studies (osteoporosis and Paget's disease), adverse events reported in 175 patients taking alendronate 40 mg/day for 3 to 12 months were similar to those in postmenopausal women treated with alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse reactions in patients taking alendronate 40 mg/day (17.7% alendronate sodium vs. 10.2% placebo). One case of esophagitis and two cases of gastritis resulted in discontinuation of treatment.
- Additionally, musculoskeletal (bone, muscle or joint) pain, which has been described in patients with Paget's disease treated with other bisphosphonates, was considered by the investigators as possibly, probably, or definitely drug related in approximately 6% of patients treated with alendronate 40 mg/day versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy. Discontinuation of therapy due to any clinical adverse events occurred in 6.4% of patients with Paget's disease treated with alendronate 40 mg/day and 2.4% of patients treated with placebo.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of alendronate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema.
- Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications, have also been reported.
- Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported.
- Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating; joint swelling; low-energy femoral shaft and subtrochanteric fractures.
- Nervous System: dizziness and vertigo.
- Pulmonary: acute asthma exacerbations.
- Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
- Special Senses: uveitis, scleritis or episcleritis.
# Drug Interactions
- Calcium Supplements/Antacids
- Co-administration of alendronate sodium and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate sodium. Therefore, instruct patients to wait at least one-half hour after taking alendronate sodium before taking any other oral medications.
- Aspirin
- In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate greater than 10 mg and aspirin-containing products.
- Nonsteroidal Anti-Inflammatory Drugs
- Alendronate sodium may be administered to patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate sodium.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no studies in pregnant women. Alendronate sodium should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
- Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.
- Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose.
- Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; intravenous calcium supplementation prevented maternal, but not fetal deaths.
- Exposure multiples based on surface area, mg/m2, were calculated using a 40-mg human daily dose. Animal dose ranged between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alendronate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Alendronate during labor and delivery.
### Nursing Mothers
- It is not known whether alendronate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate sodium is administered to nursing women.
### Pediatric Use
- Alendronate sodium tablets are not indicated for use in pediatric patients.
- The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4 to 18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate daily (weight less than 40 kg) or 10 mg alendronate daily (weight greater than or equal to 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate sodium-treated patients and 0.1 in the placebo-treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate sodium patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate sodium-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults.
- The overall safety profile of alendronate sodium in osteogenesis imperfecta patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in osteogenesis imperfecta patients treated with alendronate sodium compared to placebo. During the 24-month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo.
- In a pharmacokinetic study, 6 of 24 pediatric osteogenesis imperfecta patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium.
### Geriatic Use
- Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n=2302) were greater than or equal to 65 years of age and 17% (n=550) were greater than or equal to 75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women, osteoporosis studies in men, glucocorticoid-induced osteoporosis studies, and Paget’s disease studies, 45%, 54%, 37%, and 70%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Alendronate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Alendronate with respect to specific racial populations.
### Renal Impairment
- Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min. No dosage adjustment is necessary in patients with creatinine clearance values between 35 to 60 mL/min.
### Hepatic Impairment
- As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Alendronate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Alendronate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Alendronate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Alendronate in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2).
- Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage.
### Management
- No specific information is available on the treatment of overdosage with alendronate sodium.
- Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.
- Dialysis would not be beneficial.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Alendronate in the drug label.
# Pharmacology
## Mechanism of Action
- Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H] alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H] alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.
## Structure
- Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.
- Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.
- The empirical formula of alendronate sodium is C4H12NNaO7P2•3H2O and its formula weight is 325.12. The structural formula is:
- Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.
- Alendronate sodium tablets, USP for oral administration contain 6.53, 13.05, 45.68 or 91.35 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5, 10, 35 and 70 mg, respectively, of free acid, and the following inactive ingredients: microcrystalline cellulose, mannitol, and magnesium stearate.
## Pharmacodynamics
- Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.
- Osteoporosis in Postmenopausal Women
- Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.
- Daily oral doses of alendronate (5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen). These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months.
- Long-term treatment of osteoporosis with alendronate 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross-linked N-telopeptides of type l collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with alendronate sodium. In osteoporosis treatment studies alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and bone specific alkaline phosphatase by approximately 50%, and total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau after 6 to 12 months. In osteoporosis prevention studies alendronate 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were observed in postmenopausal women during one-year studies with once weekly alendronate 70 mg for the treatment of osteoporosis and once weekly alendronate 35 mg for the prevention of osteoporosis. These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone.
- As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with alendronate sodium. In the long-term studies, reductions from baseline in serum calcium (approximately 2%) and phosphate (approximately 4 to 6%) were evident the first month after the initiation of alendronate 10 mg. No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five. Similar reductions were observed with alendronate 5 mg/day. In one-year studies with once weekly alendronate 35 and 70 mg, similar reductions were observed at 6 and 12 months. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate sodium but also a decrease in renal phosphate reabsorption.
- Osteoporosis in Men
- Treatment of men with osteoporosis with alendronate 10 mg/day for two years reduced urinary excretion of cross-linked N-telopeptides of type I collagen by approximately 60% and bone-specific alkaline phosphatase by approximately 40%. Similar reductions were observed in a one-year study in men with osteoporosis receiving once weekly alendronate 70 mg.
- Glucocorticoid-Induced Osteoporosis
- Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip, and rib). It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Alendronate decreases bone resorption without directly inhibiting bone formation.
- In clinical studies of up to two years’ duration, alendronate 5 and 10 mg/day reduced cross-linked N-telopeptides of type I collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 15 to 30% and 8 to 18%, respectively. As a result of inhibition of bone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1 to 2%) and serum phosphate (approximately 1 to 8%).
- Paget's Disease of Bone
- Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
- Clinical manifestations of Paget’s disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
- Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate sodium 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate sodium induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.
## Pharmacokinetics
- Absorption
- Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast.
- Alendronate sodium 70 mg oral solution and alendronate sodium 70 mg tablet are equally bioavailable.
- A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
- Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.
- Distribution
- Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%.
- Metabolism
- There is no evidence that alendronate is metabolized in animals or humans.
- Excretion
- Following a single intravenous dose of [14C] alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with alendronate (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.
- Specific Populations
- Gender: Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and women.
- Geriatric: Bioavailability and disposition (urinary excretion) were similar in elderly and younger patients. No dosage adjustment is necessary in elderly patients.
- Race: Pharmacokinetic differences due to race have not been studied.
- Renal Impairment: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function.
- No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. Alendronate sodium is not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure.
- Hepatic Impairment: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.
- Drug Interactions
- Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.
- In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%).
- Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate.
## Nonclinical Toxicology
- Harderian gland (a retro-orbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week oral carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to approximately 0.1 to 1 times a maximum recommended daily dose of 40 mg (Paget’s disease) based on surface area, mg/m2. The relevance of this finding to humans is unknown.
- Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year oral carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to approximately 0.3 and 1 times a 40 mg human daily dose based on surface area, mg/m2. The relevance of this finding to humans is unknown.
- Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate gave equivocal results.
- Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (approximately 1 times a 40 mg human daily dose based on surface area, mg/m2).
- The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.
# Clinical Studies
- Daily Dosing
- The efficacy of alendronate 10 mg daily was assessed in four clinical trials. Study 1, a three-year, multicenter double-blind, placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter double blind placebo controlled Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture.
- Effect on Fracture Incidence
- To assess the effects of alendronate sodium on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of alendronate (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with alendronate sodium experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received alendronate sodium had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm).
- The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion.
- Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 2027-patient study (alendronate sodium, n=1022; placebo, n=1005) demonstrated that treatment with alendronate sodium resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6.
- Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate sodium significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%).
- In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on alendronate sodium, p=0.047. Figure 1 displays the cumulative incidence of hip fractures in this study.
- Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture)
This randomized, double-blind, placebo-controlled, 4432-patient study (alendronate sodium, n=2214; placebo, n=2218) further investigated the reduction in fracture incidence due to alendronate sodium. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in Table 7 for the patients with osteoporosis.
- Fracture Results Across Studies:
- In the Three-Year Study of FIT, alendronate sodium reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p<0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p=0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p=0.034).
- Alendronate sodium reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p<0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p<0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, alendronate sodium reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p=0.035).
- Thus, alendronate sodium reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture.
- Effect on Bone Mineral Density
- The bone mineral density efficacy of alendronate 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years’ duration.
- Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate 10 mg/day relative to placebo-treated patients at three years for each of these studies.
- At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received alendronate 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See Figure 3 for lumbar spine results.) In the two-year extension of these studies, treatment of 147 patients with alendronate 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained. Alendronate sodium was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean).
- In patients with postmenopausal osteoporosis treated with alendronate 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups.
- Bone Histology
- Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate sodium at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with alendronate sodium is of normal quality.
- Effect on Height
- Alendronate sodium, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study.
- Weekly Dosing
- The therapeutic equivalence of once weekly alendronate 70 mg (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70-mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in the 10-mg daily group (n=330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.
- Concomitant Use with Estrogen/Hormone Replacement Therapy (HRT)
- The effects on BMD of treatment with alendronate 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n=425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or alendronate sodium alone (both 6.0%).
- The effects on BMD when alendronate sodium was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n=428). The addition of alendronate 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).
- In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.
- Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with alendronate sodium and HRT, 94% on alendronate sodium alone, and 78% on HRT alone. The long-term effects of combined alendronate sodium and HRT on fracture occurrence and fracture healing have not been studied.
- Daily Dosing
- Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40 to 60 years of age. One thousand six hundred nine patients (alendronate 5 mg/day; n=498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (alendronate 5 mg/day; n=88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, alendronate 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see Figure 4). In addition, alendronate 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. Alendronate 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.
- Bone Histology
- Bone histology was normal in the 28 patients biopsied at the end of three years who received alendronate at doses of up to 10 mg/day.
- Weekly Dosing
- The therapeutic equivalence of once weekly alendronate 35 mg (n=362) and alendronate 5 mg daily (n=361) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women without osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2.9% (2.6, 3.2%; 95% CI) in the 35-mg once-weekly group (n=307) and 3.2% (2.9, 3.5%; 95% CI) in the 5-mg daily group (n=298). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers.
- The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies.
- Daily Dosing
- A two-year, double-blind, placebo-controlled, multicenter study of alendronate 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving alendronate 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with alendronate sodium also reduced height loss (alendronate sodium, -0.6 mm vs. placebo, -2.4 mm).
- Weekly Dosing
- A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or a BMD T-score less than or equal to -2 at the lumbar spine and less than or equal to -1 at the femoral neck, or a baseline osteoporotic fracture and a BMD T-score less than or equal to -1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving alendronate 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study.
- In both studies, BMD responses were similar regardless of age (greater than or equal to 65 years vs. less than 65 years), gonadal function (baseline testosterone less than 9 ng/dL vs. greater than or equal to 9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score less than or equal to -2.5 vs. greater than -2.5).
- The efficacy of alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year, double-blind, randomized, placebo-controlled, multicenter studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational [which also included alendronate 2.5 mg/day]). These studies enrolled 232 and 328 patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D. Figure 5 shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate 5 mg/day for each study.
- After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in patients who received alendronate 5 mg/day. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck (-1.2%), and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained with alendronate 5 mg/day. The increases in BMD with alendronate 10 mg/day were similar to those with alendronate 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with alendronate 10 mg/day were greater than those with alendronate 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Alendronate sodium was effective regardless of dose or duration of glucocorticoid use. In addition, alendronate sodium was similarly effective regardless of age (less than 65 vs. greater than or equal to 65 years), race (Caucasian vs. other races), gender, underlying disease, baseline BMD, baseline bone turnover, and use with a variety of common medications.
- Bone histology was normal in the 49 patients biopsied at the end of one year who received alendronate at doses of up to 10 mg/day.
- Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/day of prednisone or equivalent continued into a one-year double-blind extension. After two years of treatment, spine BMD increased by 3.7% and 5.0% relative to placebo with alendronate 5 and 10 mg/day, respectively. Significant increases in BMD (relative to placebo) were also observed at the femoral neck, trochanter, and total body.
- After one year, 2.3% of patients treated with alendronate 5 or 10 mg/day (pooled) vs. 3.7% of those treated with placebo experienced a new vertebral fracture (not significant). However, in the population studied for two years, treatment with alendronate (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) significantly reduced the incidence of patients with a new vertebral fracture (alendronate sodium 0.7% vs. placebo 6.8%).
- The efficacy of alendronate 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget's disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled, multinational study and a U.S. comparative study with etidronate disodium 400 mg/day. Figure 6 shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment.
- At six months the suppression in alkaline phosphatase in patients treated with alendronate sodium was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline greater than or equal to 60%)occurred in approximately 85% of patients treated with alendronate sodium in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. Alendronate sodium was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal).
- Bone histology was evaluated in 33 patients with Paget's disease treated with alendronate 40 mg/day for 6 months. As in patients treated for osteoporosis , alendronate sodium did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with alendronate sodium, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with alendronate sodium is of normal quality.
# How Supplied
- Alendronate sodium tablets, USP 5 mg, are available for oral administration as white, round, flat-faced, bevelled-edged tablets, engraved “A” on one side and “5” on the other side. They are supplied as follows:
- NDC 60505-2592-3 bottles of 30
- NDC 60505-2592-1 bottles of 100
- NDC 60505-2592-8 bottles of 1000
- NDC 60505-2592-0 unit dose packages of 100 (10x10)
- Alendronate sodium tablets, USP 10 mg, are available for oral administration as white, round, flat-faced, bevelled-edged tablet. Engraved “APO” on one side and “A10” on the other side. They are supplied as follows:
- NDC 60505-2593-3 bottles of 30
- NDC 60505-2593-1 bottles of 100
- NDC 60505-2593-8 bottles of 1000
- NDC 60505-2593-0 unit dose packages of 100 (10x10)
- Alendronate sodium tablets, USP 35 mg, are available for oral administration as white, oval, biconvexed tablet. Engraved “APO” on one side and “ALE35” on the other side. They are supplied as follows:
- NDC 60505-2594-3 bottles of 30
- NDC 60505-2594-1 bottles of 100
- NDC 60505-2594-8 bottles of 1000
- NDC 60505-2594-4 unit of use blister packages of 4
- NDC 60505-2594-7 unit of use blister packages of 12 (3x4)
- NDC 60505-2594-2 unit dose packages of 20
- NDC 60505-2594-0 unit dose packages of 100 (10x10)
- Alendronate sodium tablets, USP 70 mg, are available for oral administration as white, oval, biconvexed tablet. Engraved “APO” on one side and “ALE70” on the other side. They are supplied as follows:
- NDC 60505-2596-3 bottles of 30
- NDC 60505-2596-1 bottles of 100
- NDC 60505-2596-8 bottles of 1000
- NDC 60505-2596-4 unit dose packages of 4
- NDC 60505-2596-7 unit of use blister packages of 12 (3x4)
- NDC 60505-2596-2 unit dose packages of 20
- NDC 60505-2596-0 unit dose packages of 100 (10x10)
- Storage
- Store at 20° to 25°C (68° to 77°F) excursions permitted to 15° to 30°C (59° to 86°F).
- Dispense in a tight, light-resistant container.
## Storage
There is limited information regarding Alendronate Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to read the Medication Guide before starting therapy with alendronate sodium and to reread it each time the prescription is renewed.
- Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation
- Instruct patients to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist.
- Dosing Instructions
- Instruct patients that the expected benefits of alendronate sodium may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate sodium.
- Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal ulceration.
- Instruct patients to swallow each tablet of alendronate sodium with a full glass of water (6 to 8 ounces) to facilitate delivery to the stomach and thus reduce the potential for esophageal irritation.
- Instruct patients not to lie down for at least 30 minutes and until after their first food of the day.
- Instruct patients not to take alendronate sodium at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems.
- Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate sodium and consult their physician.
- If patients miss a dose of once weekly alendronate sodium, instruct patients to take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day.
# Precautions with Alcohol
- Alcohol-Alendronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alendronate®[4]
# Look-Alike Drug Names
There is limited information regarding Alendronate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Alendronate | |
77af44bc01e18cbe5856c8f6b1915dc6cb2579b6 | wikidoc | Aleppo Pine | Aleppo Pine
The Aleppo Pine (Pinus halepensis) is a pine native to the Mediterranean region. The range extends from Morocco and Spain north to southern France, Italy and Croatia, and east to Greece and northern Libya, with an outlying population (from which it was first described) in Syria (including Aleppo), Jordan and Israel. It is generally found at low altitudes, mostly from sea level to 200 m, but can grow at an altitude of up to 1000 m in southern Spain, and up to 1700 m in the south, in Morocco and Algeria.
It is a small to medium-size tree, reaching 15-25 m tall and with a trunk diameter of up to 60 cm, exceptionally up to 1 m. The bark is orange-red, thick and deeply fissured at the base of the trunk, and thin and flaky in the upper crown. The leaves ("needles") are very slender, 6-12 cm long, distinctly yellowish green and produced in pairs (rarely a few in threes). The cones are narrow conic, 5-12 cm long and 2-3 cm broad at the base when closed, green at first, ripening glossy red-brown when 24 months old. They open slowly over the next few years, a process quickened if they are exposed to heat such as in forest fires. The cones open 5-8 cm wide to allow the seeds to disperse. The seeds are 5-6 mm long, with a 20 mm wing, and are wind-dispersed.
Aleppo Pine is closely related to the Turkish Pine, Canary Island Pine and Maritime Pine which all share many of its characteristics. Some authors include the Turkish Pine as a subspecies of the Aleppo Pine, as Pinus halepensis subsp. brutia (Ten.) Holmboe, but it is usually regarded as a distinct species. It is a relatively non-variable species, with its morphological characteristics staying constant over the entire range.
It is widely planted for timber in its native area, being one of the most important trees in forestry in Algeria and Morocco. It is also a popular ornamental tree, extensively planted in parks and gardens in hot dry areas such as southern California, where its considerable heat and drought tolerance is highly valued. However, the tree is also considered a feral weed on South Australia's Eyre Peninsula, where an eradication program is in place.
The resin of the Aleppo Pine is used to flavor the Greek wine retsina.
# In art
Paul Cézanne had an Aleppo Pine in his garden at Aix-en-Provence; this tree was the inspiration and model for his painting, The Big Trees. As of 2005, the tree is still growing in Cézanne's garden. | Aleppo Pine
The Aleppo Pine (Pinus halepensis) is a pine native to the Mediterranean region. The range extends from Morocco and Spain north to southern France, Italy and Croatia, and east to Greece and northern Libya, with an outlying population (from which it was first described) in Syria (including Aleppo), Jordan and Israel. It is generally found at low altitudes, mostly from sea level to 200 m, but can grow at an altitude of up to 1000 m in southern Spain, and up to 1700 m in the south, in Morocco and Algeria.[1][2]
It is a small to medium-size tree, reaching 15-25 m tall and with a trunk diameter of up to 60 cm, exceptionally up to 1 m. The bark is orange-red, thick and deeply fissured at the base of the trunk, and thin and flaky in the upper crown. The leaves ("needles") are very slender, 6-12 cm long, distinctly yellowish green and produced in pairs (rarely a few in threes). The cones are narrow conic, 5-12 cm long and 2-3 cm broad at the base when closed, green at first, ripening glossy red-brown when 24 months old. They open slowly over the next few years, a process quickened if they are exposed to heat such as in forest fires. The cones open 5-8 cm wide to allow the seeds to disperse. The seeds are 5-6 mm long, with a 20 mm wing, and are wind-dispersed.[1][2][3]
Aleppo Pine is closely related to the Turkish Pine, Canary Island Pine and Maritime Pine which all share many of its characteristics. Some authors include the Turkish Pine as a subspecies of the Aleppo Pine, as Pinus halepensis subsp. brutia (Ten.) Holmboe,[4] but it is usually regarded as a distinct species.[1][2][3][5] It is a relatively non-variable species, with its morphological characteristics staying constant over the entire range.[1]
It is widely planted for timber in its native area, being one of the most important trees in forestry in Algeria and Morocco.[3] It is also a popular ornamental tree, extensively planted in parks and gardens in hot dry areas such as southern California, where its considerable heat and drought tolerance is highly valued. However, the tree is also considered a feral weed on South Australia's Eyre Peninsula, where an eradication program is in place.
The resin of the Aleppo Pine is used to flavor the Greek wine retsina.
## In art
Paul Cézanne had an Aleppo Pine in his garden at Aix-en-Provence; this tree was the inspiration and model for his painting, The Big Trees. As of 2005, the tree is still growing in Cézanne's garden.[6] | https://www.wikidoc.org/index.php/Aleppo_Pine | |
89452e3699f6c430bf48f0083678ba0ccf6716b1 | wikidoc | Alexithymia | Alexithymia
# Overview
Alexithymia (pronounced: Template:IPA) from the Greek words λεξις and θυμος (literally "without words for emotions") is a term coined by Peter Sifneos in 1973 to describe a state of deficiency in understanding, processing, or describing emotions.
# Classification
Alexithymia is considered to be a personality trait that places individuals at risk for other medical and psychiatric disorders while reducing the likelihood that these individuals will respond to conventional treatments for the other conditions. Alexithymia is not classified as a mental disorder in the DSM IV. It is a personality trait that varies in severity from person to person. A person's alexithymia score can be measured with questionnaires such as the Toronto Alexithymia Scale (TAS-20), the Bermond-Vorst Alexithymia Questionnaire (BVAQ) or the Observer Alexithymia Scale (OAS).
Alexithymia is defined by:
- (i) difficulty identifying feelings and distinguishing between feelings and the bodily sensations of emotional arousal
- (ii) difficulty describing feelings to other people
- (iii) constricted imaginal processes, as evidenced by a paucity of fantasies
- (iv) a stimulus-bound, externally oriented cognitive style.
In studies of the general population the degree of alexithymia was found to be influenced by age, but not by gender; the rates of alexithymia in healthy controls have been found at 8.3% (2 of 24 persons) 4.7% (2 of 43), 8.9% (16 of 179), and 7% (4 of 56). Thus, several studies have reported that the prevalence rate of alexithymia is less than 10% in healthy controls.
In another study, alexithymia was found to be approximately 13% of the population, with men (17%) almost twice as likely to be affected as women (10%). Specifically, men scored higher in difficulty describing feelings and for externally oriented thinking, but there was no gender difference whatsoever in difficulty in identifying feelings.
The alexithymia construct is strongly inversely related to the concepts of psychological mindedness and emotional intelligence and M. Bagby and G. Taylor state that there is "strong empirical support for alexithymia being a stable personality trait rather than just a consequence of psychological distress". Other opinions differ and can show evidence that it may be state-dependent.
Bagby and Taylor also suggest that there may be two kinds of alexithymia, 'primary alexithymia' which is an enduring psychological trait which does not alter over time, and 'secondary alexithymia' which is state dependent and disappears after the evoking stressful situation has changed. These two manifestations of alexithymia are otherwise called 'trait' or 'state' alexithymia.
Typical deficiencies may include problems identifying, describing, and working with one's own feelings, often marked by a lack of understanding of the feelings of others; difficulty distinguishing between feelings and the bodily sensations of emotional arousal; confusion of physical sensations often associated with emotions; few dreams or fantasies due to restricted imagination; and concrete, realistic, logical thinking, often to the exclusion of emotional responses to problems. Those who have alexithymia also report very logical and realistic dreams, such as going to the store or eating a meal. Clinical experience suggests it is the structural features of dreams more than the ability to recall them that best characterizes alexithymia.
Some alexithymic individuals may appear to contradict the above mentioned characteristics because they can experience chronic dysphoria or manifest outbursts of crying or rage. However, questioning usually reveals that they are quite incapable of describing their feelings or appear confused by questions inquiring about specifics of feelings.
According to Henry Krystal, individuals suffering from alexithymia think in an operative way and may appear to be superadjusted to reality. In psychotherapy, however, a cognitive disturbance becomes apparent as the patients tends to recount trivial, chronologically ordered actions, reactions, and events of daily life with monotonous detail. In general, these individuals lack imagination, intuition, empathy, and drive-fulfillment fantasy, especially in relation to objects. Instead, they seem oriented toward things and even treat themselves as robots. These problems seriously limit their responsiveness to psychoanalytic psychotherapy; psychosomatic illness or substance abuse is frequently exacerbated should these individuals enter psychotherapy.
A common misconception about alexithymia is that victims of this construct are totally unable to express emotions verbally and that they may even fail to acknowledge that they experience emotions. Even before coining the term, Sifneos (1967) noted patients often mentioned things like anxiety or depression. The distinguishing factor was their inability to elaborate beyond a few limited adjectives such as "happy" or "unhappy" when describing these feelings. The core issue is that alexithymics have poorly differentiated emotions limiting their ability to distinguish and describe them to others. This contributes to the sense of emotional detachment from themselves and difficulty connecting with others that is typical of the alexithymic's experience.
# Relational issues
According to Vanheule, Desmet and Meganck (2006) alexithymia creates interpersonal problems because these individuals avoid emotionally close relationships, or that if they do form relationships with others they tend to position themselves as either dependent or impersonal, "such that the relationship remains superficial." Inadequate differentiation between self and other by alexithymic individuals has been observed by Blaustein & Tuber (1998) and Taylor et al (1997).
In a study, a large group of alexithymic individuals completed the 64-item Inventory of Interpersonal problems (IIP-64) which screens for:
- (a) Domineering/Controlling, indicating difficulties relinquishing control over others;
- (b) Vindictive/Self-Centered behaviour, which describes problems of hostile dominance and the tendency to fight with others;
- (c) Cold/Distant behaviour, which refers to low degrees of affection for and connection with others;
- (d) Socially Inhibited, which assesses the tendency to feel anxious and avoidant in the presence of others;
- (e) Non-Assertiveness, which measures problems in taking initiative in relation to others and coping with social challenges;
- (f) Overly Accommodating, which indicates an excess of friendly submissiveness;
- (g) Self-Sacrificing, which indicates a tendency to affiliate excessively; and
- (h) Intrusive/Needy, which describes problems with friendly dominance.
The study found that alexithymic individuals "had significantly higher scores on all IIP-64 subscales than did the nonclinical sample."
Chaotic interpersonal relations have also been observed by Sifneos. Due to the inherent difficulties identifying and describing emotional states in self and others, alexithymia also negatively affects relationship satisfaction between couples.
# In medical and psychiatric illness
Alexithymia frequently co-occurs with other disorders, with a representative prevalence of 85% in autistic spectrum disorders, 40% in posttraumatic stress disorder, 63% in anorexia nervosa, 56% in bulimia, 45% in major depressive disorder, 34% in panic disorder, and 50% in substance abusers.
Research indicates that alexithymia overlaps with Asperger syndrome. In a 2004 study, Uta Frith reported an overlap and that at least half of the Asperger syndrome group obtained scores on the Toronto Alexithymia Scale (TAS-20) that would classify them as severely impaired. Fitzgerald & Bellgrove pointed out that, "Like Alexithymia, Asperger’s syndrome is also characterised by core disturbances in speech and language and social relationships". Hill & Berthoz agreed with Fitzgerald & Bellgrove (2006) and in response stated that "there is some form of overlap between alexithymia and ASDs". They also pointed to studies that revealed impaired Theory of Mind skill in alexithymia, neuroanatomical evidence pointing to a shared aetiology and similar social skills deficits. The exact nature of the overlap is uncertain. Alexithymic traits in AS may be linked to depression or anxiety; the mediating factors are unknown and it is possible that alexithymia predisposes to anxiety.
Alexithymia involves higher risk of developing certain personality disorders, and is correlated with particular illnesses, such as hypertension,
inflammatory bowel disease, functional dyspepsia, sexual disorders, substance use disorders, and some anxiety disorders. Alexithymia is further linked with psychosomatic disorders such as migraine headaches, lower back pain, irritable bowel syndrome, asthma, nausea, allergy, and fibromyalgia.
An inability to modulate emotions is a possibility in explaining why some alexithymics are prone to discharge tension arising from unpleasant emotional states through impulsive acts or compulsive behaviors such as binge eating, substance abuse, perverse sexual behavior, or the self-starvation of anorexia nervosa. The failure to regulate emotions cognitively might result in prolonged elevations of the autonomic nervous system (ANS) and neuroendocrine systems which can lead to somatic diseases. Alexithymics also show a limited ability to experience positive emotions leading Krystal (1988) and Sifneos (1987) to describe many of these individuals as anhedonic.
# Etiology
According to French psychoanalyst Joyce McDougall all infants are born unable to identify, organize, and speak about their emotional experiences (the word infans is from the Latin "not speaking"), and are "by reason of their immaturity inevitably alexithymic". Based on this fact McDougall writes, "Might it not be supposed that the alexithymic part of an adult personality is an extremely arrested and infantile psychic structure?"
It is unclear what causes alexithymia. Some neuropsychological studies indicate that alexithymia may be due to a disturbance to the right hemisphere of the brain, which is largely responsible for processing emotions. Other studies show evidence that there may be an interhemispheric transfer deficit among alexithymics; that is, the emotional information from the right hemisphere is not being properly transferred to the language regions in the left hemisphere, as can be caused by a decreased corpus callosum, often present in psychiatric patients who have suffered severe childhood abuse. In addition, another neuropsychological model suggests that alexithymia may be related to a dysfunction of the anterior cingulate cortex. These studies have some shortcomings, however, and the empirical evidence about the causes of alexithymia remain inconclusive.
Joyce McDougall objected to the strong focus by clinicians on neurophysiological at the expense of psychological explanations for the genesis and operation of alexithymia, and introduced the alternative term 'disaffectation' to stand for psychogenic alexithymia. For McDougall, the disaffected individual had at some point "experienced overwhelming emotion that threatened to attack their sense of integrity and identity," to which they applied psychological defenses to pulverize and eject all emotional representations from consciousness.
Although physiological effects are important to determine, the first language of an infant is nonverbal facial expressions. The mother's emotional state is important for determining how any child might develop. Neglect or indifference to varying changes in a child's facial expressions without proper feedback can promote an invalidation of the facial expressions manifested by the child. The parent's ability to reflect self-awareness to the child is another important factor. If the adult is incapable of recognizing and distinguishing emotional expressions in the child, it can influence the child's capacity to understand emotional expressions. Moreover, if a parent responds with apathy, indifference, or anger to a child's natural range of emotions, the child will learn not to trust their feelings and over time may become conditioned to numb themselves to the experiences of their emotions. | Alexithymia
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Alexithymia (pronounced: Template:IPA) from the Greek words λεξις and θυμος (literally "without words for emotions") is a term coined by Peter Sifneos in 1973[1][2] to describe a state of deficiency in understanding, processing, or describing emotions.
# Classification
Alexithymia is considered to be a personality trait that places individuals at risk for other medical and psychiatric disorders while reducing the likelihood that these individuals will respond to conventional treatments for the other conditions.[3] Alexithymia is not classified as a mental disorder in the DSM IV. It is a personality trait that varies in severity from person to person. A person's alexithymia score can be measured with questionnaires such as the Toronto Alexithymia Scale (TAS-20), the Bermond-Vorst Alexithymia Questionnaire (BVAQ)[4] or the Observer Alexithymia Scale (OAS).[3]
Alexithymia is defined by:[5]
- (i) difficulty identifying feelings and distinguishing between feelings and the bodily sensations of emotional arousal
- (ii) difficulty describing feelings to other people
- (iii) constricted imaginal processes, as evidenced by a paucity of fantasies
- (iv) a stimulus-bound, externally oriented cognitive style.
In studies of the general population the degree of alexithymia was found to be influenced by age, but not by gender; the rates of alexithymia in healthy controls have been found at 8.3% (2 of 24 persons) 4.7% (2 of 43), 8.9% (16 of 179), and 7% (4 of 56). Thus, several studies have reported that the prevalence rate of alexithymia is less than 10% in healthy controls.[6]
In another study, alexithymia was found to be approximately 13% of the population, with men (17%) almost twice as likely to be affected as women (10%). Specifically, men scored higher in difficulty describing feelings and for externally oriented thinking, but there was no gender difference whatsoever in difficulty in identifying feelings.[7]
The alexithymia construct is strongly inversely related to the concepts of psychological mindedness[8] and emotional intelligence[9][10] and M. Bagby and G. Taylor state that there is "strong empirical support for alexithymia being a stable personality trait rather than just a consequence of psychological distress".[11] Other opinions differ and can show evidence that it may be state-dependent.[12]
Bagby and Taylor also suggest that there may be two kinds of alexithymia, 'primary alexithymia' which is an enduring psychological trait which does not alter over time, and 'secondary alexithymia' which is state dependent and disappears after the evoking stressful situation has changed. These two manifestations of alexithymia are otherwise called 'trait' or 'state' alexithymia.[13]
Typical deficiencies may include problems identifying, describing, and working with one's own feelings, often marked by a lack of understanding of the feelings of others; difficulty distinguishing between feelings and the bodily sensations of emotional arousal;[1] confusion of physical sensations often associated with emotions; few dreams or fantasies due to restricted imagination; and concrete, realistic, logical thinking, often to the exclusion of emotional responses to problems. Those who have alexithymia also report very logical and realistic dreams, such as going to the store or eating a meal.[14] Clinical experience suggests it is the structural features of dreams more than the ability to recall them that best characterizes alexithymia.[1]
Some alexithymic individuals may appear to contradict the above mentioned characteristics because they can experience chronic dysphoria or manifest outbursts of crying or rage.[15][16][17] However, questioning usually reveals that they are quite incapable of describing their feelings or appear confused by questions inquiring about specifics of feelings.[5]
According to Henry Krystal, individuals suffering from alexithymia think in an operative way and may appear to be superadjusted to reality. In psychotherapy, however, a cognitive disturbance becomes apparent as the patients tends to recount trivial, chronologically ordered actions, reactions, and events of daily life with monotonous detail.[18][19] In general, these individuals lack imagination, intuition, empathy, and drive-fulfillment fantasy, especially in relation to objects. Instead, they seem oriented toward things and even treat themselves as robots. These problems seriously limit their responsiveness to psychoanalytic psychotherapy; psychosomatic illness or substance abuse is frequently exacerbated should these individuals enter psychotherapy.[5]
A common misconception about alexithymia is that victims of this construct are totally unable to express emotions verbally and that they may even fail to acknowledge that they experience emotions. Even before coining the term, Sifneos (1967) noted patients often mentioned things like anxiety or depression. The distinguishing factor was their inability to elaborate beyond a few limited adjectives such as "happy" or "unhappy" when describing these feelings.[20] The core issue is that alexithymics have poorly differentiated emotions limiting their ability to distinguish and describe them to others.[1] This contributes to the sense of emotional detachment from themselves and difficulty connecting with others that is typical of the alexithymic's experience.
# Relational issues
According to Vanheule, Desmet and Meganck (2006) alexithymia creates interpersonal problems because these individuals avoid emotionally close relationships, or that if they do form relationships with others they tend to position themselves as either dependent or impersonal, "such that the relationship remains superficial."[21] Inadequate differentiation between self and other by alexithymic individuals has been observed by Blaustein & Tuber (1998) and Taylor et al (1997).[22]
In a study, a large group of alexithymic individuals completed the 64-item Inventory of Interpersonal problems (IIP-64) which screens for:[21]
- (a) Domineering/Controlling, indicating difficulties relinquishing control over others;
- (b) Vindictive/Self-Centered behaviour, which describes problems of hostile dominance and the tendency to fight with others;
- (c) Cold/Distant behaviour, which refers to low degrees of affection for and connection with others;
- (d) Socially Inhibited, which assesses the tendency to feel anxious and avoidant in the presence of others;
- (e) Non-Assertiveness, which measures problems in taking initiative in relation to others and coping with social challenges;
- (f) Overly Accommodating, which indicates an excess of friendly submissiveness;
- (g) Self-Sacrificing, which indicates a tendency to affiliate excessively; and
- (h) Intrusive/Needy, which describes problems with friendly dominance.
The study found that alexithymic individuals "had significantly higher scores on all IIP-64 subscales than did the nonclinical sample."[21]
Chaotic interpersonal relations have also been observed by Sifneos.[23] Due to the inherent difficulties identifying and describing emotional states in self and others, alexithymia also negatively affects relationship satisfaction between couples.[24]
# In medical and psychiatric illness
Alexithymia frequently co-occurs with other disorders, with a representative prevalence of 85% in autistic spectrum disorders,[25] 40% in posttraumatic stress disorder,[26] 63% in anorexia nervosa, 56% in bulimia,[27] 45% in major depressive disorder,[12] 34% in panic disorder,[28] and 50% in substance abusers.[29]
Research indicates that alexithymia overlaps with Asperger syndrome. In a 2004 study, Uta Frith reported an overlap and that at least half of the Asperger syndrome group obtained scores on the Toronto Alexithymia Scale (TAS-20) that would classify them as severely impaired.[30] Fitzgerald & Bellgrove pointed out that, "Like Alexithymia, Asperger’s syndrome is also characterised by core disturbances in speech and language and social relationships".[31] Hill & Berthoz agreed with Fitzgerald & Bellgrove (2006) and in response stated that "there is some form of overlap between alexithymia and ASDs". They also pointed to studies that revealed impaired Theory of Mind skill in alexithymia, neuroanatomical evidence pointing to a shared aetiology and similar social skills deficits.[32] The exact nature of the overlap is uncertain. Alexithymic traits in AS may be linked to depression or anxiety;[30] the mediating factors are unknown and it is possible that alexithymia predisposes to anxiety.[33]
Alexithymia involves higher risk of developing certain personality disorders,[34] and is correlated with particular illnesses, such as hypertension,[35]
inflammatory bowel disease,[36] functional dyspepsia,[37] sexual disorders,[38] substance use disorders,[39][40] and some anxiety disorders.[41] Alexithymia is further linked with psychosomatic disorders such as migraine headaches, lower back pain, irritable bowel syndrome, asthma, nausea, allergy, and fibromyalgia.[42]
An inability to modulate emotions is a possibility in explaining why some alexithymics are prone to discharge tension arising from unpleasant emotional states through impulsive acts or compulsive behaviors such as binge eating,[43] substance abuse,[44] perverse sexual behavior, or the self-starvation of anorexia nervosa.[43] The failure to regulate emotions cognitively might result in prolonged elevations of the autonomic nervous system (ANS) and neuroendocrine systems which can lead to somatic diseases.[42] Alexithymics also show a limited ability to experience positive emotions leading Krystal (1988) and Sifneos (1987) to describe many of these individuals as anhedonic.[2]
# Etiology
According to French psychoanalyst Joyce McDougall all infants are born unable to identify, organize, and speak about their emotional experiences (the word infans is from the Latin "not speaking"), and are "by reason of their immaturity inevitably alexithymic".[45] Based on this fact McDougall writes, "Might it not be supposed that the alexithymic part of an adult personality is an extremely arrested and infantile psychic structure?"[45]
It is unclear what causes alexithymia. Some neuropsychological studies indicate that alexithymia may be due to a disturbance to the right hemisphere of the brain, which is largely responsible for processing emotions.[46] Other studies show evidence that there may be an interhemispheric transfer deficit among alexithymics; that is, the emotional information from the right hemisphere is not being properly transferred to the language regions in the left hemisphere, as can be caused by a decreased corpus callosum, often present in psychiatric patients who have suffered severe childhood abuse.[47] In addition, another neuropsychological model suggests that alexithymia may be related to a dysfunction of the anterior cingulate cortex.[48] These studies have some shortcomings, however, and the empirical evidence about the causes of alexithymia remain inconclusive.[49]
Joyce McDougall objected to the strong focus by clinicians on neurophysiological at the expense of psychological explanations for the genesis and operation of alexithymia, and introduced the alternative term 'disaffectation' to stand for psychogenic alexithymia.[50] For McDougall, the disaffected individual had at some point "experienced overwhelming emotion that threatened to attack their sense of integrity and identity," to which they applied psychological defenses to pulverize and eject all emotional representations from consciousness.[51]
Although physiological effects are important to determine, the first language of an infant is nonverbal facial expressions. The mother's emotional state is important for determining how any child might develop. Neglect or indifference to varying changes in a child's facial expressions without proper feedback can promote an invalidation of the facial expressions manifested by the child. The parent's ability to reflect self-awareness to the child is another important factor. If the adult is incapable of recognizing and distinguishing emotional expressions in the child, it can influence the child's capacity to understand emotional expressions.[1] Moreover, if a parent responds with apathy, indifference, or anger to a child's natural range of emotions, the child will learn not to trust their feelings and over time may become conditioned to numb themselves to the experiences of their emotions. | https://www.wikidoc.org/index.php/Alexithymia | |
39ef064237ebdd70d712985340ace99af4065883 | wikidoc | Alglucerase | Alglucerase
# Overview
Alglucerase was a biopharmaceutical drug for the treatment of Gaucher's disease. It was a modified form of human β-glucocerebrosidase enzyme, where the non-reducing ends of the oligosaccharide chains have been terminated with mannose residues.
Ceredase is the trade name of a citrate buffered solution of alglucerase that was manufactured by Genzyme Corporation from human placental tissue. It is given intravenously in the treatment of Type 1 Gaucher's disease. This was the first drug appoved as an enzyme replacement therapy.
It was approved by the FDA in 1991. It has been withdrawn from the market due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly, since there is no concern about diseases being transmitted from the tissue used in harvesting, and are less expensive to manufacture (see imiglucerase). | Alglucerase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Alglucerase was a biopharmaceutical drug for the treatment of Gaucher's disease. It was a modified form of human β-glucocerebrosidase enzyme, where the non-reducing ends of the oligosaccharide chains have been terminated with mannose residues.[1]
Ceredase is the trade name of a citrate buffered solution of alglucerase that was manufactured by Genzyme Corporation from human placental tissue.[1] It is given intravenously in the treatment of Type 1 Gaucher's disease. This was the first drug appoved as an enzyme replacement therapy.[1]
It was approved by the FDA in 1991.[2] It has been withdrawn from the market[3][4] due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly, since there is no concern about diseases being transmitted from the tissue used in harvesting, and are less expensive to manufacture[1] (see imiglucerase). | https://www.wikidoc.org/index.php/Alglucerase | |
6954aab69a29c02b6fac8bb62dae8e039bc4b39b | wikidoc | Allelopathy | Allelopathy
Allelopathy means that one plant harms another with specific biomolecules. While it is sometimes considered the opposite of symbiosis, it is also a component of symbiosis.
Conceptually, biomolecules (specifically termed allelochemicals) produced by a plant are released into the environment and subsequently influence the growth and development of neighbouring plants. It is important to keep in mind that allelopathy involves the addition of a chemical compound or compounds (secondary metabolites) into the environment, while resource competition involves the removal or reduction of some factor or factors in the environment (such as nutrients, water, or light).
Although allelopathic science is a relatively new field of study, there exists convincing evidence that allelopathic interactions between plants play a crucial role in both natural and manipulated ecosystems. These interactions are undoubtedly an important factor in determining species distribution and abundance within some plant communities. Allelopathic interactions are also thought to be an important factor in the success of many invasive plants. For specific examples, see Spotted Knapweed, Garlic Mustard (Alliaria petiolata), and Nutsedge.
# Mechanisms of action
There are hundreds of secondary metabolites in the plant kingdom, and many are
known to be phytotoxic (Einhellig, 2002). Allelopathic effects of these compounds are often observed to occur early in the life cycle, causing inhibition of seed germination and/or seedling growth. The compounds exhibit a wide range of mechanisms of action, from effects on DNA (alkaloids), photosynthetic and mitochondrial function (quinones), phytohormone activity, ion uptake, and water balance (phenolics). Interpretations of mechanisms of action are complicated by the fact that individual compounds can have multiple phytotoxic effects (Einhellig, 2002).
## Demonstrating allelopathy in nature
The vast majority of allelopathy research attempts to focus on direct negative plant-plant interactions caused by allelochemicals. One of the greatest challenges of this approach is showing that the effect is direct, since allelochemicals can have indirect effects on plant species through interaction with biotic (e.g. mycorrhizae) and/or abiotic soil factors (e.g. nutrient availability; anon., 2002). In terrestrial systems, the soil plays an important role as the matrix through which potential allelochemicals pass. Both abiotic and microbial decomposition will have significant effects on the concentration of allelochemicals reaching other plants.
Proving that allelopathy is occurring is difficult for the reason that it is difficult to separate the effects of allelopathy from those due to resource competition (e.g., for space, light, water, nutrients or CO2). Controlled greenhouse studies that allow for examination of a single independently varying factor may be of little interest since the factors do not vary independently in nature. Willis (1985) required that six criteria be met, and even when maximally relaxed to just three, proving allelopathy is rarely if ever accomplished (Blum et al., 1999).
- pattern of inhibition of one species by another
- putative aggressor must produce a toxin
- known mode of release of this toxin
- toxin transport or accumulation in the environment
- toxin affects the metabolism of neighbouring plants
- observed pattern of inhibition cannot be solely explained by physical competition, relative fitness for the environment, or other factors
## Role of plant stress
Allelopathy also interacts with plant stress, because stressed source plants often release a greater array and concentration of allelochemicals, and stressed target
plants may be more susceptible to allelochemicals (Reigosa et al., 2002). Measurement of the effects of allelochemicals along stressor gradients should help to elucidate the relationship between allelopathy and stress.
# Examples of allelopathy
One of the most studied aspects of allelopathy is the role of allelopathy in agriculture. Current research is focused on the effects of weeds on crops, crops on weeds (Pheng et al. 1999), and crops on crops. This research furthers the possibility of using allelochemicals as growth regulators and natural herbicides (a number of them are either commercially available or in the process of large-scale manufacture) to promote sustainable agriculture. Leptospermone is a purported allelochemical in lemon bottlebrush (Callistemon citrinus). It was investigated as a possible commercial herbicide but was found to be too weak. However, a chemical analog of leptospermone was found to be an effective herbicide. The analog is mesotrione, tradename Callisto. It is sold to control broadleaf weeds in corn but also seems to be an effective control for crabgrass in lawns.
One of the most famous cases of purported allelopathy is in desert shrubs. Salvia leucophylla was one of the most widely known early examples because it was on the cover of the journal Science in 1964. Bare zones around the shrubs were hypothesized to be caused by volatile terpenes emitted by the shrubs. However, like many allelopathy studies, it was based on artificial lab experiments and unwarranted extrapolations to natural ecosystems. In 1970, Science published a study where caging the shrubs to exclude rodents and birds allowed grass to grow in the bare zones.
A detailed history of this interesting story can be found in Halsey 2004.
In other studies allelopathy has been demonstrated to play a crucial role in forests, influencing the composition of the vegetation growth, while also providing an explanation for the patterns of forest regeneration. The black walnut (Juglans nigra) produces juglone, an allelopathic substance that interferes with the growth of other plants. Juglone is somewhat selective, with certain species greatly affected by it and others not affected at all. Eucalyptus leaf litter and root exudates are allelopathic for certain soil microbes and plant species. The tree of heaven, (Ailanthus altissima) produces allelopathic substances in its roots that inhibit the growth of many plants. Furthermore, the pace of evaluating allelochemicals released from higher plants in nature has greatly accelerated, with promising results in field screening..
Many crop cultivars showed strong allelopathic properties, of which rice (Oryza sativa) has been most studied. Rice allelopathic activity is variety dependent and origin dependent, where Japonica rice shows greater allelopathic activity than Indica and Japonica-Indica hybrid. More recently, critical review on rice allelopathy and the possibility for weed management of Khanh et al.reported that allelopathic characteristics in rice are quantitatively inherited and several allelopathy-involved traits have been identified.
Plant species Garlic mustard is an invasive plant in North American temperate forests. Its success may be partly due to its excretion of a not yet identified allelochemical that interferes with mutualisms between native tree roots and their mycorrhizal fungi.
A study of kochia (Kochia scoparia) in North Toole County (NTC), Montana by two high school students showed that when kochia precedes spring wheat (Triticum aestivum), it reduces the spring wheat's performance. Among these effects are delayed emergence, decreased rate of growth, decreased final height, and decreased average vegetative dry weight of spring wheat plants. This small study was followed by another which further showed that kochia does seem to exhibit allelopathic effects on various crops grown in northern Montana. For their work in this area, Overcast & Cox were awarded a first place team prize at the International Science and Engineering Fair (ISEF) in 2001. | Allelopathy
Allelopathy means that one plant harms another with specific biomolecules. While it is sometimes considered the opposite of symbiosis, it is also a component of symbiosis.
Conceptually, biomolecules (specifically termed allelochemicals) produced by a plant are released into the environment and subsequently influence the growth and development of neighbouring plants. It is important to keep in mind that allelopathy involves the addition of a chemical compound or compounds (secondary metabolites) into the environment, while resource competition involves the removal or reduction of some factor or factors in the environment (such as nutrients, water, or light).
Although allelopathic science is a relatively new field of study, there exists convincing evidence that allelopathic interactions between plants play a crucial role in both natural and manipulated ecosystems. These interactions are undoubtedly an important factor in determining species distribution and abundance within some plant communities. Allelopathic interactions are also thought to be an important factor in the success of many invasive plants. For specific examples, see Spotted Knapweed, Garlic Mustard (Alliaria petiolata), and Nutsedge.
# Mechanisms of action
There are hundreds of secondary metabolites in the plant kingdom, and many are
known to be phytotoxic (Einhellig, 2002). Allelopathic effects of these compounds are often observed to occur early in the life cycle, causing inhibition of seed germination and/or seedling growth. The compounds exhibit a wide range of mechanisms of action, from effects on DNA (alkaloids), photosynthetic and mitochondrial function (quinones), phytohormone activity, ion uptake, and water balance (phenolics). Interpretations of mechanisms of action are complicated by the fact that individual compounds can have multiple phytotoxic effects (Einhellig, 2002).
## Demonstrating allelopathy in nature
The vast majority of allelopathy research attempts to focus on direct negative plant-plant interactions caused by allelochemicals. One of the greatest challenges of this approach is showing that the effect is direct, since allelochemicals can have indirect effects on plant species through interaction with biotic (e.g. mycorrhizae) and/or abiotic soil factors (e.g. nutrient availability; anon., 2002). In terrestrial systems, the soil plays an important role as the matrix through which potential allelochemicals pass. Both abiotic and microbial decomposition will have significant effects on the concentration of allelochemicals reaching other plants.
Proving that allelopathy is occurring is difficult for the reason that it is difficult to separate the effects of allelopathy from those due to resource competition (e.g., for space, light, water, nutrients or CO2). Controlled greenhouse studies that allow for examination of a single independently varying factor may be of little interest since the factors do not vary independently in nature. Willis (1985) required that six criteria be met, and even when maximally relaxed to just three, proving allelopathy is rarely if ever accomplished (Blum et al., 1999).
- pattern of inhibition of one species by another
- putative aggressor must produce a toxin
- known mode of release of this toxin
- toxin transport or accumulation in the environment
- toxin affects the metabolism of neighbouring plants
- observed pattern of inhibition cannot be solely explained by physical competition, relative fitness for the environment, or other factors
## Role of plant stress
Allelopathy also interacts with plant stress, because stressed source plants often release a greater array and concentration of allelochemicals, and stressed target
plants may be more susceptible to allelochemicals (Reigosa et al., 2002). Measurement of the effects of allelochemicals along stressor gradients should help to elucidate the relationship between allelopathy and stress.
# Examples of allelopathy
One of the most studied aspects of allelopathy is the role of allelopathy in agriculture. Current research is focused on the effects of weeds on crops, crops on weeds (Pheng et al. 1999), and crops on crops. This research furthers the possibility of using allelochemicals as growth regulators and natural herbicides (a number of them are either commercially available or in the process of large-scale manufacture) to promote sustainable agriculture. Leptospermone is a purported allelochemical in lemon bottlebrush (Callistemon citrinus). It was investigated as a possible commercial herbicide but was found to be too weak. However, a chemical analog of leptospermone was found to be an effective herbicide. The analog is mesotrione, tradename Callisto.[1] It is sold to control broadleaf weeds in corn but also seems to be an effective control for crabgrass in lawns.
One of the most famous cases of purported allelopathy is in desert shrubs. Salvia leucophylla was one of the most widely known early examples because it was on the cover of the journal Science in 1964.[2] Bare zones around the shrubs were hypothesized to be caused by volatile terpenes emitted by the shrubs. However, like many allelopathy studies, it was based on artificial lab experiments and unwarranted extrapolations to natural ecosystems. In 1970, Science published a study where caging the shrubs to exclude rodents and birds allowed grass to grow in the bare zones.[3]
A detailed history of this interesting story can be found in Halsey 2004.[4]
In other studies allelopathy has been demonstrated to play a crucial role in forests, influencing the composition of the vegetation growth, while also providing an explanation for the patterns of forest regeneration. The black walnut (Juglans nigra) produces juglone, an allelopathic substance that interferes with the growth of other plants. Juglone is somewhat selective, with certain species greatly affected by it and others not affected at all. Eucalyptus leaf litter and root exudates are allelopathic for certain soil microbes and plant species. The tree of heaven, (Ailanthus altissima) produces allelopathic substances in its roots that inhibit the growth of many plants. Furthermore, the pace of evaluating allelochemicals released from higher plants in nature has greatly accelerated, with promising results in field screening.[5].
Many crop cultivars showed strong allelopathic properties, of which rice (Oryza sativa) has been most studied. Rice allelopathic activity is variety dependent and origin dependent, where Japonica rice shows greater allelopathic activity than Indica and Japonica-Indica hybrid. More recently, critical review on rice allelopathy and the possibility for weed management of Khanh et al[6].reported that allelopathic characteristics in rice are quantitatively inherited and several allelopathy-involved traits have been identified.
Plant species Garlic mustard is an invasive plant in North American temperate forests. Its success may be partly due to its excretion of a not yet identified allelochemical that interferes with mutualisms between native tree roots and their mycorrhizal fungi.[7]
A study of kochia (Kochia scoparia) in North Toole County (NTC), Montana by two high school students showed that when kochia precedes spring wheat (Triticum aestivum), it reduces the spring wheat's performance. Among these effects are delayed emergence, decreased rate of growth, decreased final height, and decreased average vegetative dry weight of spring wheat plants.[8] This small study was followed by another which further showed that kochia does seem to exhibit allelopathic effects on various crops grown in northern Montana. [9] For their work in this area, Overcast & Cox were awarded a first place team prize at the International Science and Engineering Fair (ISEF) in 2001. | https://www.wikidoc.org/index.php/Allelopathy | |
bcc52758ef8fba7f45366a09dbc2e53cb536c097 | wikidoc | Almotriptan | Almotriptan
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Almotriptan is a 5HT1B/1D receptor agonist that is FDA approved for the treatment of migraine attacks in adults with a history of migraine with or without aura and migraine headache pain in adolescents age 12 to 17 years with a history of migraine with or without aura, and who have migraine attacks usually lasting 4 hours or more. Common adverse reactions include dry mouth, paresthesia, dizziness, somnolence, headache, paresthesia, nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- AXERT® (almotriptan malate) is indicated for the acute treatment of migraine attacks in patients with a history of migraine with or without aura.
- The recommended dose of AXERT® (almotriptan malate) in adults is 6.25 mg to 12.5 mg, with the 12.5 mg dose tending to be a more effective dose in adults. As individuals may vary in their response to different doses of AXERT®, the choice of dose should be made on an individual basis.
- If the headache is relieved after the initial AXERT® dose but returns, the dose may be repeated after 2 hours. The effectiveness of a second dose has not been established in placebo-controlled trials. The maximum daily dose should not exceed 25 mg. The safety of treating an average of more than four migraines in a 30-day period has not been established.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Almotriptan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Almotriptan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- AXERT® is indicated for the acute treatment of migraine headache pain in patients with a history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated).
- The recommended dose of AXERT® (almotriptan malate) in adolescents age 12 to 17 years is 6.25 mg to 12.5 mg, with the 12.5 mg dose tending to be a more effective dose in adults. As individuals may vary in their response to different doses of AXERT®, the choice of dose should be made on an individual basis.
- If the headache is relieved after the initial AXERT® dose but returns, the dose may be repeated after 2 hours. The effectiveness of a second dose has not been established in placebo-controlled trials. The maximum daily dose should not exceed 25 mg. The safety of treating an average of more than four migraines in a 30-day period has not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Almotriptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Almotriptan in pediatric patients.
# Contraindications
- Ischemic or Vasospastic Coronary Artery Disease, or Other Significant Underlying Cardiovascular Disease
- Do not use AXERT® (almotriptan malate) in patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or in patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease.
- Cerebrovascular Syndromes
- Do not use AXERT® in patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks.
- Peripheral Vascular Disease
- Do not use AXERT® in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease.
- Uncontrolled Hypertension
- Because AXERT® may increase blood pressure, do not use AXERT® in patients with uncontrolled hypertension.
- Ergotamine-Containing and Ergot-Type Medications
- Do not use AXERT® and ergotamine-containing or ergot-derived medications like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each other.
- Concomitant Use With 5-HT1 Agonists (e.g., Triptans)
- AXERT® and other 5-HT1 agonists (e.g., triptans) should not be administered within 24 hours of each other.
- Hemiplegic or Basilar Migraine
- Do not use AXERT® in patients with hemiplegic or basilar migraine.
- Hypersensitivity
- AXERT® is contraindicated in patients with known hypersensitivity to almotriptan or any of its inactive ingredients.
# Warnings
### Precautions
- - Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events
- Cardiac Events and Fatalities with 5-HT1 Agonists
- Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of AXERT® (almotriptan malate). Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other triptans. Considering the extent of use of triptans in patients with migraine, the incidence of these events is extremely low.
- AXERT® can cause coronary vasospasm; at least one of these events occurred in a patient with no cardiac history and with documented absence of coronary artery disease. Because of the close proximity of the events to use of AXERT®, a causal relationship cannot be excluded. Patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of coronary artery disease (CAD) or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur.
- Premarketing Experience with AXERT® in Adults
- Among the 3865 subjects/patients who received AXERT® in premarketing clinical trials, one patient was hospitalized for observation after a scheduled electrocardiogram (ECG) was found to be abnormal (negative T-waves on the left leads) 48 hours after taking a single 6.25 mg dose of almotriptan. The patient, a 48-year-old female, had previously taken 3 other doses for earlier migraine attacks. Myocardial enzymes at the time of the abnormal ECG were normal. The patient was diagnosed as having had myocardial ischemia and that she had a family history of coronary disease. An ECG performed 2 days later was normal, as was a follow-up coronary angiography. The patient recovered without incident.
- Postmarketing Experience with AXERT® in Adults
- Serious cardiovascular events have been reported in association with the use of AXERT®. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to definitively determine the proportion of the reported cases that were actually caused by almotriptan or to reliably assess causation in individual cases.
- Patients with Documented Coronary Artery Disease
- Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, AXERT® should not be given to patients with documented ischemic or vasospastic coronary artery disease.
- Patients with Risk Factors for CAD
- It is strongly recommended that AXERT® not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, AXERT® should not be administered.
- For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of AXERT® take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received AXERT®. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an ECG during the interval immediately following AXERT®, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of AXERT® and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use AXERT®.
- The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to AXERT®. The ability of cardiac diagnostic procedures to detect all cardiovascular diseases or predisposition to coronary artery vasospasm is modest at best. Cardiovascular events associated with triptan treatment have occurred in patients with no cardiac history and with documented absence of coronary artery disease.
- Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw
- As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with AXERT®. Because 5-HT1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms occur. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.
- Cerebrovascular Events and Fatalities
- Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with other triptans and some events have resulted in fatalities. In a number of cases, it appeared possible that the cerebrovascular events were primary, the triptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and transient ischemic attack).
- Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia
- Triptans, including AXERT®, may cause vasospastic reactions other than coronary artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with abdominal pain and bloody diarrhea. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of triptans. Visual disorders may also be part of a migraine attack. Patients who experience symptoms or signs suggestive of decreased arterial flow following the use of any triptan, such as ischemic bowel syndrome or Raynaud's syndrome, are candidates for further evaluation.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome may occur with triptans, including AXERT®, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with AXERT® and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Medication Overuse Headache
- Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
- Increases in Blood Pressure
- As with other triptans, significant elevations in systemic blood pressure have been reported on rare occasions with AXERT® use in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. AXERT® is contraindicated in patients with uncontrolled hypertension. In normotensive healthy subjects and patients with hypertension controlled by medication, small, but clinically insignificant, increases in mean systolic (0.21 and 4.87 mm Hg, respectively) and diastolic (1.35 and 0.26 mm Hg, respectively) blood pressure relative to placebo were seen over the first 4 hours after oral administration of 12.5 mg of almotriptan.
- An 18% increase in mean pulmonary artery pressure was seen following dosing with another triptan in a study evaluating subjects undergoing cardiac catheterization.
- Hypersensitivity to Sulfonamides
- Caution should be exercised when prescribing AXERT® to patients with known hypersensitivity to sulfonamides. The chemical structure of almotriptan contains a sulfonyl group, which is structurally different from a sulfonamide. Cross-sensitivity to almotriptan in patients allergic to sulfonamides has not been systematically evaluated.
- Impaired Hepatic or Renal Function
- AXERT® should be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as those with impaired hepatic or renal function.
- Binding to Melanin-Containing Tissues
- When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled almotriptan, the elimination half-life of radioactivity from the eye was 22 days. This finding suggests that almotriptan and/or its metabolites may bind to melanin in the eye. Because almotriptan could accumulate in melanin-rich tissues over time, there is the possibility that it could cause toxicity in these tissues with extended use. However, no adverse retinal effects related to treatment with almotriptan were noted in a 52-week toxicity study in dogs given up to 12.5 mg/kg/day (resulting in exposure to parent drug approximately 20 times that in humans receiving the maximum recommended human dose of 25 mg/day). Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.
- Corneal Opacities
- Three male dogs (out of a total of 14 treated) in a 52-week toxicity study of oral almotriptan developed slight corneal opacities that were noted after 51 weeks, but not after 25 weeks of treatment. The doses at which this occurred were 2, 5, and 12.5 mg/kg/day. The opacity reversed after a 4-week drug-free period in the affected dog treated with the highest dose. Systemic exposure (plasma AUC) to parent drug at 2 mg/kg/day was approximately 2.5 times the exposure in humans receiving the maximum recommended human daily dose of 25 mg. A no-effect dose was not established.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events were assessed in controlled clinical trials that included 1840 adult patients who received one or two doses of AXERT® and 386 adult patients who received placebo. The most common adverse reactions during treatment with AXERT® were nausea, somnolence, headache, paresthesia, and dry mouth. In long-term open-label studies where patients were allowed to treat multiple attacks for up to 1 year, 5% (63 out of 1347 patients) withdrew due to adverse experiences.
- Adverse events were assessed in controlled clinical trials that included 362 adolescent patients who received AXERT® and 172 adolescent patients who received placebo. The most common adverse reactions during treatment with AXERT® were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. In a long-term, open-label study where patients were allowed to treat multiple attacks for up to 1 year, 2% (10 out of 420 adolescent patients) withdrew due to adverse events.
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- Adults
- Table 1 lists the adverse events that occurred in at least 1% of the adult patients treated with AXERT®, and at an incidence greater than in patients treated with placebo, regardless of drug relationship.
- The incidence of adverse events in controlled clinical trials was not affected by gender, weight, age, presence of aura, or use of prophylactic medications or oral contraceptives. There were insufficient data to assess the effect of race on the incidence of adverse events.
- Adolescents
- Table 2 lists the adverse reactions reported by 1% or more of AXERT®-treated adolescents age 12 to 17 years in 1 placebo-controlled, double-blind clinical trial.
- In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. The reports include adverse reactions in 5 adult controlled studies and 1 adolescent controlled study. Variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used AXERT® and reported a reaction divided by the total number of patients exposed to AXERT® (n=3047, all doses). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are those occurring in 1/100 or more patients, infrequent adverse reactions are those occurring in fewer than 1/100 to 1/1000 patients, and rare adverse reactions are those occurring in fewer than 1/1000 patients.
Frequent: Headache. Infrequent: Abdominal cramp or pain, Asthenia, Chills, Back pain, Chest pain, Neck pain, Fatigue, and Rigid neck. Rare: Fever and Photosensitivity reaction.
Infrequent: Vasodilation, Palpitations, and Tachycardia. Rare: Hypertension and Syncope.
Infrequent: Diarrhea, Vomiting, Dyspepsia, Gastroenteritis, and Increased thirst. Rare: Colitis, Gastritis, Esophageal reflux, and Increased salivation.
Infrequent: Hyperglycemia and Increased serum creatine phosphokinase. Rare: Increased gamma glutamyl transpeptidase and Hypercholesteremia.
Infrequent: Myalgia. Rare: Arthralgia, Arthritis, Myopathy, and Muscle weakness.
Frequent: Dizziness and Somnolence. Infrequent: Tremor, Vertigo, Anxiety, Hypoesthesia, Restlessness, CNS stimulation, and Shakiness. Rare: Change in dreams, Impaired concentration, Abnormal coordination, Depressive symptoms, Euphoria, Hyperreflexia, Hypertonia, Nervousness, Neuropathy, Nightmares, Nystagmus, and Insomnia.
Infrequent: Pharyngitis, Rhinitis, Dyspnea, Laryngismus, Sinusitis, and Bronchitis. Rare: Hyperventilation, Laryngitis, Sneezing, and Epistaxis.
Infrequent: Diaphoresis, Pruritus, and Rash. Rare: Dermatitis and Erythema.
Infrequent: Ear pain and Tinnitus. Rare: Diplopia, Dry eyes, Eye pain, Otitis media, Parosmia, Scotoma, Conjunctivitis, Eye irritation, Hyperacusis, and Taste alteration.
Infrequent: Dysmenorrhea.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of AXERT®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions (including angioedema, anaphylactic reactions and anaphylactic shock)
Confusional state, Restlessness
Hemiplegia, Hypoesthesia, Seizures
Blepharospasm, Visual impairment, Vision blurred
Vertigo
Acute myocardial infarction, Coronary artery vasospasm, Angina pectoris, Tachycardia
Abdominal discomfort, Abdominal pain, Abdominal pain upper, Colitis, Hypoesthesia oral, Swollen tongue
Cold sweat, Erythema, Hyperhidrosis
Arthralgia, Myalgia, Pain in extremity
Breast pain
Malaise, Peripheral coldness.
# Drug Interactions
- Ergot-Containing Drugs
- These drugs have been reported to cause prolonged vasospastic reactions. Because, in theory, vasospastic effects may be additive, ergotamine-containing or ergot-type medications (like dihydroergotamine, ergotamine tartrate, or methysergide) and AXERT® (almotriptan malate) should not be used within 24 hours of each other.
- 5-HT1 Agonists (e.g., Triptans)
- Concomitant use of other 5-HT1 agonists (e.g., triptans) within 24 hours of treatment with AXERT® is contraindicated.
- Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors
- Cases of life-threatening serotonin syndrome have been reported during combined use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Ketoconazole and Other Potent CYP3A4 Inhibitors
- Co-administration of almotriptan and oral ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used concomitantly with other potent CYP3A4 inhibitors.
- In patients concomitantly using potent CYP3A4 inhibitors, the recommended starting dose of AXERT® is 6.25 mg. The maximum daily dose should not exceed 12.5 mg within a 24-hour period. Concomitant use of AXERT® and potent CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In animal studies, almotriptan produced developmental toxicity (increased embryolethality and fetal skeletal variations, and decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, AXERT® (almotriptan malate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to pregnant rats throughout the period of organogenesis, increased incidences of fetal skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or greater and an increase in embryolethality was seen at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a body surface area (mg/m2) basis. Similar studies in pregnant rabbits conducted with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m2 basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats throughout the periods of gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. The no-effect dose in this study (100 mg/kg/day) is 40 times the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Almotriptan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Almotriptan during labor and delivery.
### Nursing Mothers
- It is not known whether almotriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AXERT® is administered to a nursing woman. Levels of almotriptan in rat milk were up to 7 times higher than in rat plasma.
### Pediatric Use
- Safety and efficacy of AXERT® in pediatric patients under the age of 12 years have not been established. The pharmacokinetics, efficacy, and safety of AXERT® have been evaluated in adolescent patients, age 12 to 17 years.
- In a clinical study, AXERT® 6.25 mg and 12.5 mg were found to be effective for the relief of migraine headache pain in adolescent patients age 12 to 17 years. Efficacy on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. The most common adverse reactions (incidence of ≥1%) associated with AXERT® treatment were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. The safety and tolerability profile of AXERT® treatment in adolescents is similar to the profile observed in adults.
- Postmarketing experience with other triptans include a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.
### Geriatic Use
- Clinical studies of AXERT® did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Clearance of almotriptan was lower in elderly volunteers than in younger individuals, but there were no observed differences in the safety and tolerability between the two populations. In general, dose selection for an elderly patient should be cautious, usually starting at the low dose, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The recommended dose of AXERT® for elderly patients with normal renal function for their age is the same as that recommended for younger adults.
### Gender
There is no FDA guidance on the use of Almotriptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Almotriptan with respect to specific racial populations.
### Renal Impairment
- The recommended starting dose of AXERT® in patients with severe renal impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period.
### Hepatic Impairment
- The recommended starting dose of AXERT® in patients with hepatic impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Almotriptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Almotriptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Almotriptan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Almotriptan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Patients and volunteers receiving single oral doses of 100 to 150 mg of almotriptan did not experience significant adverse events. Six additional normal volunteers received single oral doses of 200 mg without serious adverse events. During clinical trials with AXERT® (almotriptan malate), one patient ingested 62.5 mg in a 5-hour period and another patient ingested 100 mg in a 38-hour period. Neither patient experienced adverse reactions.
- Based on the pharmacology of triptans, hypertension or other more serious cardiovascular symptoms could occur after overdosage.
### Management
- There is no specific antidote to AXERT®. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.
- Clinical and electrocardiographic monitoring should be continued for at least 20 hours even if clinical symptoms are not observed.
- It is unknown what effect hemodialysis or peritoneal dialysis has on plasma concentrations of almotriptan.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Almotriptan in the drug label.
# Pharmacology
## Mechanism of Action
- Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors. Almotriptan has weak affinity for 5-HT1A and 5-HT7 receptors, but has no significant affinity or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT6; alpha or beta adrenergic; adenosine (A1, A2); angiotensin (AT1, AT2); dopamine (D1, D2); endothelin (ETA, ETB); or tachykinin (NK1, NK2, NK3) binding sites.
## Structure
- AXERT® (almotriptan malate) Tablets contain almotriptan malate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist. Almotriptan malate is chemically designated as 1--1H-indol-5-yl]methyl]sulfonyl]pyrrolidine (±)-hydroxybutanedioate (1:1) and its structural formula is:
- Its empirical formula is C17H25N3O2S-C4H6O5, representing a molecular weight of 469.56. Almotriptan is a white to slightly yellow crystalline powder that is soluble in water. AXERT® for oral administration contains almotriptan malate equivalent to 6.25 or 12.5 mg of almotriptan. Each compressed tablet contains the following inactive ingredients: carnauba wax, cellulose, FD&C Blue No. 2 (12.5 mg only), hypromellose, iron oxide (6.25 mg only), mannitol, polyethylene glycol, povidone, propylene glycol, sodium starch glycolate, sodium stearyl fumarate and titanium dioxide.
## Pharmacodynamics
- Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system. The therapeutic activity of almotriptan in migraine can most likely be attributed to agonist effects at 5-HT1B/1D receptors on the extracerebral, intracranial blood vessels that become dilated during a migraine attack and on nerve terminals in the trigeminal system. Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathways.
## Pharmacokinetics
- Absorption
- The absolute bioavailability of almotriptan is about 70%, with peak plasma levels occurring 1 to 3 hours after administration; food does not affect pharmacokinetics.
- Distribution
- Almotriptan is minimally protein bound (approximately 35%) and the mean apparent volume of distribution is approximately 180 to 200 liters.
- Metabolism
- Almotriptan is metabolized by two major and one minor pathways. Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and cytochrome P450-mediated oxidation (approximately 12% of the dose) are the major routes of metabolism, while flavin monooxygenase is the minor route. MAO-A is responsible for the formation of the indoleacetic acid metabolite, whereas cytochrome P450 (3A4 and 2D6) catalyzes the hydroxylation of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde dehydrogenase to the gamma-aminobutyric acid derivative. Both metabolites are inactive.
- Excretion
- Almotriptan has a mean half-life of 3 to 4 hours. Almotriptan is eliminated primarily by renal excretion (about 75% of the oral dose), with approximately 40% of an administered dose excreted unchanged in urine. Renal clearance exceeds the glomerular filtration rate by approximately 3-fold, indicating an active mechanism. Approximately 13% of the administered dose is excreted via feces, both unchanged and metabolized.
- Drug-Drug Interactions
- All drug interaction studies were performed in healthy volunteers using a single 12.5 mg dose of almotriptan and multiple doses of the other drug.
- Monoamine Oxidase Inhibitors
- Co-administration of almotriptan and moclobemide (150 mg twice daily for 8 days) resulted in a 27% decrease in almotriptan clearance and an increase in Cmax of approximately 6%. No dose adjustment is necessary.
- Propranolol
- Co-administration of almotriptan and propranolol (80 mg twice daily for 7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.
- Fluoxetine
- Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased 18%. This difference is not clinically significant.
- Verapamil
- Co-administration of almotriptan and verapamil (120 mg sustained-release tablets twice daily for 7 days), an inhibitor of CYP3A4, resulted in a 20% increase in the area under the plasma concentration-time curve, and in a 24% increase in maximal plasma concentrations of almotriptan. Neither of these changes is clinically significant. No dose adjustment is necessary.
- Ketoconazole and other Potent CYP3A4 Inhibitors
- Co-administration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used with other potent CYP3A4 inhibitors.
- Special Populations
- Geriatric
- Renal and total clearance, and amount of drug excreted in the urine, were lower in elderly healthy volunteers (age 65 to 76 years) than in younger healthy volunteers (age 19 to 34 years), resulting in longer terminal half-life (3.7 hours vs. 3.2 hours) and a 25% higher area under the plasma concentration-time curve in the elderly subjects. The differences, however, do not appear to be clinically significant.
- Pediatric
- A pharmacokinetics study of almotriptan was conducted in adolescents (12 to 17 years) and adults (18 to 55 years) with or without a history of migraine. No differences were observed in the rate or extent of absorption of almotriptan in adolescents compared with adults.
- Gender
- No significant gender differences were observed in pharmacokinetic parameters.
- Race
- No significant differences were observed in pharmacokinetic parameters between Caucasian and African-American volunteers.
- Hepatic Impairment
- The pharmacokinetics of almotriptan have not been assessed in patients with hepatic impairment. Based on the known mechanisms of clearance of almotriptan, the maximum decrease expected in almotriptan clearance due to hepatic impairment would be 60%.
- Renal Impairment
- The clearance of almotriptan was approximately 65% lower in patients with severe renal impairment (Cl/F=19.8 L/hour; creatinine clearance between 10 and 30 mL/min) and approximately 40% lower in patients with moderate renal impairment (Cl/F=34.2 L/hour; creatinine clearance between 31 and 71 mL/min) than in healthy volunteers (Cl/F=57 L/hour). Maximal plasma concentrations of almotriptan increased by approximately 80% in these patients.
## Nonclinical Toxicology
- Carcinogenesis
- Almotriptan was administered to mice and rats for up to 103–104 weeks at oral doses up to 250 mg/kg/day and 75 mg/kg/day, respectively. These doses were associated with plasma exposures (AUC) to parent drug that were approximately 40 and 80 times, in mice and rats respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 25 mg/day. Because of high mortality rates in both studies, which reached statistical significance in high-dose female mice, all female rats, all male mice, and high-dose female mice were terminated between weeks 96 and 98. There was no increase in tumors related to almotriptan administration.
- Mutagenesis
- Almotriptan was not mutagenic in two in vitro gene mutation assays, the Ames test, and the mouse lymphoma tk assay. Almotriptan was not clastogenic in an in vivo mouse micronucleus assay.
- Impairment of Fertility
- When male and female rats received almotriptan (25, 100, or 400 mg/kg/day) orally prior to and during mating and gestation, prolongation of the estrous cycle was observed at the mid-dose and greater, and fertility was impaired at the highest dose. Subsequent mating of treated with untreated animals indicated that the decrease in fertility was due to an effect on females. The no-effect dose for reproductive toxicity in rats (25 mg/kg/day) is approximately 10 times the MRHD on a mg/m2 basis.
# Clinical Studies
- Adults
- The efficacy of AXERT® (almotriptan malate) was established in three multi-center, randomized, double-blind, placebo-controlled European trials. Patients enrolled in these studies were primarily female (86%) and Caucasian (more than 98%), with a mean age of 41 years (range of 18 to 72). Patients were instructed to treat a moderate to severe migraine headache. Two hours after taking one dose of study medication, patients evaluated their headache pain. If the pain had not decreased in severity to mild or no pain, the patient was allowed to take an escape medication. If the pain had decreased to mild or no pain at 2 hours but subsequently increased in severity between 2 and 24 hours, it was considered a relapse and the patient was instructed to take a second dose of study medication. Associated symptoms of nausea, vomiting, photophobia, and phonophobia were also evaluated.
- In these studies, the percentage of patients achieving a response (mild or no pain) 2 hours after treatment was significantly greater in patients who received either AXERT® 6.25 mg or 12.5 mg, compared with those who received placebo. A higher percentage of patients reported pain relief after treatment with the 12.5 mg dose than with the 6.25 mg dose. Doses greater than 12.5 mg did not lead to a significantly better response. These results are summarized in Table 3.
- The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT® in adults is shown in Figure 1.
- This Kaplan-Meier plot is based on data obtained in the three placebo-controlled clinical trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not achieving pain relief by 2 hours were censored at 2 hours.
- For patients with migraine-associated photophobia, phonophobia, nausea, and vomiting at baseline, there was a decreased incidence of these symptoms following administration of AXERT® compared with placebo.
- Two to 24 hours following the initial dose of study medication, patients were allowed to take an escape medication or a second dose of study medication for pain response. The estimated probability of patients taking escape medication or a second dose of study medication over the 24 hours following the initial dose of study medication is shown in Figure 2.
- This Kaplan-Meier plot is based on data obtained in the three placebo-controlled trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not using additional treatment were censored at 24 hours. Remedication was not allowed within 2 hours after the initial dose of AXERT®.
- The efficacy of AXERT® was unaffected by the presence of aura; by gender, weight, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, and tricyclic antidepressants); or oral contraceptives. There were insufficient data to assess the effect of race on efficacy.
- The efficacy of AXERT® in adolescent patients age 12 to 17 years was evaluated in a double-blind, randomized, placebo-controlled study. Patients enrolled in that study had at least a 1-year history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated). Patients enrolled in the study were primarily females (60%) and Caucasian (75%), while 15% of patients were black, and 10% were of other races. Patients were instructed to treat a moderate to severe migraine headache. Two hours after taking one dose of study medication, patients evaluated their headache pain. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated.
- In this study, the percentage of patients achieving a pain relief response (mild or no pain) 2 hours after treatment was statistically significantly greater in patients who received AXERT® 6.25 mg or 12.5 mg compared with those who received placebo. There was no additional benefit on pain relief provided by the 12.5 mg dose. The 2-hour pain relief results are summarized in Table 4.
- The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT® in adolescents age 12 to 17 years is shown in Figure 3.
- The prevalence of the migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not significantly different between patients who received AXERT® 6.25 mg or 12.5 mg and those who received placebo.
# How Supplied
- AXERT® (almotriptan malate) Tablets are available as follows:
- 6.25 mg: White, coated, circular, biconvex tablets with red code imprint "2080."
- Unit Dose (aluminum blister pack)
- 6 tablets NDC 50458-211-01
- 12.5 mg: White, coated, circular, biconvex tablets with blue stylized imprint "A."
- Unit Dose (aluminum blister pack)
- 12 tablets NDC 50458-210-01
- Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F).
## Storage
There is limited information regarding Almotriptan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Drug Interactions
- Advise patients to talk with their physician or pharmacist before taking any new medicines, including prescription and non-prescription drugs and supplements.
- Hypersensitivity
- Inform patients to tell their physician if they develop a rash, itching, or breathing difficulties after taking AXERT®.
- Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, Other Vasospasm-Related Events, and Cerebrovascular Events
- Inform patients that AXERT® (almotriptan malate) may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, or slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Apprise the patient of the importance of this follow-up.
- Serotonin Syndrome
- Caution patients about the risk of serotonin syndrome with the use of AXERT® or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Medication Overuse Headache
- Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).
- Pregnancy
- Advise patients to notify their physician if they become pregnant during treatment or intend to become pregnant.
- Nursing Mothers
- Advise patients to notify their physician if they are breastfeeding or plan to breastfeed.
- Ability to Operate Machinery or Vehicles
- Counsel patients that AXERT® may cause dizziness, somnolence, visual disturbances, and other CNS symptoms that can interfere with driving or operating machinery. Accordingly, advise the patient not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience with AXERT® to gauge whether it affects their mental or visual performance adversely.
# Precautions with Alcohol
- Alcohol-Almotriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- AXERT®
# Look-Alike Drug Names
- Axert® — Antivert®
# Drug Shortage Status
# Price | Almotriptan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Almotriptan is a 5HT1B/1D receptor agonist that is FDA approved for the treatment of migraine attacks in adults with a history of migraine with or without aura and migraine headache pain in adolescents age 12 to 17 years with a history of migraine with or without aura, and who have migraine attacks usually lasting 4 hours or more. Common adverse reactions include dry mouth, paresthesia, dizziness, somnolence, headache, paresthesia, nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- AXERT® (almotriptan malate) is indicated for the acute treatment of migraine attacks in patients with a history of migraine with or without aura.
- The recommended dose of AXERT® (almotriptan malate) in adults is 6.25 mg to 12.5 mg, with the 12.5 mg dose tending to be a more effective dose in adults. As individuals may vary in their response to different doses of AXERT®, the choice of dose should be made on an individual basis.
- If the headache is relieved after the initial AXERT® dose but returns, the dose may be repeated after 2 hours. The effectiveness of a second dose has not been established in placebo-controlled trials. The maximum daily dose should not exceed 25 mg. The safety of treating an average of more than four migraines in a 30-day period has not been established.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Almotriptan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Almotriptan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- AXERT® is indicated for the acute treatment of migraine headache pain in patients with a history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated).
- The recommended dose of AXERT® (almotriptan malate) in adolescents age 12 to 17 years is 6.25 mg to 12.5 mg, with the 12.5 mg dose tending to be a more effective dose in adults. As individuals may vary in their response to different doses of AXERT®, the choice of dose should be made on an individual basis.
- If the headache is relieved after the initial AXERT® dose but returns, the dose may be repeated after 2 hours. The effectiveness of a second dose has not been established in placebo-controlled trials. The maximum daily dose should not exceed 25 mg. The safety of treating an average of more than four migraines in a 30-day period has not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Almotriptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Almotriptan in pediatric patients.
# Contraindications
- Ischemic or Vasospastic Coronary Artery Disease, or Other Significant Underlying Cardiovascular Disease
- Do not use AXERT® (almotriptan malate) in patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or in patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease.
- Cerebrovascular Syndromes
- Do not use AXERT® in patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks.
- Peripheral Vascular Disease
- Do not use AXERT® in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease.
- Uncontrolled Hypertension
- Because AXERT® may increase blood pressure, do not use AXERT® in patients with uncontrolled hypertension.
- Ergotamine-Containing and Ergot-Type Medications
- Do not use AXERT® and ergotamine-containing or ergot-derived medications like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each other.
- Concomitant Use With 5-HT1 Agonists (e.g., Triptans)
- AXERT® and other 5-HT1 agonists (e.g., triptans) should not be administered within 24 hours of each other.
- Hemiplegic or Basilar Migraine
- Do not use AXERT® in patients with hemiplegic or basilar migraine.
- Hypersensitivity
- AXERT® is contraindicated in patients with known hypersensitivity to almotriptan or any of its inactive ingredients.
# Warnings
### Precautions
- * Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events
- Cardiac Events and Fatalities with 5-HT1 Agonists
- Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of AXERT® (almotriptan malate). Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other triptans. Considering the extent of use of triptans in patients with migraine, the incidence of these events is extremely low.
- AXERT® can cause coronary vasospasm; at least one of these events occurred in a patient with no cardiac history and with documented absence of coronary artery disease. Because of the close proximity of the events to use of AXERT®, a causal relationship cannot be excluded. Patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of coronary artery disease (CAD) or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur.
- Premarketing Experience with AXERT® in Adults
- Among the 3865 subjects/patients who received AXERT® in premarketing clinical trials, one patient was hospitalized for observation after a scheduled electrocardiogram (ECG) was found to be abnormal (negative T-waves on the left leads) 48 hours after taking a single 6.25 mg dose of almotriptan. The patient, a 48-year-old female, had previously taken 3 other doses for earlier migraine attacks. Myocardial enzymes at the time of the abnormal ECG were normal. The patient was diagnosed as having had myocardial ischemia and that she had a family history of coronary disease. An ECG performed 2 days later was normal, as was a follow-up coronary angiography. The patient recovered without incident.
- Postmarketing Experience with AXERT® in Adults
- Serious cardiovascular events have been reported in association with the use of AXERT®. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to definitively determine the proportion of the reported cases that were actually caused by almotriptan or to reliably assess causation in individual cases.
- Patients with Documented Coronary Artery Disease
- Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, AXERT® should not be given to patients with documented ischemic or vasospastic coronary artery disease.
- Patients with Risk Factors for CAD
- It is strongly recommended that AXERT® not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, AXERT® should not be administered.
- For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of AXERT® take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received AXERT®. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an ECG during the interval immediately following AXERT®, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of AXERT® and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use AXERT®.
- The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to AXERT®. The ability of cardiac diagnostic procedures to detect all cardiovascular diseases or predisposition to coronary artery vasospasm is modest at best. Cardiovascular events associated with triptan treatment have occurred in patients with no cardiac history and with documented absence of coronary artery disease.
- Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw
- As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with AXERT®. Because 5-HT1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms occur. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.
- Cerebrovascular Events and Fatalities
- Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with other triptans and some events have resulted in fatalities. In a number of cases, it appeared possible that the cerebrovascular events were primary, the triptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and transient ischemic attack).
- Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia
- Triptans, including AXERT®, may cause vasospastic reactions other than coronary artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with abdominal pain and bloody diarrhea. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of triptans. Visual disorders may also be part of a migraine attack. Patients who experience symptoms or signs suggestive of decreased arterial flow following the use of any triptan, such as ischemic bowel syndrome or Raynaud's syndrome, are candidates for further evaluation.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome may occur with triptans, including AXERT®, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with AXERT® and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Medication Overuse Headache
- Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
- Increases in Blood Pressure
- As with other triptans, significant elevations in systemic blood pressure have been reported on rare occasions with AXERT® use in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. AXERT® is contraindicated in patients with uncontrolled hypertension. In normotensive healthy subjects and patients with hypertension controlled by medication, small, but clinically insignificant, increases in mean systolic (0.21 and 4.87 mm Hg, respectively) and diastolic (1.35 and 0.26 mm Hg, respectively) blood pressure relative to placebo were seen over the first 4 hours after oral administration of 12.5 mg of almotriptan.
- An 18% increase in mean pulmonary artery pressure was seen following dosing with another triptan in a study evaluating subjects undergoing cardiac catheterization.
- Hypersensitivity to Sulfonamides
- Caution should be exercised when prescribing AXERT® to patients with known hypersensitivity to sulfonamides. The chemical structure of almotriptan contains a sulfonyl group, which is structurally different from a sulfonamide. Cross-sensitivity to almotriptan in patients allergic to sulfonamides has not been systematically evaluated.
- Impaired Hepatic or Renal Function
- AXERT® should be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as those with impaired hepatic or renal function.
- Binding to Melanin-Containing Tissues
- When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled almotriptan, the elimination half-life of radioactivity from the eye was 22 days. This finding suggests that almotriptan and/or its metabolites may bind to melanin in the eye. Because almotriptan could accumulate in melanin-rich tissues over time, there is the possibility that it could cause toxicity in these tissues with extended use. However, no adverse retinal effects related to treatment with almotriptan were noted in a 52-week toxicity study in dogs given up to 12.5 mg/kg/day (resulting in exposure [AUC] to parent drug approximately 20 times that in humans receiving the maximum recommended human dose of 25 mg/day). Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.
- Corneal Opacities
- Three male dogs (out of a total of 14 treated) in a 52-week toxicity study of oral almotriptan developed slight corneal opacities that were noted after 51 weeks, but not after 25 weeks of treatment. The doses at which this occurred were 2, 5, and 12.5 mg/kg/day. The opacity reversed after a 4-week drug-free period in the affected dog treated with the highest dose. Systemic exposure (plasma AUC) to parent drug at 2 mg/kg/day was approximately 2.5 times the exposure in humans receiving the maximum recommended human daily dose of 25 mg. A no-effect dose was not established.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events were assessed in controlled clinical trials that included 1840 adult patients who received one or two doses of AXERT® and 386 adult patients who received placebo. The most common adverse reactions during treatment with AXERT® were nausea, somnolence, headache, paresthesia, and dry mouth. In long-term open-label studies where patients were allowed to treat multiple attacks for up to 1 year, 5% (63 out of 1347 patients) withdrew due to adverse experiences.
- Adverse events were assessed in controlled clinical trials that included 362 adolescent patients who received AXERT® and 172 adolescent patients who received placebo. The most common adverse reactions during treatment with AXERT® were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. In a long-term, open-label study where patients were allowed to treat multiple attacks for up to 1 year, 2% (10 out of 420 adolescent patients) withdrew due to adverse events.
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- Adults
- Table 1 lists the adverse events that occurred in at least 1% of the adult patients treated with AXERT®, and at an incidence greater than in patients treated with placebo, regardless of drug relationship.
- The incidence of adverse events in controlled clinical trials was not affected by gender, weight, age, presence of aura, or use of prophylactic medications or oral contraceptives. There were insufficient data to assess the effect of race on the incidence of adverse events.
- Adolescents
- Table 2 lists the adverse reactions reported by 1% or more of AXERT®-treated adolescents age 12 to 17 years in 1 placebo-controlled, double-blind clinical trial.
- In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. The reports include adverse reactions in 5 adult controlled studies and 1 adolescent controlled study. Variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used AXERT® and reported a reaction divided by the total number of patients exposed to AXERT® (n=3047, all doses). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are those occurring in 1/100 or more patients, infrequent adverse reactions are those occurring in fewer than 1/100 to 1/1000 patients, and rare adverse reactions are those occurring in fewer than 1/1000 patients.
Frequent: Headache. Infrequent: Abdominal cramp or pain, Asthenia, Chills, Back pain, Chest pain, Neck pain, Fatigue, and Rigid neck. Rare: Fever and Photosensitivity reaction.
Infrequent: Vasodilation, Palpitations, and Tachycardia. Rare: Hypertension and Syncope.
Infrequent: Diarrhea, Vomiting, Dyspepsia, Gastroenteritis, and Increased thirst. Rare: Colitis, Gastritis, Esophageal reflux, and Increased salivation.
Infrequent: Hyperglycemia and Increased serum creatine phosphokinase. Rare: Increased gamma glutamyl transpeptidase and Hypercholesteremia.
Infrequent: Myalgia. Rare: Arthralgia, Arthritis, Myopathy, and Muscle weakness.
Frequent: Dizziness and Somnolence. Infrequent: Tremor, Vertigo, Anxiety, Hypoesthesia, Restlessness, CNS stimulation, and Shakiness. Rare: Change in dreams, Impaired concentration, Abnormal coordination, Depressive symptoms, Euphoria, Hyperreflexia, Hypertonia, Nervousness, Neuropathy, Nightmares, Nystagmus, and Insomnia.
Infrequent: Pharyngitis, Rhinitis, Dyspnea, Laryngismus, Sinusitis, and Bronchitis. Rare: Hyperventilation, Laryngitis, Sneezing, and Epistaxis.
Infrequent: Diaphoresis, Pruritus, and Rash. Rare: Dermatitis and Erythema.
Infrequent: Ear pain and Tinnitus. Rare: Diplopia, Dry eyes, Eye pain, Otitis media, Parosmia, Scotoma, Conjunctivitis, Eye irritation, Hyperacusis, and Taste alteration.
Infrequent: Dysmenorrhea.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of AXERT®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions (including angioedema, anaphylactic reactions and anaphylactic shock)
Confusional state, Restlessness
Hemiplegia, Hypoesthesia, Seizures
Blepharospasm, Visual impairment, Vision blurred
Vertigo
Acute myocardial infarction, Coronary artery vasospasm, Angina pectoris, Tachycardia
Abdominal discomfort, Abdominal pain, Abdominal pain upper, Colitis, Hypoesthesia oral, Swollen tongue
Cold sweat, Erythema, Hyperhidrosis
Arthralgia, Myalgia, Pain in extremity
Breast pain
Malaise, Peripheral coldness.
# Drug Interactions
- Ergot-Containing Drugs
- These drugs have been reported to cause prolonged vasospastic reactions. Because, in theory, vasospastic effects may be additive, ergotamine-containing or ergot-type medications (like dihydroergotamine, ergotamine tartrate, or methysergide) and AXERT® (almotriptan malate) should not be used within 24 hours of each other.
- 5-HT1 Agonists (e.g., Triptans)
- Concomitant use of other 5-HT1 agonists (e.g., triptans) within 24 hours of treatment with AXERT® is contraindicated.
- Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors
- Cases of life-threatening serotonin syndrome have been reported during combined use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Ketoconazole and Other Potent CYP3A4 Inhibitors
- Co-administration of almotriptan and oral ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used concomitantly with other potent CYP3A4 inhibitors.
- In patients concomitantly using potent CYP3A4 inhibitors, the recommended starting dose of AXERT® is 6.25 mg. The maximum daily dose should not exceed 12.5 mg within a 24-hour period. Concomitant use of AXERT® and potent CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In animal studies, almotriptan produced developmental toxicity (increased embryolethality and fetal skeletal variations, and decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, AXERT® (almotriptan malate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to pregnant rats throughout the period of organogenesis, increased incidences of fetal skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or greater and an increase in embryolethality was seen at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a body surface area (mg/m2) basis. Similar studies in pregnant rabbits conducted with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m2 basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats throughout the periods of gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. The no-effect dose in this study (100 mg/kg/day) is 40 times the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Almotriptan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Almotriptan during labor and delivery.
### Nursing Mothers
- It is not known whether almotriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AXERT® is administered to a nursing woman. Levels of almotriptan in rat milk were up to 7 times higher than in rat plasma.
### Pediatric Use
- Safety and efficacy of AXERT® in pediatric patients under the age of 12 years have not been established. The pharmacokinetics, efficacy, and safety of AXERT® have been evaluated in adolescent patients, age 12 to 17 years.
- In a clinical study, AXERT® 6.25 mg and 12.5 mg were found to be effective for the relief of migraine headache pain in adolescent patients age 12 to 17 years. Efficacy on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. The most common adverse reactions (incidence of ≥1%) associated with AXERT® treatment were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. The safety and tolerability profile of AXERT® treatment in adolescents is similar to the profile observed in adults.
- Postmarketing experience with other triptans include a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.
### Geriatic Use
- Clinical studies of AXERT® did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Clearance of almotriptan was lower in elderly volunteers than in younger individuals, but there were no observed differences in the safety and tolerability between the two populations. In general, dose selection for an elderly patient should be cautious, usually starting at the low dose, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The recommended dose of AXERT® for elderly patients with normal renal function for their age is the same as that recommended for younger adults.
### Gender
There is no FDA guidance on the use of Almotriptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Almotriptan with respect to specific racial populations.
### Renal Impairment
- The recommended starting dose of AXERT® in patients with severe renal impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period.
### Hepatic Impairment
- The recommended starting dose of AXERT® in patients with hepatic impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Almotriptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Almotriptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Almotriptan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Almotriptan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Patients and volunteers receiving single oral doses of 100 to 150 mg of almotriptan did not experience significant adverse events. Six additional normal volunteers received single oral doses of 200 mg without serious adverse events. During clinical trials with AXERT® (almotriptan malate), one patient ingested 62.5 mg in a 5-hour period and another patient ingested 100 mg in a 38-hour period. Neither patient experienced adverse reactions.
- Based on the pharmacology of triptans, hypertension or other more serious cardiovascular symptoms could occur after overdosage.
### Management
- There is no specific antidote to AXERT®. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.
- Clinical and electrocardiographic monitoring should be continued for at least 20 hours even if clinical symptoms are not observed.
- It is unknown what effect hemodialysis or peritoneal dialysis has on plasma concentrations of almotriptan.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Almotriptan in the drug label.
# Pharmacology
## Mechanism of Action
- Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors. Almotriptan has weak affinity for 5-HT1A and 5-HT7 receptors, but has no significant affinity or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT6; alpha or beta adrenergic; adenosine (A1, A2); angiotensin (AT1, AT2); dopamine (D1, D2); endothelin (ETA, ETB); or tachykinin (NK1, NK2, NK3) binding sites.
## Structure
- AXERT® (almotriptan malate) Tablets contain almotriptan malate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist. Almotriptan malate is chemically designated as 1-[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine (±)-hydroxybutanedioate (1:1) and its structural formula is:
- Its empirical formula is C17H25N3O2S-C4H6O5, representing a molecular weight of 469.56. Almotriptan is a white to slightly yellow crystalline powder that is soluble in water. AXERT® for oral administration contains almotriptan malate equivalent to 6.25 or 12.5 mg of almotriptan. Each compressed tablet contains the following inactive ingredients: carnauba wax, cellulose, FD&C Blue No. 2 (12.5 mg only), hypromellose, iron oxide (6.25 mg only), mannitol, polyethylene glycol, povidone, propylene glycol, sodium starch glycolate, sodium stearyl fumarate and titanium dioxide.
## Pharmacodynamics
- Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system. The therapeutic activity of almotriptan in migraine can most likely be attributed to agonist effects at 5-HT1B/1D receptors on the extracerebral, intracranial blood vessels that become dilated during a migraine attack and on nerve terminals in the trigeminal system. Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathways.
## Pharmacokinetics
- Absorption
- The absolute bioavailability of almotriptan is about 70%, with peak plasma levels occurring 1 to 3 hours after administration; food does not affect pharmacokinetics.
- Distribution
- Almotriptan is minimally protein bound (approximately 35%) and the mean apparent volume of distribution is approximately 180 to 200 liters.
- Metabolism
- Almotriptan is metabolized by two major and one minor pathways. Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and cytochrome P450-mediated oxidation (approximately 12% of the dose) are the major routes of metabolism, while flavin monooxygenase is the minor route. MAO-A is responsible for the formation of the indoleacetic acid metabolite, whereas cytochrome P450 (3A4 and 2D6) catalyzes the hydroxylation of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde dehydrogenase to the gamma-aminobutyric acid derivative. Both metabolites are inactive.
- Excretion
- Almotriptan has a mean half-life of 3 to 4 hours. Almotriptan is eliminated primarily by renal excretion (about 75% of the oral dose), with approximately 40% of an administered dose excreted unchanged in urine. Renal clearance exceeds the glomerular filtration rate by approximately 3-fold, indicating an active mechanism. Approximately 13% of the administered dose is excreted via feces, both unchanged and metabolized.
- Drug-Drug Interactions
- All drug interaction studies were performed in healthy volunteers using a single 12.5 mg dose of almotriptan and multiple doses of the other drug.
- Monoamine Oxidase Inhibitors
- Co-administration of almotriptan and moclobemide (150 mg twice daily for 8 days) resulted in a 27% decrease in almotriptan clearance and an increase in Cmax of approximately 6%. No dose adjustment is necessary.
- Propranolol
- Co-administration of almotriptan and propranolol (80 mg twice daily for 7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.
- Fluoxetine
- Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased 18%. This difference is not clinically significant.
- Verapamil
- Co-administration of almotriptan and verapamil (120 mg sustained-release tablets twice daily for 7 days), an inhibitor of CYP3A4, resulted in a 20% increase in the area under the plasma concentration-time curve, and in a 24% increase in maximal plasma concentrations of almotriptan. Neither of these changes is clinically significant. No dose adjustment is necessary.
- Ketoconazole and other Potent CYP3A4 Inhibitors
- Co-administration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used with other potent CYP3A4 inhibitors.
- Special Populations
- Geriatric
- Renal and total clearance, and amount of drug excreted in the urine, were lower in elderly healthy volunteers (age 65 to 76 years) than in younger healthy volunteers (age 19 to 34 years), resulting in longer terminal half-life (3.7 hours vs. 3.2 hours) and a 25% higher area under the plasma concentration-time curve in the elderly subjects. The differences, however, do not appear to be clinically significant.
- Pediatric
- A pharmacokinetics study of almotriptan was conducted in adolescents (12 to 17 years) and adults (18 to 55 years) with or without a history of migraine. No differences were observed in the rate or extent of absorption of almotriptan in adolescents compared with adults.
- Gender
- No significant gender differences were observed in pharmacokinetic parameters.
- Race
- No significant differences were observed in pharmacokinetic parameters between Caucasian and African-American volunteers.
- Hepatic Impairment
- The pharmacokinetics of almotriptan have not been assessed in patients with hepatic impairment. Based on the known mechanisms of clearance of almotriptan, the maximum decrease expected in almotriptan clearance due to hepatic impairment would be 60%.
- Renal Impairment
- The clearance of almotriptan was approximately 65% lower in patients with severe renal impairment (Cl/F=19.8 L/hour; creatinine clearance between 10 and 30 mL/min) and approximately 40% lower in patients with moderate renal impairment (Cl/F=34.2 L/hour; creatinine clearance between 31 and 71 mL/min) than in healthy volunteers (Cl/F=57 L/hour). Maximal plasma concentrations of almotriptan increased by approximately 80% in these patients.
## Nonclinical Toxicology
- Carcinogenesis
- Almotriptan was administered to mice and rats for up to 103–104 weeks at oral doses up to 250 mg/kg/day and 75 mg/kg/day, respectively. These doses were associated with plasma exposures (AUC) to parent drug that were approximately 40 and 80 times, in mice and rats respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 25 mg/day. Because of high mortality rates in both studies, which reached statistical significance in high-dose female mice, all female rats, all male mice, and high-dose female mice were terminated between weeks 96 and 98. There was no increase in tumors related to almotriptan administration.
- Mutagenesis
- Almotriptan was not mutagenic in two in vitro gene mutation assays, the Ames test, and the mouse lymphoma tk assay. Almotriptan was not clastogenic in an in vivo mouse micronucleus assay.
- Impairment of Fertility
- When male and female rats received almotriptan (25, 100, or 400 mg/kg/day) orally prior to and during mating and gestation, prolongation of the estrous cycle was observed at the mid-dose and greater, and fertility was impaired at the highest dose. Subsequent mating of treated with untreated animals indicated that the decrease in fertility was due to an effect on females. The no-effect dose for reproductive toxicity in rats (25 mg/kg/day) is approximately 10 times the MRHD on a mg/m2 basis.
# Clinical Studies
- Adults
- The efficacy of AXERT® (almotriptan malate) was established in three multi-center, randomized, double-blind, placebo-controlled European trials. Patients enrolled in these studies were primarily female (86%) and Caucasian (more than 98%), with a mean age of 41 years (range of 18 to 72). Patients were instructed to treat a moderate to severe migraine headache. Two hours after taking one dose of study medication, patients evaluated their headache pain. If the pain had not decreased in severity to mild or no pain, the patient was allowed to take an escape medication. If the pain had decreased to mild or no pain at 2 hours but subsequently increased in severity between 2 and 24 hours, it was considered a relapse and the patient was instructed to take a second dose of study medication. Associated symptoms of nausea, vomiting, photophobia, and phonophobia were also evaluated.
- In these studies, the percentage of patients achieving a response (mild or no pain) 2 hours after treatment was significantly greater in patients who received either AXERT® 6.25 mg or 12.5 mg, compared with those who received placebo. A higher percentage of patients reported pain relief after treatment with the 12.5 mg dose than with the 6.25 mg dose. Doses greater than 12.5 mg did not lead to a significantly better response. These results are summarized in Table 3.
- The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT® in adults is shown in Figure 1.
- This Kaplan-Meier plot is based on data obtained in the three placebo-controlled clinical trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not achieving pain relief by 2 hours were censored at 2 hours.
- For patients with migraine-associated photophobia, phonophobia, nausea, and vomiting at baseline, there was a decreased incidence of these symptoms following administration of AXERT® compared with placebo.
- Two to 24 hours following the initial dose of study medication, patients were allowed to take an escape medication or a second dose of study medication for pain response. The estimated probability of patients taking escape medication or a second dose of study medication over the 24 hours following the initial dose of study medication is shown in Figure 2.
- This Kaplan-Meier plot is based on data obtained in the three placebo-controlled trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not using additional treatment were censored at 24 hours. Remedication was not allowed within 2 hours after the initial dose of AXERT®.
- The efficacy of AXERT® was unaffected by the presence of aura; by gender, weight, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, and tricyclic antidepressants); or oral contraceptives. There were insufficient data to assess the effect of race on efficacy.
- The efficacy of AXERT® in adolescent patients age 12 to 17 years was evaluated in a double-blind, randomized, placebo-controlled study. Patients enrolled in that study had at least a 1-year history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated). Patients enrolled in the study were primarily females (60%) and Caucasian (75%), while 15% of patients were black, and 10% were of other races. Patients were instructed to treat a moderate to severe migraine headache. Two hours after taking one dose of study medication, patients evaluated their headache pain. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated.
- In this study, the percentage of patients achieving a pain relief response (mild or no pain) 2 hours after treatment was statistically significantly greater in patients who received AXERT® 6.25 mg or 12.5 mg compared with those who received placebo. There was no additional benefit on pain relief provided by the 12.5 mg dose. The 2-hour pain relief results are summarized in Table 4.
- The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT® in adolescents age 12 to 17 years is shown in Figure 3.
- The prevalence of the migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not significantly different between patients who received AXERT® 6.25 mg or 12.5 mg and those who received placebo.
# How Supplied
- AXERT® (almotriptan malate) Tablets are available as follows:
- 6.25 mg: White, coated, circular, biconvex tablets with red code imprint "2080."
- Unit Dose (aluminum blister pack)
- 6 tablets NDC 50458-211-01
- 12.5 mg: White, coated, circular, biconvex tablets with blue stylized imprint "A."
- Unit Dose (aluminum blister pack)
- 12 tablets NDC 50458-210-01
- Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F).
## Storage
There is limited information regarding Almotriptan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Drug Interactions
- Advise patients to talk with their physician or pharmacist before taking any new medicines, including prescription and non-prescription drugs and supplements.
- Hypersensitivity
- Inform patients to tell their physician if they develop a rash, itching, or breathing difficulties after taking AXERT®.
- Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, Other Vasospasm-Related Events, and Cerebrovascular Events
- Inform patients that AXERT® (almotriptan malate) may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, or slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Apprise the patient of the importance of this follow-up.
- Serotonin Syndrome
- Caution patients about the risk of serotonin syndrome with the use of AXERT® or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Medication Overuse Headache
- Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).
- Pregnancy
- Advise patients to notify their physician if they become pregnant during treatment or intend to become pregnant.
- Nursing Mothers
- Advise patients to notify their physician if they are breastfeeding or plan to breastfeed.
- Ability to Operate Machinery or Vehicles
- Counsel patients that AXERT® may cause dizziness, somnolence, visual disturbances, and other CNS symptoms that can interfere with driving or operating machinery. Accordingly, advise the patient not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience with AXERT® to gauge whether it affects their mental or visual performance adversely.
# Precautions with Alcohol
- Alcohol-Almotriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- AXERT®[1]
# Look-Alike Drug Names
- Axert® — Antivert®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Almotriptan | |
44f98ed53c34cd7f3cda7816b29515e73811231c | wikidoc | Iduronidase | Iduronidase
Iduronidase (EC 3.2.1.76, L-iduronidase, alpha-L-iduronidase, laronidase), sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan alpha-L-iduronohydrolase. This enzyme catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.
It is a glycoprotein enzyme found in the lysosomes of cells. It is involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. The enzyme acts by hydrolyzing the terminal alpha-L-induronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kilodaltons.
# Pathology
A deficiency in the IDUA protein is associated with mucopolysaccharidoses (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as Hurler syndrome and type I,S is known as Scheie syndrome, which has a milder prognosis compared to Hurler's. In this syndrome, glycosaminoglycans accumulate in the lysosomes and cause substantial disease in many different tissues of the body. IDUA mutations result in the MPS 1 phenotype, which is inherited in an autosomal recessive fashion.
The defective alpha-L-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies.
Prenatal diagnosis of this enzyme deficiency is possible.
# Aldurazyme
## General
Aldurazyme is the name of the commercialized variant of the enzyme Iduronidase, which hydrolyzes the alpha-L-iduronic acid residues of dermatan sulfate and heparin sulfate. Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is the manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corporation (a subsidiary of Sanofi). Aldurazyme is administered as a slow intravenous infusion. The recombinant enzyme is 628 amino acids in length with 6 N-linked oligosaccharide modification sites and two oligosaccharide chains terminating in mannose sugars.
## Pre-clinical work
Dosing for human clinical studies was based on canine MPS I studies.
## Clinical trials
Three clinical trials were performed to establish the pharmacology, efficacy, and safety of weekly intravenous administration of the drug. These studies included a Phase I open-label study, a Phase III randomized, double-blind, placebo-controlled study, and a Phase III open-label extension study. A Phase 2 Young Pediatric study was also conducted.
Clinical trials and post-market safety data indicate that the most common adverse side effect of Aldurazyme is allergic reaction. In order to prevent allergic reaction and respiratory distress, the packet insert of Aldurazyme suggests that patients be administered antihistamines before infusion. Allergic reaction occurs in approximately 1% of patients. It is recommended that patients who are high-risk for respiratory distress be given their infusion in a facility equipped to deal with an anaphylactic response. (High-risk factors include sleep apnea, respiratory impairment, respiratory illness, or previous experience with allergic reaction to Aldurazyme. It is noted that risk-benefit must be weighed for patients with history of severe allergic response as to whether the drug should be administered again.) In a 2002 memorandum, Melanie Hartsough, Ph.D., DTP of the FDA's Department of Health and Human Services stated, "Aggregation of product could enhance immune responses, specifically neutralizing antibody, which may limit the response to therapy, whereas highly deaggregated product may induce immune tolerance." It appears that she then went on to ask for further justification of some relevant aspect of the production process, though the majority of this particular memorandum has not been publicly released and it is unclear as to whether this concern is relevant to the high rate of allergic response to this drug.
Additionally, it is recommended that patients be administered antipyretics before use. According to Aldurazyme's website, the most common adverse effects observed in a 26-week, placebo-controlled clinical trial of patients 6 years old or older are flushing, pyrexia, headache, and rash. Flushing was noted in 23% of patients, or five people, in this relatively small clinical study. This trial was extended. In the extension, it was noted that abdominal pain and infusion-site reaction occurred in some patients.
The website also states that in a 52-week open-label uncontrolled clinical trial, the most common serious reactions in children younger than 6 were "otitis media (20%), and central venous catherization required for ALDURAZYME infusion (15%). The most commonly reported adverse reactions in patients 6 years and younger were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash."
A phase-four clinical trial is currently recruiting participants to investigate whether Aldurazyme passes through breastmilk and whether it has any effect on nursing infants.
## Regulation
Aldurazyme was the first drug approved by the United States Food and Drug Administration to be marketed as a treatment for MPS I. It was approved in April 2003. Marketing authorization in the European Union was granted in June 2003 by the European Commission. Aldurazyme enjoys orphan drug status in both the United States and the European Union, though in both its orphan drug exclusivity period has expired. (Orphan drug exclusivity, which prevents the FDA or similar European body from approving the same drug proposed by another company for the same listed use lasts only seven years in the United States and ten years in the European Union.) Aldurazyme was granted orphan designation for Treatment of patients with mucopolysaccharidosis-I on September 24, 1997.
As of 2014, Aldurazyme was mandated to be produced using Good Manufacturing Practices (GMP) and, along with several other recombinant enzyme products produced by Biomarin, was manufactured at the production facility located in Novato, California. Both packaging and vialing were performed by contractors. All suppliers and contractors also are mandated to follow GMP, and they, as well as BioMarin, are subject to inspection and review. BioMarin's facility has received both FDA and European Commission approval.
## Commercialization plan
Aldurazyme is manufactured by BioMarin in California. It is commercialized and distributed by Genzyme in the United States, the European Union, and worldwide. The patent for Aldurazyme was filed by BioMarin on November 12, 1999, patent no. US 6426208 B1, "Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating diseases caused by deficiencies thereof".
BioMarin reported their common stock to be $.001 par value at the conclusion of the 2014 fiscal year. Aldurazyme yielded a net $105.6 million net product revenue out of $738.4 million in net profit revenues in 2014, $83.6 million out of $538.4 million in 2013, and $82.2 million out of $496.5 million in 2012, making it BioMarin's third-most profitable product behind Naglazyme and Kuvan. In 2011, Aldurazyme yielded a net product revenue of $82.8 million out of $437.6 million net revenue, and in 2010 it netted $71.2 million out of $369.7 million in net product revenues. Aldurazyme netted $70.2 million in profit revenues in 2009 out of a total $315.7 $72.5 million in revenue were netted in 2008 out of Biomarin's $251.9 million in product revenues that year.
BioMarin described its business strategy as the following in their 2014 United States Securities and Exchange Commission Form 10-K:
BioMarin Pharmaceutical Inc. (BioMarin, we, us or our) develops and commercializes innovative pharmaceuticals for serious diseases and medical conditions. We select product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products.
Based on this business model, it is easy to understand why BioMarin would have targeted a disease like MPS I for treatment. It is, as described, an orphan condition with a well-defined mechanism. Furthermore, before the development of Aldurazyme, there were no drugs to treat MPS I, allowing BioMarin to be first-to-market with its new pharmaceutical. Since the release of Aldurazyme, one more drug has been released to treat MPS; Elaprase is a treatment for MPS II.
In 2016, Aldurazyme had an average cost-per-patient of $355,816.
## Collaboration between BioMarin and Genzyme
BioMarin/Genzyme is a 50/50 Limited Liability Company which co-owns the intellectual rights to Aldurazyme and works collaboratively on research and development. BioMarin is responsible for the production of Aldurazyme. It sells the finished product to Genzyme, which is a fully owned subsidiary of Sanofi. Genzyme pays a 39.5% - 50% royalty quarterly on worldwide net product sales to BioMarin. A portion of this royalty is considered to be product transfer royalties, meaning that if any Aldurazyme goes unsold, BioMarin merely retains the product transfer royalty, while not receiving any further royalties. Only in the case of defective product is Genzyme reimbursed for Aldurazyme product. | Iduronidase
Iduronidase (EC 3.2.1.76, L-iduronidase, alpha-L-iduronidase, laronidase), sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan alpha-L-iduronohydrolase.[1][2][3] This enzyme catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.[4]
It is a glycoprotein enzyme found in the lysosomes of cells. It is involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. The enzyme acts by hydrolyzing the terminal alpha-L-induronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kilodaltons.[4]
# Pathology
A deficiency in the IDUA protein is associated with mucopolysaccharidoses (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as Hurler syndrome and type I,S is known as Scheie syndrome, which has a milder prognosis compared to Hurler's. In this syndrome, glycosaminoglycans accumulate in the lysosomes and cause substantial disease in many different tissues of the body. IDUA mutations result in the MPS 1 phenotype, which is inherited in an autosomal recessive fashion.[5]
The defective alpha-L-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies.
Prenatal diagnosis of this enzyme deficiency is possible.
# Aldurazyme
## General
Aldurazyme is the name of the commercialized variant of the enzyme Iduronidase, which hydrolyzes the alpha-L-iduronic acid residues of dermatan sulfate and heparin sulfate. Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is the manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corporation (a subsidiary of Sanofi). Aldurazyme is administered as a slow intravenous infusion. The recombinant enzyme is 628 amino acids in length with 6 N-linked oligosaccharide modification sites and two oligosaccharide chains terminating in mannose sugars.[4]
## Pre-clinical work
Dosing for human clinical studies was based on canine MPS I studies.[6]
## Clinical trials
Three clinical trials were performed to establish the pharmacology, efficacy, and safety of weekly intravenous administration of the drug. These studies included a Phase I open-label study, a Phase III randomized, double-blind, placebo-controlled study, and a Phase III open-label extension study. A Phase 2 Young Pediatric study was also conducted.[6]
Clinical trials and post-market safety data indicate that the most common adverse side effect of Aldurazyme is allergic reaction.[6] In order to prevent allergic reaction and respiratory distress, the packet insert of Aldurazyme suggests that patients be administered antihistamines before infusion.[6] Allergic reaction occurs in approximately 1% of patients. It is recommended that patients who are high-risk for respiratory distress be given their infusion in a facility equipped to deal with an anaphylactic response.[6] (High-risk factors include sleep apnea, respiratory impairment, respiratory illness, or previous experience with allergic reaction to Aldurazyme. It is noted that risk-benefit must be weighed for patients with history of severe allergic response as to whether the drug should be administered again.)[6] In a 2002 memorandum, Melanie Hartsough, Ph.D., DTP of the FDA's Department of Health and Human Services stated, "Aggregation of product could enhance immune responses, specifically neutralizing antibody, which may limit the response to therapy, whereas highly deaggregated product may induce immune tolerance." It appears that she then went on to ask for further justification of some relevant aspect of the production process, though the majority of this particular memorandum has not been publicly released and it is unclear as to whether this concern is relevant to the high rate of allergic response to this drug.[7]
Additionally, it is recommended that patients be administered antipyretics before use. According to Aldurazyme's website, the most common adverse effects observed in a 26-week, placebo-controlled clinical trial of patients 6 years old or older are flushing, pyrexia, headache, and rash. Flushing was noted in 23% of patients, or five people, in this relatively small clinical study. This trial was extended. In the extension, it was noted that abdominal pain and infusion-site reaction occurred in some patients.[6]
The website also states that in a 52-week open-label uncontrolled clinical trial, the most common serious reactions in children younger than 6 were "otitis media (20%), and central venous catherization required for ALDURAZYME infusion (15%). The most commonly reported adverse reactions in patients 6 years and younger were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash."[6]
A phase-four clinical trial is currently recruiting participants to investigate whether Aldurazyme passes through breastmilk and whether it has any effect on nursing infants.[8]
## Regulation
Aldurazyme was the first drug approved by the United States Food and Drug Administration to be marketed as a treatment for MPS I. It was approved in April 2003. Marketing authorization in the European Union was granted in June 2003 by the European Commission. Aldurazyme enjoys orphan drug status in both the United States and the European Union, though in both its orphan drug exclusivity period has expired. (Orphan drug exclusivity, which prevents the FDA or similar European body from approving the same drug proposed by another company for the same listed use lasts only seven years in the United States and ten years in the European Union.) Aldurazyme was granted orphan designation for Treatment of patients with mucopolysaccharidosis-I on September 24, 1997.[9][10][11]
As of 2014, Aldurazyme was mandated to be produced using Good Manufacturing Practices (GMP) and, along with several other recombinant enzyme products produced by Biomarin, was manufactured at the production facility located in Novato, California. Both packaging and vialing were performed by contractors. All suppliers and contractors also are mandated to follow GMP, and they, as well as BioMarin, are subject to inspection and review. BioMarin's facility has received both FDA and European Commission approval.[12]
## Commercialization plan
Aldurazyme is manufactured by BioMarin in California. It is commercialized and distributed by Genzyme in the United States, the European Union, and worldwide.[9] The patent for Aldurazyme was filed by BioMarin on November 12, 1999, patent no. US 6426208 B1, "Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating diseases caused by deficiencies thereof".[13]
BioMarin reported their common stock to be $.001 par value at the conclusion of the 2014 fiscal year. Aldurazyme yielded a net $105.6 million net product revenue out of $738.4 million in net profit revenues in 2014, $83.6 million out of $538.4 million in 2013, and $82.2 million out of $496.5 million in 2012, making it BioMarin's third-most profitable product behind Naglazyme and Kuvan.[12] In 2011, Aldurazyme yielded a net product revenue of $82.8 million out of $437.6 million net revenue, and in 2010 it netted $71.2 million out of $369.7 million in net product revenues.[14] Aldurazyme netted $70.2 million in profit revenues in 2009 out of a total $315.7 $72.5 million in revenue were netted in 2008 out of Biomarin's $251.9 million in product revenues that year.[10][15]
BioMarin described its business strategy as the following in their 2014 United States Securities and Exchange Commission Form 10-K:
BioMarin Pharmaceutical Inc. (BioMarin, we, us or our) develops and commercializes innovative pharmaceuticals for serious diseases and medical conditions. We select product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products.
Based on this business model, it is easy to understand why BioMarin would have targeted a disease like MPS I for treatment. It is, as described, an orphan condition with a well-defined mechanism. Furthermore, before the development of Aldurazyme, there were no drugs to treat MPS I, allowing BioMarin to be first-to-market with its new pharmaceutical. Since the release of Aldurazyme, one more drug has been released to treat MPS; Elaprase is a treatment for MPS II.
In 2016, Aldurazyme had an average cost-per-patient of $355,816.[16]
## Collaboration between BioMarin and Genzyme
BioMarin/Genzyme is a 50/50 Limited Liability Company which co-owns the intellectual rights to Aldurazyme and works collaboratively on research and development. BioMarin is responsible for the production of Aldurazyme. It sells the finished product to Genzyme, which is a fully owned subsidiary of Sanofi. Genzyme pays a 39.5% - 50% royalty quarterly on worldwide net product sales to BioMarin. A portion of this royalty is considered to be product transfer royalties, meaning that if any Aldurazyme goes unsold, BioMarin merely retains the product transfer royalty, while not receiving any further royalties. Only in the case of defective product is Genzyme reimbursed for Aldurazyme product.[12] | https://www.wikidoc.org/index.php/Alpha-L_iduronidase | |
259cf4daa9eef630c06f8598b988361726ecd45a | wikidoc | Lipoic acid | Lipoic acid
# Overview
Lipoic acid (LA), also known as α-lipoic acid and alpha lipoic acid (ALA) and thioctic acid is an organosulfur compound derived from octanoic acid. ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries.
# Physical and chemical properties
Lipoic acid (LA), also known as α-lipoic acid and alpha lipoic acid (ALA) and thioctic acid is an organosulfur compound derived from octanoic acid. LA contains two sulfur atoms (at C6 and C8) connected by a disulfide bond and is thus considered to be oxidized although either sulfur atom can exist in higher oxidation states.
The carbon atom at C6 is chiral and the molecule exists as two enantiomers (R)-(+)-lipoic acid (RLA) and (S)-(-)-lipoic acid (SLA) and as a racemic mixture (R/S)-lipoic acid (R/S-LA).
LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.
For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for R/S-LA.
# Biological function
"Lipoate" is the conjugate base of lipoic acid, and the most prevalent form of LA under physiologic conditions. Most endogenously produced RLA is not “free” because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains. One of the most studied roles of RLA is as a cofactor of the pyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).
Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.
## Biosynthesis and attachment
The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis in the form of octanoyl-acyl carrier protein. In eukaryotes, a second fatty acid biosynthetic pathway in mitochondria is used for this purpose. The octanoate is transferred as a thioester of acyl carrier protein from fatty acid biosynthesis to an amide of the lipoyl domain protein by an enzyme called an octanoyltransferase. Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase. Free lipoate can be used by some organisms an enzyme called lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.
## Enzymatic Activity
Lipoic acid is cofactor for at least five enzyme systems. Two of these are in the citric acid cycle through which many organisms turn nutrients into energy. Lipoylated enzymes have lipoic acid attached to them covalently. The lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes, and methylamine group in the glycine cleavage complex or glycine dehydrogenase.
2-Oxoacid dehydrogenase transfer reactions occur by a similar mechanism in:
- the pyruvate dehydrogenase complex
- the α-ketoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase complex
- the branched-chain oxoacid dehydrogenase (BCDH) complex
- the acetoin dehydrogenase complex.
The most-studied of these is the pyruvate dehydrogenase complex. These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase, respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites. The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.
Lipoic acid serves as co-factor to the acetoin dehydrogenase complex catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A, in some bacteria, allowing acetoin to be used as the sole carbon source.
The Glycine cleavage system differs from the other complexes, and has a different nomenclature. The individual components are free but it is sometimes incorrectly called a complex. In this system, the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase to synthesize serine from glycine. This system is part of plant photorespiration.
## Biological sources and degradation
Lipoic acid is present in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract. Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources. In addition, the amount of lipoic acid present in dietary sources is very low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid. As a result, all lipoic acid available as a supplement is chemically synthesized.
Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma. RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively.
Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-L-lysine amide bond. Both synthetic lipoamide and (R)-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases, which release free (R)-lipoic acid and either L-lysine or ammonia.
Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine. Certain bacteria can use lipoic acid as a carbon, sulfur, and energy source. An abundant intermediate in lipoic acid degradation was the shorter bisnorlipoic acid. Although fatty acid degradation enzymes are likely involved, gene products responsible for use of lipoic acid as a sulfur source are unknown.
Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals. Lipoic acid is partially degraded by a variety of transformations, which can occur in various combinations. Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice. Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized. Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.
# Chemical synthesis of lipoic acid
SLA did not exist prior to chemical synthesis in 1952. SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent. The first synthetic procedures appeared for RLA and SLA in the mid-1950s. Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa. Although RLA is favored nutritionally due to its “vitamin-like” role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechanisms of action, but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).
# Pharmacology of lipoic acid
## Pharmacokinetics
A 2007 human pharmacokinetic study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form. Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.
The various forms of LA are not bioequivalent. Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.
The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.
## Pharmacodynamics
The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA. Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms. LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E. LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA. The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects. This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins. Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.
All the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, glutathione reductase (GR) and thioredoxin reductase (Trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (R)-(+)-lipoic acid is enzymatically or chemically reduced to (R)-(-)-dihydrolipoic acid whereas (S)-(-)-lipoic acid is reduced to (S)-(+)-dihydrolipoic acid. Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.
RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulphoraphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents. This stress response indirectly improves the antioxidant capacity of the cell.
The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.
Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.
# Uses
R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets, and aqueous liquids, and have been marketed as antioxidants. This label has recently been challenged. In Japan, LA is marketed primarily as a "weight loss" and "energy" supplement. The relationships between supplemental doses and therapeutic doses have not been clearly defined. Because lipoic acid is not an essential nutrient, no Recommended Daily Allowance (RDA) has been established. In Germany, LA is approved as a drug against diabetes comorbidities since 1966 and available by prescription.
# Clinical research
- According to the American Cancer Society, "there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer".
- For peripheral diabetic neuropathy, intravenous administration of alpha lipoic acid leads to a short-term improvement, but there is no good evidence of meaningful benefit when taking it by mouth.
- A review of literature, using studies available from January 2008, did not find any randomized controlled trials using lipoic acid to treat dementia. Due to the absence of evidence it could not support lipoic acid for the treatment of any form of Dementia.
- There is weak evidence alpha lipoic acid may help with the management of burning mouth syndrome.
- There is no evidence alpha lipoic acid helps people with mitochondrial disorders.
- There is limited evidence lipoic acid may have potential as a drug for treating multiple sclerosis.
## Clinical Adverse effects
Side effects of alpha lipoic acid may include headache, tingling or a "pins and needles" sensation, skin rash, or muscle cramps. There have been a few reports in Japan of a rare condition called insulin autoimmune syndrome in people using alpha lipoic acid. The condition causes hypoglycemia and antibodies directed against the body's own insulin without previous insulin therapy. The safety of alpha lipoic acid in pregnant or nursing women, children, or people with kidney or liver disease is unknown.
# Other lipoic acids
- β-lipoic acid is a thiosulfinate of α-lipoic acid | Lipoic acid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lipoic acid (LA), also known as α-lipoic acid and alpha lipoic acid (ALA) and thioctic acid is an organosulfur compound derived from octanoic acid. ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries.
# Physical and chemical properties
Lipoic acid (LA), also known as α-lipoic acid[1] and alpha lipoic acid (ALA) and thioctic acid[2] is an organosulfur compound derived from octanoic acid. LA contains two sulfur atoms (at C6 and C8) connected by a disulfide bond and is thus considered to be oxidized although either sulfur atom can exist in higher oxidation states.
The carbon atom at C6 is chiral and the molecule exists as two enantiomers (R)-(+)-lipoic acid (RLA) and (S)-(-)-lipoic acid (SLA) and as a racemic mixture (R/S)-lipoic acid (R/S-LA).
LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.[citation needed]
For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for R/S-LA.[3]
# Biological function
"Lipoate" is the conjugate base of lipoic acid, and the most prevalent form of LA under physiologic conditions. Most endogenously produced RLA is not “free” because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains. One of the most studied roles of RLA is as a cofactor of the pyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).
Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.[4]
## Biosynthesis and attachment
The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis in the form of octanoyl-acyl carrier protein. In eukaryotes, a second fatty acid biosynthetic pathway in mitochondria is used for this purpose.[5][6] The octanoate is transferred as a thioester of acyl carrier protein from fatty acid biosynthesis to an amide of the lipoyl domain protein by an enzyme called an octanoyltransferase. Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase [7] As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase.[8] Free lipoate can be used by some organisms an enzyme called lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.[9]
## Enzymatic Activity
Lipoic acid is cofactor for at least five enzyme systems. Two of these are in the citric acid cycle through which many organisms turn nutrients into energy. Lipoylated enzymes have lipoic acid attached to them covalently. The lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes, and methylamine group in the glycine cleavage complex or glycine dehydrogenase.
2-Oxoacid dehydrogenase transfer reactions occur by a similar mechanism in:
- the pyruvate dehydrogenase complex
- the α-ketoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase complex
- the branched-chain oxoacid dehydrogenase (BCDH) complex
- the acetoin dehydrogenase complex.
The most-studied of these is the pyruvate dehydrogenase complex. These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase, respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites.[10][11] The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.[12]
Lipoic acid serves as co-factor to the acetoin dehydrogenase complex catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A, in some bacteria, allowing acetoin to be used as the sole carbon source.
The Glycine cleavage system differs from the other complexes, and has a different nomenclature. The individual components are free but it is sometimes incorrectly called a complex. In this system, the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase to synthesize serine from glycine. This system is part of plant photorespiration.[13]
## Biological sources and degradation
Lipoic acid is present in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[14] Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources. In addition, the amount of lipoic acid present in dietary sources is very low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.[15] As a result, all lipoic acid available as a supplement is chemically synthesized.
Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.[16] RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively.[17][18][19]
Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-L-lysine amide bond.[20] Both synthetic lipoamide and (R)-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases, which release free (R)-lipoic acid and either L-lysine or ammonia.[21][22][22][23][24][25]
Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine. Certain bacteria can use lipoic acid as a carbon, sulfur, and energy source. An abundant intermediate in lipoic acid degradation was the shorter bisnorlipoic acid.[26][27] Although fatty acid degradation enzymes are likely involved, gene products responsible for use of lipoic acid as a sulfur source are unknown.
Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.[28] Lipoic acid is partially degraded by a variety of transformations, which can occur in various combinations. Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice.[28] Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.[29] Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.
# Chemical synthesis of lipoic acid
SLA did not exist prior to chemical synthesis in 1952.[30][31] SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent.[32] The first synthetic procedures appeared for RLA and SLA in the mid-1950s.[33][34][35][36] Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa.[37][38] Although RLA is favored nutritionally due to its “vitamin-like” role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechanisms of action, but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).[39][40]
# Pharmacology of lipoic acid
## Pharmacokinetics
A 2007 human pharmacokinetic study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.[41] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.[41]
The various forms of LA are not bioequivalent.[32] Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.[41]
The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.[42]
## Pharmacodynamics
The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.[1] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[43] LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E.[43] LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.[1][44] The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects.[45] This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins.[39] Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.[1][44][46]
All the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, glutathione reductase (GR) and thioredoxin reductase (Trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (R)-(+)-lipoic acid is enzymatically or chemically reduced to (R)-(-)-dihydrolipoic acid whereas (S)-(-)-lipoic acid is reduced to (S)-(+)-dihydrolipoic acid.[47][48][49][50][51][52][53] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.[54]
RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulphoraphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.[46][55] This stress response indirectly improves the antioxidant capacity of the cell.[1]
The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.[56][57]
Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[58][59][60][61][62]
# Uses
R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets, and aqueous liquids, and have been marketed as antioxidants. This label has recently been challenged.[1] In Japan, LA is marketed primarily as a "weight loss" and "energy" supplement.[citation needed] The relationships between supplemental doses and therapeutic doses have not been clearly defined. Because lipoic acid is not an essential nutrient, no Recommended Daily Allowance (RDA) has been established. In Germany, LA is approved as a drug against diabetes comorbidities since 1966 and available by prescription.[63]
# Clinical research
- According to the American Cancer Society, "there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer".[64]
- For peripheral diabetic neuropathy, intravenous administration of alpha lipoic acid leads to a short-term improvement, but there is no good evidence of meaningful benefit when taking it by mouth.[65]
- A review of literature, using studies available from January 2008, did not find any randomized controlled trials using lipoic acid to treat dementia. Due to the absence of evidence it could not support lipoic acid for the treatment of any form of Dementia.[66]
- There is weak evidence alpha lipoic acid may help with the management of burning mouth syndrome.[67]
- There is no evidence alpha lipoic acid helps people with mitochondrial disorders.[68]
- There is limited evidence lipoic acid may have potential as a drug for treating multiple sclerosis.[69]
## Clinical Adverse effects
Side effects of alpha lipoic acid may include headache, tingling or a "pins and needles" sensation, skin rash, or muscle cramps. There have been a few reports in Japan of a rare condition called insulin autoimmune syndrome in people using alpha lipoic acid.[70] The condition causes hypoglycemia and antibodies directed against the body's own insulin without previous insulin therapy. The safety of alpha lipoic acid in pregnant or nursing women, children, or people with kidney or liver disease is unknown.[citation needed]
# Other lipoic acids
- β-lipoic acid is a thiosulfinate of α-lipoic acid | https://www.wikidoc.org/index.php/Alpha-lipoic_acid | |
a6f9c501b47ea48767207dfd97bd84c485ff992a | wikidoc | Alpha decay | Alpha decay
Alpha decay is a type of radioactive decay in which an atomic nucleus emits an alpha particle (two protons and two neutrons bound together into a particle identical to a helium nucleus) and transforms (or 'decays') into an atom with a mass number 4 less and atomic number 2 less. For example:
{}^2{}^{38}_{92}\hbox{U}\;\to\;{}^2{}^{34}_{90}\hbox{Th}\;+\;{}^4_2\hbox{He}^{2+},
although this is typically written as:
{}^{238}\hbox{U}\;\to\;^{234}\hbox{Th}\;+\;\alpha.
(The second form is preferred because the first form appears electrically unbalanced. Fundamentally, the recoiling nucleus is very quickly stripped of two electrons to neutralize the ionized helium cation.)
An alpha particle is the same as a helium-4 nucleus, and both mass number and atomic number are the same.
Alpha decay is a form of nuclear fission where the parent atom splits into two daughter products. Alpha decay is fundamentally a quantum tunneling process. Unlike beta decay, alpha decay is governed by the strong nuclear force.
Alpha particles have a typical kinetic energy of 5 MeV (that is ≈0.13% of their total energy, i.e. 110 TJ/kg) and a speed of 15,000 km/s. This corresponds to a speed of around 0.05c. Because of their relatively large mass, +2 charge and relatively low velocity, they are very likely to interact with other atoms and lose their energy, so their forward motion is effectively stopped within a few centimeters of air.
Most of the helium produced on Earth comes from the alpha decay of underground deposits of minerals containing uranium or thorium. The helium is brought to the surface as a by-product of natural gas production.
# History
By 1928, George Gamow had solved the theory of the alpha decay via tunneling. The alpha particle is trapped in a potential well by the nucleus. Classically, it is forbidden to escape, but according to the then newly discovered principles of Quantum mechanics, it has a tiny (but non-zero) probability of "tunneling" through the barrier and appearing on the other side to escape the nucleus.
# Uses
Americium-241, an alpha-emitter, is used in smoke detectors. The alpha particles ionize air between a small gap. A small current is passed through that ionized air. Smoke particles from fire that enter the air gap reduce the current flow, sounding the alarm.
Alpha decay can provide a safe power source for radioisotope thermoelectric generators used for space probes and artificial heart pacemakers. Alpha decay is much more easily shielded against than other forms of radioactive decay. Plutonium-238, for example, requires only 2.5 mm of lead shielding to protect against unwanted radiation.
Static Eliminators typically use Polonium-210, an alpha emitter, to ionize air, allowing the 'static cling' to more rapdily dissipate.
# Toxicity
Being relatively heavy and positively charged, alpha particles tend to have a very short mean free path, and quickly lose kinetic energy within a short distance of their source. This results in several MeV being deposited in a relatively small volume of material. This increases the chance of cellular damage in cases of internal contamination. In general, external alpha radiation is not harmful since alpha particles are effectively shielded by a few centimeters of air, a piece of paper, or the thin layer of dead skin cells. Even touching an alpha source is usually not harmful, though many alpha sources also are accompanied by beta-emitting radiodaughters, and alpha emission is also accompanied by gamma photon emission. If substances emitting alpha particles are ingested, inhaled, injected or introduced through the skin, then it could result in a measurable dose.
The Relative Biological Effectiveness (RBE) is a measure of the fact that alpha radiation is more effective at causing certain biological effects, notably either cancer or cell-death, compared to photon or beta radiation, for equivalent radiation exposure. This is generally attributable to the high Linear Energy Transfer (LET), which is about one ionization of a chemical bond for every Angstrom of travel by the alpha particle. The RBE has been set at the value of 20 for alpha radiation by various government regulations. The RBE is set at 10 for neutron irradiation, and at 1 for beta and ionizing photon radiation.
However, another component of alpha radiation is the recoil of the parent nucleus, due to the conservation of momentum requiring the parent nucleus to recoil, much like the 'kick' of a rifle butt when a bullet goes in the opposite direction. This gives a significant amount of energy to the recoil nucleus, which also causes ionizaton damage. The total energy of the recoil nucleus is readily calculable, and is roughly the weight of the alpha (4 amu) divided by the weight of the parent (typically about 200 amu) times the total energy of the alpha. By some estimates, this might account for most of the internal radiation damage, as the recoil nuclei are typically heavy metals which preferentially collect on the chromosomes. In some studies, this has resulted in a RBE approaching 1,000 instead of the value used in governmental regulations.
The largest natural contributor to public radiation dose is radon, a naturally occurring, radioactive gas found in soil and rock. If the gas is inhaled, some of the radon particles may attach to the inner lining of the lung. These particles continue to decay, emitting alpha particles which can damage cells in the lung tissue.. The death of Marie Curie at age 66 from leukemia was likely caused by prolonged exposure to high doses of ionizing radiation. Curie worked extensively with Radium, which decays into Radon, along with other radioactive materials that emit beta and gamma rays.
The 2006 assassination of Russian dissident Alexander Litvinenko is thought to have been caused by poisoning with Polonium-210, an alpha emitter. | Alpha decay
Template:Nuclear physics
Alpha decay is a type of radioactive decay in which an atomic nucleus emits an alpha particle (two protons and two neutrons bound together into a particle identical to a helium nucleus) and transforms (or 'decays') into an atom with a mass number 4 less and atomic number 2 less. For example:
{}^2{}^{38}_{92}\hbox{U}\;\to\;{}^2{}^{34}_{90}\hbox{Th}\;+\;{}^4_2\hbox{He}^{2+},
</math>[1]
although this is typically written as:
{}^{238}\hbox{U}\;\to\;^{234}\hbox{Th}\;+\;\alpha.
</math>
(The second form is preferred because the first form appears electrically unbalanced. Fundamentally, the recoiling nucleus is very quickly stripped of two electrons to neutralize the ionized helium cation.)
An alpha particle is the same as a helium-4 nucleus, and both mass number and atomic number are the same.
Alpha decay is a form of nuclear fission where the parent atom splits into two daughter products. Alpha decay is fundamentally a quantum tunneling process. Unlike beta decay, alpha decay is governed by the strong nuclear force.
Alpha particles have a typical kinetic energy of 5 MeV (that is ≈0.13% of their total energy, i.e. 110 TJ/kg) and a speed of 15,000 km/s. This corresponds to a speed of around 0.05c. Because of their relatively large mass, +2 charge and relatively low velocity, they are very likely to interact with other atoms and lose their energy, so their forward motion is effectively stopped within a few centimeters of air.
Most of the helium produced on Earth comes from the alpha decay of underground deposits of minerals containing uranium or thorium. The helium is brought to the surface as a by-product of natural gas production.
# History
By 1928, George Gamow had solved the theory of the alpha decay via tunneling. The alpha particle is trapped in a potential well by the nucleus. Classically, it is forbidden to escape, but according to the then newly discovered principles of Quantum mechanics, it has a tiny (but non-zero) probability of "tunneling" through the barrier and appearing on the other side to escape the nucleus.
# Uses
Americium-241, an alpha-emitter, is used in smoke detectors. The alpha particles ionize air between a small gap. A small current is passed through that ionized air. Smoke particles from fire that enter the air gap reduce the current flow, sounding the alarm.
Alpha decay can provide a safe power source for radioisotope thermoelectric generators used for space probes and artificial heart pacemakers. Alpha decay is much more easily shielded against than other forms of radioactive decay. Plutonium-238, for example, requires only 2.5 mm of lead shielding to protect against unwanted radiation.
Static Eliminators typically use Polonium-210, an alpha emitter, to ionize air, allowing the 'static cling' to more rapdily dissipate.
# Toxicity
Being relatively heavy and positively charged, alpha particles tend to have a very short mean free path, and quickly lose kinetic energy within a short distance of their source. This results in several MeV being deposited in a relatively small volume of material. This increases the chance of cellular damage in cases of internal contamination. In general, external alpha radiation is not harmful since alpha particles are effectively shielded by a few centimeters of air, a piece of paper, or the thin layer of dead skin cells. Even touching an alpha source is usually not harmful, though many alpha sources also are accompanied by beta-emitting radiodaughters, and alpha emission is also accompanied by gamma photon emission. If substances emitting alpha particles are ingested, inhaled, injected or introduced through the skin, then it could result in a measurable dose.
The Relative Biological Effectiveness (RBE) is a measure of the fact that alpha radiation is more effective at causing certain biological effects, notably either cancer or cell-death, compared to photon or beta radiation, for equivalent radiation exposure. This is generally attributable to the high Linear Energy Transfer (LET), which is about one ionization of a chemical bond for every Angstrom of travel by the alpha particle. The RBE has been set at the value of 20 for alpha radiation by various government regulations. The RBE is set at 10 for neutron irradiation, and at 1 for beta and ionizing photon radiation.
However, another component of alpha radiation is the recoil of the parent nucleus, due to the conservation of momentum requiring the parent nucleus to recoil, much like the 'kick' of a rifle butt when a bullet goes in the opposite direction. This gives a significant amount of energy to the recoil nucleus, which also causes ionizaton damage. The total energy of the recoil nucleus is readily calculable, and is roughly the weight of the alpha (4 amu) divided by the weight of the parent (typically about 200 amu) times the total energy of the alpha. By some estimates, this might account for most of the internal radiation damage, as the recoil nuclei are typically heavy metals which preferentially collect on the chromosomes. In some studies[2], this has resulted in a RBE approaching 1,000 instead of the value used in governmental regulations.
The largest natural contributor to public radiation dose is radon, a naturally occurring, radioactive gas found in soil and rock[3]. If the gas is inhaled, some of the radon particles may attach to the inner lining of the lung. These particles continue to decay, emitting alpha particles which can damage cells in the lung tissue.[4]. The death of Marie Curie at age 66 from leukemia was likely caused by prolonged exposure to high doses of ionizing radiation. Curie worked extensively with Radium, which decays into Radon[5], along with other radioactive materials that emit beta and gamma rays.
The 2006 assassination of Russian dissident Alexander Litvinenko is thought to have been caused by poisoning with Polonium-210, an alpha emitter. | https://www.wikidoc.org/index.php/Alpha_decay | |
8b0f6b2872d40d778e30308eded89b728a0150c2 | wikidoc | Altretamine | Altretamine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Altretamine is an alkylating agent that is FDA approved for the treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting ,Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) and mild to moderate dose-related myelosuppression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Altretamine capsules is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.
- Altretamine is administered orally. Doses are calculated on the basis of body surface area.
- Altretamine may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m2/day. The total daily dose should be given as 4 divided oral doses after meals and at bedtime. There is no pharmacokinetic information supporting this dosing regimen and the effect of food on Altretamine bioavailability or pharmacokinetics has not been evaluated.
- Altretamine should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m2/day for any of the following situations:
- Gastrointestinal intolerance unresponsive to symptomatic measures;
- White blood count <2000/mm3 or granulocyte count <1000/mm3;
- Platelet count <75,000/mm3;
- Progressive neurotoxicity.
- If neurologic symptoms fail to stabilize on the reduced dose schedule, Altretamine should be discontinued indefinitely.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (2-9). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Altretamine in adult patients.
### Non–Guideline-Supported Use
- Altretamine 260 milligrams (mg)/square meter/day (maximum daily dose 400 mg) in 4 divided doses after meals and at bedtime for 14 consecutive days of each 28-day cycle for 6 cycles
- Small cell lung cancer vary between 60 to 400 milligrams/square meter/day given for 5 to 21 days
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Altretamine in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and effectiveness of Altretamine in children have not been established.
### Non–Guideline-Supported Use
The safety and effectiveness of Altretamine in children have not been established.
# Contraindications
- Altretamine is contraindicated in patients who have shown hypersensitivity to it.
- Altretamine should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity.
- Altretamine has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.
# Warnings
- Concurrent administration of Altretamine and antidepressants of the monoamine oxidase inhibitor(MAO) class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with Altretamine and MAO inhibitors.
- Altretamine causes mild to moderate myelosuppression and neurotoxicity. Blood counts and a neurologic examination should be performed prior to the initiation of each course of therapy and the dose of Altretamine adjusted as clinically indicated
### Precautions
- Neurologic examination should be performed regularly
# Adverse Reactions
## Clinical Trials Experience
- With continuous high-dose daily Altretamine, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires Altretamine dose reduction or, rarely, discontinuation of Altretamine therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of Altretamine. In 2 clinical studies of single-agent Altretamine utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Altretamine due to severe nausea and vomiting.
- Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have been reported. They are more likely to occur in patients receiving continuous high-dose daily altretamine capsules than moderate-dose Altretamine administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of Altretamine and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Altretamine and/or cisplatin.
- Altretamine causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm3 occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm3. Thrombocytopenia below 50,000 platelets/mm3 was seen in <10% of patients. When given in doses of 8-12 mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3-4 weeks, and normal counts were regained by 6 weeks. With continuous administration at doses of 6-8 mg/kg/day, nadirs are reached in 6-8 weeks (median).
- Data in the following table are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent Altretamine. In one study, Altretamine, 260 mg/m2/day, was administered for 14 days of a 28 day cycle. In another study, Altretamine, 6-8 mg/kg/day, was administered for 21 days of a 28 day cycle.
- Additional adverse reaction information is available from 13 single-agent altretamine studies (total of 1014 patients) conducted under the auspices of the National Cancer Institute. The treated patients had a variety of tumors and many were heavily pretreated with other chemotherapies; most of these trials utilized high, continuous daily doses of altretamine (612 mg/kg/day). In general, adverse reaction experiences were similar in the two trials described above. Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia, each occurring in <1% of patients.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Altretamine in the drug label.
# Drug Interactions
- Concurrent administration of Altretamine and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension.
- Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.
- Data from a randomized trial of Altretamine and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Altretamine and/or cisplatin .
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Altretamine has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. Altretamine may cause fetal damage when administered to a pregnant woman. If Altretamine is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Altretamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Altretamine during labor and delivery.
### Nursing Mothers
- It is not known whether altretamine is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to Altretamine treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Altretamine.
### Pediatric Use
The safety and effectiveness of Altretamine in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Altretamine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Altretamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Altretamine with respect to specific racial populations.
### Renal Impairment
- There have been no formal pharmacokinetic studies in patients with compromised renal function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
### Hepatic Impairment
- There have been no formal pharmacokinetic studies in patients with compromised hepatic function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Altretamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Altretamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Altretamine, and as clinically indicated .
# IV Compatibility
There is limited information regarding IV Compatibility of Altretamine in the drug label.
# Overdosage
- No case of acute overdosage in humans has been described. The oral LD50 dose in rats was 1050 mg/kg and 437 mg/kg in mice.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which Altretamine exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Altretamine resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of Altretamine and its metabolites have been negative. Altretamine has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement for cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.
## Structure
- Altretamine, is a synthetic cytotoxic antineoplastic s-triazine derivative. Altretamine contain 50 mg of altretamine for oral administration. Inert ingredients include lactose, anhydrous and calcium stearate. Altretamine, known chemically as N,N,N',N',N”,N”-hexamethyl-1,3,5-triazine-2,4,6-triamine, has the following structural formula:
- Its empirical formula is C9H18N6 with a molecular weight of 210.28. Altretamine is a white crystalline powder, melting at 172°± 1°C. Altretamine is practically insoluble in water but is increasingly soluble at pH 3 and below.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Altretamine in the drug label.
## Pharmacokinetics
- Altretamine is well-absorbed following oral administration in humans, but undergoes rapid and extensive demethylation in the liver, producing variation in altretamine plasma levels. The principal metabolites are pentamethylmelamine and tetramethylmelamine.
- Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of Altretamine to 11 patients with advanced ovarian cancer in doses of 120-300 mg/m2, peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3 hours, varying from 0.2 to 20.8 mg/l. Half-life of the β-phase of elimination ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.
- Following oral administration of 14C-ring-labeled altretamine (4 mg/kg), urinary recovery of radioactivity was 61% at 24 hours and 90% at 72 hours. Human urinary metabolites were Ndemethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.
- After intraperitoneal administration of 14C-ring-labeled altretamine to mice, tissue distribution was rapid in all organs, reaching a maximum at 30 minutes. The excretory organs (liver and kidney) and the small intestine showed high concentrations of radioactivity, whereas relatively low concentrations were found in other organs, including the brain.
- There have been no formal pharmacokinetic studies in patients with compromised hepatic and/or renal function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
- Altretamine has been administered in 4 divided doses, with meals and at bedtime, though there is no pharmacokinetic data on this schedule nor information from formal interaction studies about the effect of food on its bioavailability or pharmacokinetics.
- In two studies in patients with persistent or recurrent ovarian cancer following first-line treatment with cisplatin and/or alkylating agent-based combinations, Altretamine was administered as a single agent for 14 or 21 days of a 28 day cycle. In the 51 patients with measurable or evaluable disease, there were 6 clinical complete responses, 1 pathologic complete response, and 2 partial responses for an overall response rate of 18%. The duration of these responses ranged from 2 months in a patient with a palpable pelvic mass to 36 months in a patient who achieved a pathologic complete response. In some patients, tumor regression was associated with improvement in symptoms and performance status.
## Nonclinical Toxicology
- The carcinogenic potential of Altretamine has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. Altretamine was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. Altretamine administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased post-natal survival at 120 mg/m2/day and was embryocidal at 240 mg/m2/day. Administration of 120 mg/m2/day Altretamine to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Male rats treated with Altretamine at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.
# Clinical Studies
There is limited information regarding Clinical Studies of Altretamine in the drug label.
# How Supplied
- HEXALEN® (altretamine) capsules is available in 50 mg clear, hard gelatin capsules imprinted with the following inscription:
- USB 001.
- Bottles of 100 capsules
- (NDC 58063-001-70)
## Storage
- Store up to 25ºC (77ºF); excursions permitted to 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Altretamine in the drug label.
# Precautions with Alcohol
- Alcohol-Altretamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Hexalen ®
# Look-Alike Drug Names
There is limited information regarding Altretamine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Altretamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Altretamine is an alkylating agent that is FDA approved for the treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting ,Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) and mild to moderate dose-related myelosuppression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Altretamine capsules is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.
- Altretamine is administered orally. Doses are calculated on the basis of body surface area.
- Altretamine may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m2/day. The total daily dose should be given as 4 divided oral doses after meals and at bedtime. There is no pharmacokinetic information supporting this dosing regimen and the effect of food on Altretamine bioavailability or pharmacokinetics has not been evaluated.
- Altretamine should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m2/day for any of the following situations:
- Gastrointestinal intolerance unresponsive to symptomatic measures;
- White blood count <2000/mm3 or granulocyte count <1000/mm3;
- Platelet count <75,000/mm3;
- Progressive neurotoxicity.
- If neurologic symptoms fail to stabilize on the reduced dose schedule, Altretamine should be discontinued indefinitely.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (2-9). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Altretamine in adult patients.
### Non–Guideline-Supported Use
- Altretamine 260 milligrams (mg)/square meter/day (maximum daily dose 400 mg) in 4 divided doses after meals and at bedtime for 14 consecutive days of each 28-day cycle for 6 cycles
[1]
- Small cell lung cancer vary between 60 to 400 milligrams/square meter/day given for 5 to 21 days [2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Altretamine in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and effectiveness of Altretamine in children have not been established.
### Non–Guideline-Supported Use
The safety and effectiveness of Altretamine in children have not been established.
# Contraindications
- Altretamine is contraindicated in patients who have shown hypersensitivity to it.
- Altretamine should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity.
- Altretamine has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.
# Warnings
- Concurrent administration of Altretamine and antidepressants of the monoamine oxidase inhibitor(MAO) class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with Altretamine and MAO inhibitors.
- Altretamine causes mild to moderate myelosuppression and neurotoxicity. Blood counts and a neurologic examination should be performed prior to the initiation of each course of therapy and the dose of Altretamine adjusted as clinically indicated
### Precautions
- Neurologic examination should be performed regularly
# Adverse Reactions
## Clinical Trials Experience
- With continuous high-dose daily Altretamine, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires Altretamine dose reduction or, rarely, discontinuation of Altretamine therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of Altretamine. In 2 clinical studies of single-agent Altretamine utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Altretamine due to severe nausea and vomiting.
- Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have been reported. They are more likely to occur in patients receiving continuous high-dose daily altretamine capsules than moderate-dose Altretamine administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of Altretamine and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Altretamine and/or cisplatin.
- Altretamine causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm3 occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm3. Thrombocytopenia below 50,000 platelets/mm3 was seen in <10% of patients. When given in doses of 8-12 mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3-4 weeks, and normal counts were regained by 6 weeks. With continuous administration at doses of 6-8 mg/kg/day, nadirs are reached in 6-8 weeks (median).
- Data in the following table are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent Altretamine. In one study, Altretamine, 260 mg/m2/day, was administered for 14 days of a 28 day cycle. In another study, Altretamine, 6-8 mg/kg/day, was administered for 21 days of a 28 day cycle.
- Additional adverse reaction information is available from 13 single-agent altretamine studies (total of 1014 patients) conducted under the auspices of the National Cancer Institute. The treated patients had a variety of tumors and many were heavily pretreated with other chemotherapies; most of these trials utilized high, continuous daily doses of altretamine (612 mg/kg/day). In general, adverse reaction experiences were similar in the two trials described above. Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia, each occurring in <1% of patients.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Altretamine in the drug label.
# Drug Interactions
- Concurrent administration of Altretamine and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension.
- Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.
- Data from a randomized trial of Altretamine and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Altretamine and/or cisplatin .
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Altretamine has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. Altretamine may cause fetal damage when administered to a pregnant woman. If Altretamine is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Altretamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Altretamine during labor and delivery.
### Nursing Mothers
- It is not known whether altretamine is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to Altretamine treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Altretamine.
### Pediatric Use
The safety and effectiveness of Altretamine in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Altretamine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Altretamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Altretamine with respect to specific racial populations.
### Renal Impairment
- There have been no formal pharmacokinetic studies in patients with compromised renal function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
### Hepatic Impairment
- There have been no formal pharmacokinetic studies in patients with compromised hepatic function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Altretamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Altretamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Altretamine, and as clinically indicated .
# IV Compatibility
There is limited information regarding IV Compatibility of Altretamine in the drug label.
# Overdosage
- No case of acute overdosage in humans has been described. The oral LD50 dose in rats was 1050 mg/kg and 437 mg/kg in mice.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which Altretamine exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Altretamine resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of Altretamine and its metabolites have been negative. Altretamine has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement for cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.
## Structure
- Altretamine, is a synthetic cytotoxic antineoplastic s-triazine derivative. Altretamine contain 50 mg of altretamine for oral administration. Inert ingredients include lactose, anhydrous and calcium stearate. Altretamine, known chemically as N,N,N',N',N”,N”-hexamethyl-1,3,5-triazine-2,4,6-triamine, has the following structural formula:
- Its empirical formula is C9H18N6 with a molecular weight of 210.28. Altretamine is a white crystalline powder, melting at 172°± 1°C. Altretamine is practically insoluble in water but is increasingly soluble at pH 3 and below.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Altretamine in the drug label.
## Pharmacokinetics
- Altretamine is well-absorbed following oral administration in humans, but undergoes rapid and extensive demethylation in the liver, producing variation in altretamine plasma levels. The principal metabolites are pentamethylmelamine and tetramethylmelamine.
- Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of Altretamine to 11 patients with advanced ovarian cancer in doses of 120-300 mg/m2, peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3 hours, varying from 0.2 to 20.8 mg/l. Half-life of the β-phase of elimination ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.
- Following oral administration of 14C-ring-labeled altretamine (4 mg/kg), urinary recovery of radioactivity was 61% at 24 hours and 90% at 72 hours. Human urinary metabolites were Ndemethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.
- After intraperitoneal administration of 14C-ring-labeled altretamine to mice, tissue distribution was rapid in all organs, reaching a maximum at 30 minutes. The excretory organs (liver and kidney) and the small intestine showed high concentrations of radioactivity, whereas relatively low concentrations were found in other organs, including the brain.
- There have been no formal pharmacokinetic studies in patients with compromised hepatic and/or renal function, though Altretamine has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
- Altretamine has been administered in 4 divided doses, with meals and at bedtime, though there is no pharmacokinetic data on this schedule nor information from formal interaction studies about the effect of food on its bioavailability or pharmacokinetics.
- In two studies in patients with persistent or recurrent ovarian cancer following first-line treatment with cisplatin and/or alkylating agent-based combinations, Altretamine was administered as a single agent for 14 or 21 days of a 28 day cycle. In the 51 patients with measurable or evaluable disease, there were 6 clinical complete responses, 1 pathologic complete response, and 2 partial responses for an overall response rate of 18%. The duration of these responses ranged from 2 months in a patient with a palpable pelvic mass to 36 months in a patient who achieved a pathologic complete response. In some patients, tumor regression was associated with improvement in symptoms and performance status.
## Nonclinical Toxicology
- The carcinogenic potential of Altretamine has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. Altretamine was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. Altretamine administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased post-natal survival at 120 mg/m2/day and was embryocidal at 240 mg/m2/day. Administration of 120 mg/m2/day Altretamine to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Male rats treated with Altretamine at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.
# Clinical Studies
There is limited information regarding Clinical Studies of Altretamine in the drug label.
# How Supplied
- HEXALEN® (altretamine) capsules is available in 50 mg clear, hard gelatin capsules imprinted with the following inscription:
- USB 001.
- Bottles of 100 capsules
- (NDC 58063-001-70)
## Storage
- Store up to 25ºC (77ºF); excursions permitted to 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Altretamine in the drug label.
# Precautions with Alcohol
- Alcohol-Altretamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Hexalen ®
# Look-Alike Drug Names
There is limited information regarding Altretamine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Altretamine | |
3ed0645bcc2ba20eb0454532c59bbd1c5b45071d | wikidoc | Glimepiride | Glimepiride
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# Overview
Glimepiride is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, headache, nausea, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Glimepiride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
- Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.
- Dosing Information
- Glimepiride tablets should be administered with breakfast or the first main meal of the day.
- The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.
- After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.
- The maximum recommended dose is 8 mg once daily.
- Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
- When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Glimepiride in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Glimepiride in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Glimepiride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Glimepiride in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Glimepiride in pediatric patients.
# Contraindications
- Glimepiride tablet is contraindicated in patients with a history of a hypersensitivity reaction to:
- Glimepiride or any of the product’s ingredients.
- Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to glimepiride. Do not use glimepiride in patients who have a history of an allergic reaction to sulfonamide derivatives.
- Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea).
# Warnings
Hypoglycemia
- All sulfonylureas, including glimepiride, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
- Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti- diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
- Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
Hypersensitivity Reactions
- There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Hemolytic Anemia
- Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency.
Increased Risk of Cardiovascular Mortality with Sulfonylureas
- The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy.
- Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:
- Hypoglycemia
- Hemolytic anemia
- In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.
- Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among glimepiride-treated patients and more commonly than in patients who received placebo.
Hypoglycemia:
- In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.
- In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.
- Weight gain: glimepiride, like all sulfonylureas, can cause weight gain.
- Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride- treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock).
- Laboratory Tests:
- Elevated Serum Alanine Aminotransferase (ALT): In 11 pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of glimepiride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Serious hypersensitivity reactions, including anaphylaxis, angioedema, and
- Stevens-Johnson Syndrome
- Hemolytic anemia in patients with and without G6PD deficiency
- Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
- Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
- Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and pancytopenia
- Hepatic porphyria reactions and disulfiram-like reactions
- Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone
# Drug Interactions
Drugs Affecting Glucose Metabolism
- A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
- The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycemic control.
- The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia.
- Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride’s glucose-lowering effect.
- Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion.
- The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.
Miconazole
- A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.
Cytochrome P450 2C9 Interactions
- There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control.
Concomitant Administration of Colesevelam
- Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. Therefore, AMARYL should be administered at least 4 hours prior to colesevelam.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of glimepiride in pregnant women. In animal studies there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas. Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.
- Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glimepiride in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Glimepiride during labor and delivery.
### Nursing Mothers
- It is not known whether glimepiride is excreted in human milk. During pre- and post-natal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Based on these animal data and the potential for hypoglycemia in a nursing infant, a decision should be made whether to discontinue nursing or discontinue glimepiride, taking into account the importance of glimepiride to the mother.
### Pediatric Use
- The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.
- The pharmacokinetics of a 1 mg single dose of glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (± SD) AUC(0-last) (339±203 nghr/mL), Cmax (102±48 ng/mL) and t1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC(0-last) 315±96 nghr/mL, Cmax 103±34 ng/mL and t1/2 5.3±4.1 hours).
- The safety and efficacy of glimepiride in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (n=135) or metformin (n=137). Both treatment-naïve patients (those treated with only diet and exercise for at least 2 weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least 3 months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) through Week 12, targeting a self- monitored fasting fingerstick blood glucose < 126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).
- After 24 weeks, the overall mean treatment difference in HbA1c between glimepiride and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%).
- Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c with glimepiride compared to metformin.
- The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.
- Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of pediatric patients treated with glimepiride and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).
### Geriatic Use
- In clinical trials of glimepiride, 1053 of 3491 patients (30%) were >65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42).
- Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly. Use caution when initiating glimepiride and increasing the dose of glimepiride in this patient population.
### Gender
- There is no FDA guidance on the use of Glimepiride with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Glimepiride with respect to specific racial populations.
### Renal Impairment
- To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride is 1 mg daily for all patients with type 2 diabetes and renal impairment.
- A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal impairment using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine clearance ranged from 10 to 60 mL/min. The pharmacokinetics of glimepiride were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of glimepiride increased when kidney function was impaired. Both studies also demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Glimepiride in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Glimepiride in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Glimepiride in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Recommended Dosing
- Glimepiride tablets should be administered with breakfast or the first main meal of the day.
- The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.
- After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.
- The maximum recommended dose is 8 mg once daily.
- Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
- When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.
Dosage forms and strengths
- Glimepiride tablet is formulated as tablets of:
- 1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side and break line on the other)
- 2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 2’ on one side and break line on the other)
- 4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 4’ on one side and break line on the other)
### Monitoring
- Monitor for hypersensitivity Reactions: Postmarketing reports include anaphylaxis, angioedema and Stevens-Johnson Syndrome. Promptly discontinue glimepiride, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
- A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
- Geriatric or Renally Impaired Patients are at risk for hypoglycemia with glimepiride. Use caution in dose selection and titration, and monitor closely
# IV Compatibility
There is limited information regarding the compatibility of Glimepiride and IV administrations.
# Overdosage
- An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery.
# Pharmacology
## Mechanism of Action
- Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta- cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
## Structure
- Glimepiride is an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as 1-((p-(2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1‑carboxamido) ethyl]phenyl]sulfonyl-3-(trans-4-methylcyclohexyl)urea (C24H34N4O5S) with a molecular weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water.
- The structural formula is:
- Glimepiride tablets contain the active ingredient glimepiride and the following inactive ingredients: lactose monohydrate, sodium starch glycolate, povidone, and magnesium stearate. In addition, glimepiride tablets 1 mg contain ferric oxide red, glimepiride tablets 2 mg contain ferric oxide yellow and FD&C blue #2 aluminum lake, and glimepiride tablets 4 mg contain FD&C blue #2 aluminum lake.
## Pharmacodynamics
- In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2 to 3 hours after single oral doses of glimepiride. The effects of glimepiride on HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials.
## Pharmacokinetics
- Absorption: Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose. When glimepiride was given with meals, the mean Cmax and AUC (area under the curve) were decreased by 8% and 9%, respectively.
- Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.
- In healthy subjects, the intra-and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15 to 23% and 24 to 29%, respectively.
- Distribution: After intravenous dosing in healthy subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
- Metabolism: Glimepiride is completely metabolized by oxidative biotransformation after either an intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one- third of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.
- Excretion: When 14C-glimepiride was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 80 to 90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces. M1 and M2 accounted for approximately 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or feces. After intravenous dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.
- Geriatric Patients: A comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was evaluated in a multiple-dose study using glimepiride 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was approximately 13% lower than that for the younger patients; the mean weight- adjusted clearance for the older patients was approximately 11% higher than that for the younger patients.
- Gender: There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.
- Race: No studies have been conducted to assess the effects of race on glimepiride pharmacokinetics but in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the reduction in HbA1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).
- Renal Impairment: In a single-dose, open-label study glimepiride 3 mg was administered to patients with mild, moderate and severe renal impairment as estimated by creatinine clearance (CLcr): Group I consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II consisted of 3 patients with moderate renal impairment (CLcr = 20 to 50 mL/min) and Group III consisted of 7 patients with severe renal impairment (CLcr < 20 mL/min). Although, glimepiride serum concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher mean AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs in Group I. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and 9.3% for Group III.
- Hepatic Impairment: It is unknown whether there is an effect of hepatic impairment on glimepiride pharmacokinetics because the pharmacokinetics of glimepiride has not been adequately evaluated in patients with hepatic impairment.
- Obese Patients: The pharmacokinetics of glimepiride and its metabolites were measured in a single-dose study involving 28 patients with type 2 diabetes who either had normal body weight or were morbidly obese. While the tmax, clearance, and volume of distribution of glimepiride in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower Cmax and AUC than those of normal body weight. The mean Cmax, AUC0-24, AUC0-∞ values of glimepiride in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ± 1030 hoursng/mL vs. 2820 ± 1110 hoursng/mL and 4000 ± 1320 hoursng/mL vs. 3280 ± 1360 hoursng/mL, respectively.
- Drug Interactions:
- Aspirin: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 1 mg dose of glimepiride was administered. The glimepiride doses were separated by a 14-day washout period. Co-administration of aspirin and glimepiride resulted in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride Cmax.
- Colesevelam: Concomitant administration of colesevelam and glimepiride resulted in reductions in glimepiride AUC0-∞ and Cmax of 18% and 8%, respectively. When glimepiride was administered 4 hours prior to colesevelam, there was no significant change in glimepiride AUC0-∞ or Cmax, -6% and 3%, respectively.
- Cimetidine and Ranitidine: In a randomized, open-label, 3-way crossover study, healthy subjects received either a single 4 mg dose of glimepiride alone, glimepiride with ranitidine (150 mg twice daily for 4 days; glimepiride was administered on Day 3), or glimepiride with cimetidine (800 mg daily for 4 days; glimepiride was administered on Day 3). Co‑administration of cimetidine or ranitidine with a single 4 mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride.
- Propranolol: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or propranolol 40 mg three times daily for a total treatment period of 5 days. On Day 4 or each study period, a single 2 mg dose of glimepiride was administered. The glimepiride doses were separated by a 14-day washout period. Concomitant administration of propranolol and glimepiride significantly increased glimepiride Cmax, AUC, and T1/2 by 23%, 22%, and 15%, respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and M2 from urine was not changed.
- Warfarin: In an open-label, two-way, crossover study, healthy subjects received 4 mg of glimepiride daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting glimepiride and on Day 4 of glimepiride administration. The concomitant administration of glimepiride did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Glimepiride resulted in a statistically significant decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and Impairment of Fertility
- Studies in rats at doses of up to 5000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation that was dose-related and was thought to be the result of chronic pancreatic stimulation.
- No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46‑ 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.
- Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test).
- There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
# Clinical Studies
Monotherapy
- A total of 304 patients with type 2 diabetes already treated with sulfonylurea therapy participated in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of glimepiride monotherapy. Patients discontinued their sulfonylurea therapy then entered a 3-week placebo washout period followed by randomization into 1 of 4 treatment groups: placebo (n=74), glimepiride 1 mg (n=78), glimepiride 4 mg (n=76) and glimepiride 8 mg (n=76). All patients randomized to glimepiride started 1 mg daily. Patients randomized to glimepiride 4 mg or 8 mg had blinded, forced titration of the glimepiride dose at weekly intervals, first to 4 mg and then to 8 mg, as long as the dose was tolerated, until the randomized dose was reached. Patients randomized to the 4 mg dose reached the assigned dose at Week 2. Patients randomized to the 8 mg dose reached the assigned dose at Week 3. Once the randomized dose level was reached, patients were to be maintained at that dose until Week 14. Approximately 66% of the placebo-treated patients completed the trial compared to 81% of patients treated with glimepiride 1 mg and 92% of patients treated with glimepiride 4 mg or 8 mg. Compared to placebo, treatment with glimepiride 1 mg, 4 mg and 8 mg daily provided statistically significant improvements in HbA1C compared to placebo (Table 3).
- A total of 249 patients who were treatment-naïve or who had received limited treatment with antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either glimepiride (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of glimepiride was 1 mg daily and was titrated upward or downward at 2-week intervals to a goal FPG of 90 to 150 mg/dL. Blood glucose levels for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose adjustment, patients were maintained at their optimal dose (1, 2, 3, 4, 6 or 8 mg) for the remaining 12 weeks of the trial. Treatment with glimepiride provided statistically significant improvements in HbA1C and FPG compared to placebo (Table 4).
# How Supplied
- Glimepiride tablets USP are available in the following strengths and package sizes:
- 1 mg tablets: pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side and break line on the other side, and supplied as:
- NDC 68001-177-00 bottles of 100
- NDC 68001-177-03 bottles of 500
## Storage
- Store at 25°C (77°F); excursions permitted to 20 to 25°C (68 to 77°F) (see USP Controlled Room Temperature).
- Dispense in well-closed containers with safety closures.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Inform patients about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose.
- Inform patients about the potential side effects of glimepiride including hypoglycemia and weight gain.
- Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
- Patients with diabetes should be advised to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.
# Precautions with Alcohol
- Hypoglycemia is more likely to occur when alcohol is ingested.
# Brand Names
Amaryl
# Look-Alike Drug Names
There is limited information regarding Glimepiride Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Glimepiride
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Overview
Glimepiride is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, headache, nausea, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Glimepiride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use
- Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.
- Dosing Information
- Glimepiride tablets should be administered with breakfast or the first main meal of the day.
- The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.
- After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.
- The maximum recommended dose is 8 mg once daily.
- Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
- When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Glimepiride in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Glimepiride in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Glimepiride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Glimepiride in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Glimepiride in pediatric patients.
# Contraindications
- Glimepiride tablet is contraindicated in patients with a history of a hypersensitivity reaction to:
- Glimepiride or any of the product’s ingredients.
- Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to glimepiride. Do not use glimepiride in patients who have a history of an allergic reaction to sulfonamide derivatives.
- Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea).
# Warnings
Hypoglycemia
- All sulfonylureas, including glimepiride, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
- Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti- diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.
- Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
Hypersensitivity Reactions
- There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.
Hemolytic Anemia
- Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency.
Increased Risk of Cardiovascular Mortality with Sulfonylureas
- The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy.
- Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:
- Hypoglycemia
- Hemolytic anemia
- In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.
- Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among glimepiride-treated patients and more commonly than in patients who received placebo.
Hypoglycemia:
- In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.
- In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.
- Weight gain: glimepiride, like all sulfonylureas, can cause weight gain.
- Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride- treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock).
- Laboratory Tests:
- Elevated Serum Alanine Aminotransferase (ALT): In 11 pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride-treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of glimepiride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Serious hypersensitivity reactions, including anaphylaxis, angioedema, and
- Stevens-Johnson Syndrome
- Hemolytic anemia in patients with and without G6PD deficiency
- Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.
- Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis
- Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and pancytopenia
- Hepatic porphyria reactions and disulfiram-like reactions
- Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone
# Drug Interactions
Drugs Affecting Glucose Metabolism
- A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
- The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycemic control.
- The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia.
- Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride’s glucose-lowering effect.
- Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion.
- The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.
Miconazole
- A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.
Cytochrome P450 2C9 Interactions
- There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control.
Concomitant Administration of Colesevelam
- Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. Therefore, AMARYL should be administered at least 4 hours prior to colesevelam.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of glimepiride in pregnant women. In animal studies there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas. Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.
- Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glimepiride in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Glimepiride during labor and delivery.
### Nursing Mothers
- It is not known whether glimepiride is excreted in human milk. During pre- and post-natal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Based on these animal data and the potential for hypoglycemia in a nursing infant, a decision should be made whether to discontinue nursing or discontinue glimepiride, taking into account the importance of glimepiride to the mother.
### Pediatric Use
- The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.
- The pharmacokinetics of a 1 mg single dose of glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (± SD) AUC(0-last) (339±203 ng•hr/mL), Cmax (102±48 ng/mL) and t1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC(0-last) 315±96 ng•hr/mL, Cmax 103±34 ng/mL and t1/2 5.3±4.1 hours).
- The safety and efficacy of glimepiride in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (n=135) or metformin (n=137). Both treatment-naïve patients (those treated with only diet and exercise for at least 2 weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least 3 months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) through Week 12, targeting a self- monitored fasting fingerstick blood glucose < 126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).
- After 24 weeks, the overall mean treatment difference in HbA1c between glimepiride and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%).
- Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c with glimepiride compared to metformin.
- The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.
- Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of pediatric patients treated with glimepiride and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).
### Geriatic Use
- In clinical trials of glimepiride, 1053 of 3491 patients (30%) were >65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42).
- Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly. Use caution when initiating glimepiride and increasing the dose of glimepiride in this patient population.
### Gender
- There is no FDA guidance on the use of Glimepiride with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Glimepiride with respect to specific racial populations.
### Renal Impairment
- To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride is 1 mg daily for all patients with type 2 diabetes and renal impairment.
- A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal impairment using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine clearance ranged from 10 to 60 mL/min. The pharmacokinetics of glimepiride were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of glimepiride increased when kidney function was impaired. Both studies also demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Glimepiride in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Glimepiride in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Glimepiride in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Recommended Dosing
- Glimepiride tablets should be administered with breakfast or the first main meal of the day.
- The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.
- After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.
- The maximum recommended dose is 8 mg once daily.
- Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.
- When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.
Dosage forms and strengths
- Glimepiride tablet is formulated as tablets of:
- 1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side and break line on the other)
- 2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 2’ on one side and break line on the other)
- 4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 4’ on one side and break line on the other)
### Monitoring
- Monitor for hypersensitivity Reactions: Postmarketing reports include anaphylaxis, angioedema and Stevens-Johnson Syndrome. Promptly discontinue glimepiride, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
- A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
- Geriatric or Renally Impaired Patients are at risk for hypoglycemia with glimepiride. Use caution in dose selection and titration, and monitor closely
# IV Compatibility
There is limited information regarding the compatibility of Glimepiride and IV administrations.
# Overdosage
- An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery.
# Pharmacology
## Mechanism of Action
- Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta- cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
## Structure
- Glimepiride is an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as 1-((p-(2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1‑carboxamido) ethyl]phenyl]sulfonyl-3-(trans-4-methylcyclohexyl)urea (C24H34N4O5S) with a molecular weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water.
- The structural formula is:
- Glimepiride tablets contain the active ingredient glimepiride and the following inactive ingredients: lactose monohydrate, sodium starch glycolate, povidone, and magnesium stearate. In addition, glimepiride tablets 1 mg contain ferric oxide red, glimepiride tablets 2 mg contain ferric oxide yellow and FD&C blue #2 aluminum lake, and glimepiride tablets 4 mg contain FD&C blue #2 aluminum lake.
## Pharmacodynamics
- In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2 to 3 hours after single oral doses of glimepiride. The effects of glimepiride on HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials.
## Pharmacokinetics
- Absorption: Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose. When glimepiride was given with meals, the mean Cmax and AUC (area under the curve) were decreased by 8% and 9%, respectively.
- Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.
- In healthy subjects, the intra-and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15 to 23% and 24 to 29%, respectively.
- Distribution: After intravenous dosing in healthy subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
- Metabolism: Glimepiride is completely metabolized by oxidative biotransformation after either an intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one- third of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.
- Excretion: When 14C-glimepiride was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 80 to 90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces. M1 and M2 accounted for approximately 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or feces. After intravenous dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.
- Geriatric Patients: A comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was evaluated in a multiple-dose study using glimepiride 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was approximately 13% lower than that for the younger patients; the mean weight- adjusted clearance for the older patients was approximately 11% higher than that for the younger patients.
- Gender: There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.
- Race: No studies have been conducted to assess the effects of race on glimepiride pharmacokinetics but in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the reduction in HbA1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).
- Renal Impairment: In a single-dose, open-label study glimepiride 3 mg was administered to patients with mild, moderate and severe renal impairment as estimated by creatinine clearance (CLcr): Group I consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II consisted of 3 patients with moderate renal impairment (CLcr = 20 to 50 mL/min) and Group III consisted of 7 patients with severe renal impairment (CLcr < 20 mL/min). Although, glimepiride serum concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher mean AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs in Group I. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and 9.3% for Group III.
- Hepatic Impairment: It is unknown whether there is an effect of hepatic impairment on glimepiride pharmacokinetics because the pharmacokinetics of glimepiride has not been adequately evaluated in patients with hepatic impairment.
- Obese Patients: The pharmacokinetics of glimepiride and its metabolites were measured in a single-dose study involving 28 patients with type 2 diabetes who either had normal body weight or were morbidly obese. While the tmax, clearance, and volume of distribution of glimepiride in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower Cmax and AUC than those of normal body weight. The mean Cmax, AUC0-24, AUC0-∞ values of glimepiride in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ± 1030 hours•ng/mL vs. 2820 ± 1110 hours•ng/mL and 4000 ± 1320 hours•ng/mL vs. 3280 ± 1360 hours•ng/mL, respectively.
- Drug Interactions:
- Aspirin: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 1 mg dose of glimepiride was administered. The glimepiride doses were separated by a 14-day washout period. Co-administration of aspirin and glimepiride resulted in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride Cmax.
- Colesevelam: Concomitant administration of colesevelam and glimepiride resulted in reductions in glimepiride AUC0-∞ and Cmax of 18% and 8%, respectively. When glimepiride was administered 4 hours prior to colesevelam, there was no significant change in glimepiride AUC0-∞ or Cmax, -6% and 3%, respectively.
- Cimetidine and Ranitidine: In a randomized, open-label, 3-way crossover study, healthy subjects received either a single 4 mg dose of glimepiride alone, glimepiride with ranitidine (150 mg twice daily for 4 days; glimepiride was administered on Day 3), or glimepiride with cimetidine (800 mg daily for 4 days; glimepiride was administered on Day 3). Co‑administration of cimetidine or ranitidine with a single 4 mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride.
- Propranolol: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or propranolol 40 mg three times daily for a total treatment period of 5 days. On Day 4 or each study period, a single 2 mg dose of glimepiride was administered. The glimepiride doses were separated by a 14-day washout period. Concomitant administration of propranolol and glimepiride significantly increased glimepiride Cmax, AUC, and T1/2 by 23%, 22%, and 15%, respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and M2 from urine was not changed.
- Warfarin: In an open-label, two-way, crossover study, healthy subjects received 4 mg of glimepiride daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting glimepiride and on Day 4 of glimepiride administration. The concomitant administration of glimepiride did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Glimepiride resulted in a statistically significant decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and Impairment of Fertility
- Studies in rats at doses of up to 5000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation that was dose-related and was thought to be the result of chronic pancreatic stimulation.
- No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46‑ 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.
- Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test).
- There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
# Clinical Studies
Monotherapy
- A total of 304 patients with type 2 diabetes already treated with sulfonylurea therapy participated in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of glimepiride monotherapy. Patients discontinued their sulfonylurea therapy then entered a 3-week placebo washout period followed by randomization into 1 of 4 treatment groups: placebo (n=74), glimepiride 1 mg (n=78), glimepiride 4 mg (n=76) and glimepiride 8 mg (n=76). All patients randomized to glimepiride started 1 mg daily. Patients randomized to glimepiride 4 mg or 8 mg had blinded, forced titration of the glimepiride dose at weekly intervals, first to 4 mg and then to 8 mg, as long as the dose was tolerated, until the randomized dose was reached. Patients randomized to the 4 mg dose reached the assigned dose at Week 2. Patients randomized to the 8 mg dose reached the assigned dose at Week 3. Once the randomized dose level was reached, patients were to be maintained at that dose until Week 14. Approximately 66% of the placebo-treated patients completed the trial compared to 81% of patients treated with glimepiride 1 mg and 92% of patients treated with glimepiride 4 mg or 8 mg. Compared to placebo, treatment with glimepiride 1 mg, 4 mg and 8 mg daily provided statistically significant improvements in HbA1C compared to placebo (Table 3).
- A total of 249 patients who were treatment-naïve or who had received limited treatment with antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either glimepiride (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of glimepiride was 1 mg daily and was titrated upward or downward at 2-week intervals to a goal FPG of 90 to 150 mg/dL. Blood glucose levels for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose adjustment, patients were maintained at their optimal dose (1, 2, 3, 4, 6 or 8 mg) for the remaining 12 weeks of the trial. Treatment with glimepiride provided statistically significant improvements in HbA1C and FPG compared to placebo (Table 4).
# How Supplied
- Glimepiride tablets USP are available in the following strengths and package sizes:
- 1 mg tablets: pink coloured, oval shaped, biconvex, uncoated tablets debossed with ‘AHI 1’ on one side and break line on the other side, and supplied as:
- NDC 68001-177-00 bottles of 100
- NDC 68001-177-03 bottles of 500
## Storage
- Store at 25°C (77°F); excursions permitted to 20 to 25°C (68 to 77°F) (see USP Controlled Room Temperature).
- Dispense in well-closed containers with safety closures.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Inform patients about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose.
- Inform patients about the potential side effects of glimepiride including hypoglycemia and weight gain.
- Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
- Patients with diabetes should be advised to inform their healthcare provider if they are pregnant, contemplating pregnancy, breastfeeding, or contemplating breastfeeding.
# Precautions with Alcohol
- Hypoglycemia is more likely to occur when alcohol is ingested.
# Brand Names
Amaryl
# Look-Alike Drug Names
There is limited information regarding Glimepiride Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Amarel | |
9622ddd760a25c7dd03abc03365e1195928087f0 | wikidoc | Amaxophobia | Amaxophobia
# Overview
Amaxophobia, hamaxophobia, ochophobia, or motorphobia is an abnormal or persistent fear of being in, or riding in, a vehicle. Amaxophobia is a clinical phobia classified as a specific phobia, fear of a single specific panic trigger.
Amaxophobic sufferers riding in a vehicle will typically fear the accident and its consequences, especially injury or death. They may do backseat driving, which involves haranguing the driver which can distract the driver and increase the odds of car crash. In addition, sufferers may fear enclosed spaces or being trapped in a vehicle. Amaxophobic people may try to look for jobs or careers that do not require car rides, which may limit potential lifetime achievements.
The term amaxophobia comes from the Greek ἄμαξα (ámaxa) or ἅμαξα (hamaxa), "a carriage" and φόβος (phóbos), "fear".
# Symptoms and treatment
Many amaxophobics may feel a sense of panic or feeling out of control. Other symptoms include headache, nausea, dizziness, terror, and other facets of panic attacks when sufferer is in a vehicle.
Therapies are recommended to treat amaxophobia, such as cognitive "tapping" therapy used to erase negative memory that caused fear. Psychotherapy is a traditional treatment method, and talk therapy is used to soothe the sufferer. Anti-depressants are often recommended tool to treat amaxophobia, especially in the modern world when/where vehicles are common. | Amaxophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amaxophobia, hamaxophobia, ochophobia, or motorphobia is an abnormal or persistent fear of being in, or riding in, a vehicle. Amaxophobia is a clinical phobia classified as a specific phobia, fear of a single specific panic trigger.[citation needed]
Amaxophobic sufferers riding in a vehicle will typically fear the accident and its consequences, especially injury or death. They may do backseat driving, which involves haranguing the driver which can distract the driver and increase the odds of car crash.[citation needed] In addition, sufferers may fear enclosed spaces or being trapped in a vehicle. Amaxophobic people may try to look for jobs or careers that do not require car rides, which may limit potential lifetime achievements.[citation needed]
The term amaxophobia comes from the Greek ἄμαξα (ámaxa) or ἅμαξα (hamaxa), "a carriage" and φόβος (phóbos), "fear".
# Symptoms and treatment
Many amaxophobics may feel a sense of panic or feeling out of control. Other symptoms include headache, nausea, dizziness, terror, and other facets of panic attacks when sufferer is in a vehicle.[citation needed]
Therapies are recommended to treat amaxophobia, such as cognitive "tapping" therapy used to erase negative memory that caused fear. Psychotherapy is a traditional treatment method, and talk therapy is used to soothe the sufferer. Anti-depressants are often recommended tool to treat amaxophobia, especially in the modern world when/where vehicles are common. | https://www.wikidoc.org/index.php/Amaxophobia | |
c67d7d903a54a87c86100484d0821b62aec94e5d | wikidoc | Ambivalence | Ambivalence
# Background
Ambivalence is a state of having emotions of both positive and negative valence or of having thoughts or actions in contradiction with each other, when they are related to the same object, idea or person (for example, feeling both love and hatred for someone or something). The term is also commonly used to refer to situations where 'mixed feelings' of a more general sort are experienced or where a person experiences uncertainty or indecisiveness concerning something.
# Ambivalence in psychoanalysis
In psychoanalytic terminology, however, a more refined definition applies: the term (introduced into the discipline by Bleuler in 1911), refers to an underlying emotional attitude in which the co-existing contradictory impulses (usually love and hate) derive from a common source and are thus held to be interdependent. Moreover, when the term is used in this psychoanalytic sense it would not usually be expected that the person embodying this 'ambivalence' would actually feel both of the two contradictory emotions as such: except in obsessional neurosis, which sees both sides being more or less 'balanced' in consciousness, one or other of the conflicting sides is usually repressed. (Thus, for example, an analysand's 'love' for his father might be quite consciously experienced and openly expressed – while his 'hate' for the same object might be heavily repressed and only indirectly expressed, and thus only revealed in analysis).
Another relevant distinction is that whereas the psychoanalytic notion of 'ambivalence' sees it as engendered by all neurotic conflict, a person's everyday 'mixed feelings' may easily be based on a quite realistic assessment of the imperfect, inconsistent or self-contradictory nature of the thing being considered.
# Intellectual ambivalence
Intellectual ambivalence refers to an inability or unwillingness to commit oneself to a definite answer, position, or conclusion in thought ("yea or nay"), normally either because a definite stance is deliberately avoided or evaded for some personal motive, or because sufficient grounds (logical or experiential evidence) warranting a definite stance are lacking. To resolve intellectual ambivalence into a definite position is frequently a task for criticism or critique. The main problem with intellectual ambivalence is that it provides no clear guide or orientation for action and leadership. It is difficult to act or lead on the basis that something "might or might not be the case", that something "might or might not be a good idea" etc. In order to act or lead, definite ideas are necessary rather than uncertainty which incapacitates choices and decisions. Thus it often happens that someone in a leadership function pretends to be very "definite" about an issue, because the function requires it, even though he or she is in truth ambivalent about the issue. | Ambivalence
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Ambivalence is a state of having emotions of both positive and negative valence or of having thoughts or actions in contradiction with each other, when they are related to the same object, idea or person (for example, feeling both love and hatred for someone or something). The term is also commonly used to refer to situations where 'mixed feelings' of a more general sort are experienced or where a person experiences uncertainty or indecisiveness concerning something.
Template:Emotion
# Ambivalence in psychoanalysis
In psychoanalytic terminology, however, a more refined definition applies: the term (introduced into the discipline by Bleuler in 1911), refers to an underlying emotional attitude in which the co-existing contradictory impulses (usually love and hate) derive from a common source and are thus held to be interdependent. Moreover, when the term is used in this psychoanalytic sense it would not usually be expected that the person embodying this 'ambivalence' would actually feel both of the two contradictory emotions as such: except in obsessional neurosis, which sees both sides being more or less 'balanced' in consciousness, one or other of the conflicting sides is usually repressed. (Thus, for example, an analysand's 'love' for his father might be quite consciously experienced and openly expressed – while his 'hate' for the same object might be heavily repressed and only indirectly expressed, and thus only revealed in analysis).
Another relevant distinction is that whereas the psychoanalytic notion of 'ambivalence' sees it as engendered by all neurotic conflict, a person's everyday 'mixed feelings' may easily be based on a quite realistic assessment of the imperfect, inconsistent or self-contradictory nature of the thing being considered.
# Intellectual ambivalence
Intellectual ambivalence refers to an inability or unwillingness to commit oneself to a definite answer, position, or conclusion in thought ("yea or nay"), normally either because a definite stance is deliberately avoided or evaded for some personal motive, or because sufficient grounds (logical or experiential evidence) warranting a definite stance are lacking. To resolve intellectual ambivalence into a definite position is frequently a task for criticism or critique. The main problem with intellectual ambivalence is that it provides no clear guide or orientation for action and leadership. It is difficult to act or lead on the basis that something "might or might not be the case", that something "might or might not be a good idea" etc. In order to act or lead, definite ideas are necessary rather than uncertainty which incapacitates choices and decisions. Thus it often happens that someone in a leadership function pretends to be very "definite" about an issue, because the function requires it, even though he or she is in truth ambivalent about the issue. | https://www.wikidoc.org/index.php/Ambivalence | |
2edb785fc9e8937a2982cc2e94b4a4ebbf39fd17 | wikidoc | Ambrisentan | Ambrisentan
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ambrisentan is an endothelin receptor antagonist that is FDA approved for the {{{indicationType}}} of pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, decreased hemoglobin, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).
- Dosing Information
- Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.
- Tablets may be administered with or without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH).
- Initiate treatment with Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambrisentan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambrisentan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of Letairis in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambrisentan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambrisentan in pediatric patients.
# Contraindications
- Pregnancy
- Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in females who are pregnant. Letairis was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Idiopathic Pulmonary Fibrosis
- Letairis is contraindicated in patients with idiopathic pulmonary fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3)
# Warnings
- Letairis may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.
- Letairis is only available for females through a restricted program under a REMS.
- For all females, Letairis is available only through a restricted program called the Letairis REMS, because of the risk of embryo-fetal toxicity.
- Notable requirements of the Letairis REMS program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the Letairis REMS program prior to initiating Letairis. Male patients are not enrolled in the REMS.
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
- Pharmacies that dispense Letairis must be certified with the program and must dispense to female patients who are authorized to receive Letairis.
- Further information is available at www.letairisrems.com or 1-866-664-5327.
- Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg Letairis compared to placebo. Most edema was mild to moderate in severity, and it occurred with greater frequency and severity in elderly patients.
- In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting Letairis. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.
- If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Letairis or underlying heart failure, and the possible need for specific treatment or discontinuation of Letairis therapy.
- If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Letairis, the possibility of PVOD should be considered, and if confirmed Letairis should be discontinued.
- Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Letairis may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility.
- Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Letairis. These decreases were observed within the first few weeks of treatment with Letairis, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving Letairis in the 12-week placebo-controlled studies was 0.8 g/dL.
- Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving Letairis (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis.
- In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment.
- There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion.
- Measure hemoglobin prior to initiation of Letairis, at one month, and periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing Letairis.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Safety data for Letairis were obtained from two 12-week, placebo-controlled studies in patients with pulmonary arterial hypertension (PAH) (ARIES-1 and ARIES-2) and four nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to Letairis in these studies ranged from 1 day to 4 years (N = 418 for at least 6 months and N = 343 for at least 1 year).
- In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in >3% more patients receiving Letairis than receiving placebo are shown in Table 1.
- Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.
- Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients (<65 years) receiving Letairis (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving Letairis (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.
- The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for Letairis (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for Letairis (5%; 13/261 patients).
- During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 × upper limit of normal (ULN) were 0% on Letairis and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.
- In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations >3 × ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT elevations 8 × ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 × ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on Letairis 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of Letairis to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that Letairis led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that Letairis may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.
## Postmarketing Experience
- The following adverse reactions were identified during postapproval use of Letairis. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia, heart failure (associated with fluid retention), hypersensitivity (eg, angioedema, rash), nausea, and vomiting.
- Elevations of liver aminotransferases (ALT, AST) have been reported with Letairis use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.
# Drug Interactions
- Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine.
- Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 µM, 45 µM, and approximately 100 µM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.
- The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Risk Summary
- Letairis may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus.
- Animal Data
- Letairis was teratogenic at oral doses of ≥ 15 mg/kg/day (AUC 51.7 hµg/mL) in rats and ≥ 7 mg/kg/day (24.7 hµg/mL) in rabbits; it was not studied at lower doses. These doses are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 hµg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid.
- A preclinical study in rats has shown decreased survival of newborn pups (mid and high doses) and effects on testicle size and fertility of pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17 ×, 51 ×, and 170 × (on a mg/kg:mg/m2 basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ambrisentan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ambrisentan during labor and delivery.
### Nursing Mothers
- It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Letairis, a decision should be made whether to discontinue nursing or discontinue Letairis, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Letairis in pediatric patients have not been established.
### Geriatic Use
- In the two placebo-controlled clinical studies of Letairis, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with Letairis than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients.
### Gender
There is no FDA guidance on the use of Ambrisentan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ambrisentan with respect to specific racial populations.
### Renal Impairment
- The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure to ambrisentan. Dose adjustment of Letairis in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment.
- The impact of hemodialysis on the disposition of ambrisentan has not been investigated.
### Hepatic Impairment
- Pre-existing Hepatic Impairment
- The influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan. Letairis is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Letairis in patients with mild pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients.
- Elevation of Liver Transaminases
- Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure. In patients who develop hepatic impairment after Letairis initiation, the cause of liver injury should be fully investigated. Discontinue Letairis if elevations of liver aminotransferases are >5 × ULN or if elevations are accompanied by bilirubin >2 × ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.
### Females of Reproductive Potential and Males
- Pregnancy Testing
- Female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and 1 month after stopping treatment with Letairis. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options.
- Contraception
- Female patients of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for 1 month after stopping treatment with Letairis. Patients may choose one highly effective form of contraception (intrauterine device (IUD), contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling.
- Infertility in Males
- In a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Letairis have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility.
### Immunocompromised Patients
There is no FDA guidance one the use of Ambrisentan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ambrisentan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ambrisentan in the drug label.
# Overdosage
## Acute Overdose
- There is no experience with overdosage of Letairis. The highest single dose of Letairis administered to healthy volunteers was 100 mg, and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Massive overdosage could potentially result in hypotension that may require intervention.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ambrisentan in the drug label.
# Pharmacology
## Mechanism of Action
- Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.
- In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.
- Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known.
## Structure
- Letairis is the brand name for ambrisentan, an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2--3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C22H22N2O4 and a molecular weight of 378.42. It contains a single chiral center determined to be the (S) configuration and has the following structural formula:
- Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0. Ambrisentan is practically insoluble in water and in aqueous solutions at low pH. Solubility increases in aqueous solutions at higher pH. In the solid state ambrisentan is very stable, is not hygroscopic, and is not light sensitive.
- Letairis is available as 5 mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Each square, pale pink Letairis tablet contains 5 mg of ambrisentan. Each oval, deep pink Letairis tablet contains 10 mg of ambrisentan. Letairis tablets are unscored.
## Pharmacodynamics
- Cardiac Electrophysiology
- In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either Letairis 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Letairis 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of Letairis increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving Letairis 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.
## Pharmacokinetics
- The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose on a mg/m2 basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high- and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was a positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group.
- Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA synthesis assay).
- The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses ≥10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses ≥50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of ≥10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present.
# Clinical Studies
- Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of Letairis and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Letairis to placebo. In both studies, Letairis or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36® Health Survey were assessed.
- Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.
- Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.
- Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 2 and Figure 4.
- In both studies, treatment with Letairis resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Letairis, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Letairis were smaller for elderly patients (age ≥65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.
- The effects of Letairis on walk distances at trough drug levels are not known. Because only once-daily dosing was studied in the clinical trials, the efficacy and safety of more frequent dosing regimens for Letairis are not known. If exercise ability is not sustained throughout the day in a patient, consider other PAH treatments that have been studied with more-frequent dosing regimens.
- Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the Letairis clinical trials are shown in Table 3 and Figure 5.
- There was a significant delay in the time to clinical worsening for patients receiving Letairis compared to placebo. Results in subgroups such as the elderly were also favorable.
- In long-term follow-up of patients who were treated with Letairis (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N = 383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on Letairis for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis on mortality.
- A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Letairis (N = 329) to placebo (N = 163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on Letairis. More patients taking Letairis died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%).
# How Supplied
- Letairis film-coated tablets are supplied as follows:
- Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F).
- Store Letairis in its original packaging.
## Storage
There is limited information regarding Ambrisentan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Ambrisentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Letairis®
# Look-Alike Drug Names
- Letairis® — Letaris®
# Drug Shortage Status
# Price | Ambrisentan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Ambrisentan is an endothelin receptor antagonist that is FDA approved for the {{{indicationType}}} of pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, decreased hemoglobin, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).
- Dosing Information
- Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.
- Tablets may be administered with or without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH).
- Initiate treatment with Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambrisentan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambrisentan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of Letairis in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ambrisentan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ambrisentan in pediatric patients.
# Contraindications
- Pregnancy
- Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in females who are pregnant. Letairis was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Idiopathic Pulmonary Fibrosis
- Letairis is contraindicated in patients with idiopathic pulmonary fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3)
# Warnings
- Letairis may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.
- Letairis is only available for females through a restricted program under a REMS.
- For all females, Letairis is available only through a restricted program called the Letairis REMS, because of the risk of embryo-fetal toxicity.
- Notable requirements of the Letairis REMS program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the Letairis REMS program prior to initiating Letairis. Male patients are not enrolled in the REMS.
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
- Pharmacies that dispense Letairis must be certified with the program and must dispense to female patients who are authorized to receive Letairis.
- Further information is available at www.letairisrems.com or 1-866-664-5327.
- Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg Letairis compared to placebo. Most edema was mild to moderate in severity, and it occurred with greater frequency and severity in elderly patients.
- In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting Letairis. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.
- If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Letairis or underlying heart failure, and the possible need for specific treatment or discontinuation of Letairis therapy.
- If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Letairis, the possibility of PVOD should be considered, and if confirmed Letairis should be discontinued.
- Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Letairis may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility.
- Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Letairis. These decreases were observed within the first few weeks of treatment with Letairis, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving Letairis in the 12-week placebo-controlled studies was 0.8 g/dL.
- Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving Letairis (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis.
- In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment.
- There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion.
- Measure hemoglobin prior to initiation of Letairis, at one month, and periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing Letairis.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Safety data for Letairis were obtained from two 12-week, placebo-controlled studies in patients with pulmonary arterial hypertension (PAH) (ARIES-1 and ARIES-2) and four nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to Letairis in these studies ranged from 1 day to 4 years (N = 418 for at least 6 months and N = 343 for at least 1 year).
- In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in >3% more patients receiving Letairis than receiving placebo are shown in Table 1.
- Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.
- Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients (<65 years) receiving Letairis (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving Letairis (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.
- The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for Letairis (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for Letairis (5%; 13/261 patients).
- During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 × upper limit of normal (ULN) were 0% on Letairis and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.
- In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations >3 × ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5 × ULN, but 9 patients had elevations >8 × ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 × ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on Letairis 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of Letairis to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that Letairis led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that Letairis may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.
## Postmarketing Experience
- The following adverse reactions were identified during postapproval use of Letairis. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia, heart failure (associated with fluid retention), hypersensitivity (eg, angioedema, rash), nausea, and vomiting.
- Elevations of liver aminotransferases (ALT, AST) have been reported with Letairis use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.
# Drug Interactions
- Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine.
- Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 µM, 45 µM, and approximately 100 µM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.
- The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Risk Summary
- Letairis may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus.
- Animal Data
- Letairis was teratogenic at oral doses of ≥ 15 mg/kg/day (AUC 51.7 h•µg/mL) in rats and ≥ 7 mg/kg/day (24.7 h•µg/mL) in rabbits; it was not studied at lower doses. These doses are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•µg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid.
- A preclinical study in rats has shown decreased survival of newborn pups (mid and high doses) and effects on testicle size and fertility of pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17 ×, 51 ×, and 170 × (on a mg/kg:mg/m2 basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ambrisentan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ambrisentan during labor and delivery.
### Nursing Mothers
- It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Letairis, a decision should be made whether to discontinue nursing or discontinue Letairis, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Letairis in pediatric patients have not been established.
### Geriatic Use
- In the two placebo-controlled clinical studies of Letairis, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with Letairis than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients.
### Gender
There is no FDA guidance on the use of Ambrisentan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ambrisentan with respect to specific racial populations.
### Renal Impairment
- The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure to ambrisentan. Dose adjustment of Letairis in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment.
- The impact of hemodialysis on the disposition of ambrisentan has not been investigated.
### Hepatic Impairment
- Pre-existing Hepatic Impairment
- The influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan. Letairis is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Letairis in patients with mild pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients.
- Elevation of Liver Transaminases
- Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure. In patients who develop hepatic impairment after Letairis initiation, the cause of liver injury should be fully investigated. Discontinue Letairis if elevations of liver aminotransferases are >5 × ULN or if elevations are accompanied by bilirubin >2 × ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.
### Females of Reproductive Potential and Males
- Pregnancy Testing
- Female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and 1 month after stopping treatment with Letairis. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options.
- Contraception
- Female patients of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for 1 month after stopping treatment with Letairis. Patients may choose one highly effective form of contraception (intrauterine device (IUD), contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling.
- Infertility in Males
- In a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Letairis have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility.
### Immunocompromised Patients
There is no FDA guidance one the use of Ambrisentan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ambrisentan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ambrisentan in the drug label.
# Overdosage
## Acute Overdose
- There is no experience with overdosage of Letairis. The highest single dose of Letairis administered to healthy volunteers was 100 mg, and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Massive overdosage could potentially result in hypotension that may require intervention.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ambrisentan in the drug label.
# Pharmacology
## Mechanism of Action
- Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.
- In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.
- Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known.
## Structure
- Letairis is the brand name for ambrisentan, an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C22H22N2O4 and a molecular weight of 378.42. It contains a single chiral center determined to be the (S) configuration and has the following structural formula:
- Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0. Ambrisentan is practically insoluble in water and in aqueous solutions at low pH. Solubility increases in aqueous solutions at higher pH. In the solid state ambrisentan is very stable, is not hygroscopic, and is not light sensitive.
- Letairis is available as 5 mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Each square, pale pink Letairis tablet contains 5 mg of ambrisentan. Each oval, deep pink Letairis tablet contains 10 mg of ambrisentan. Letairis tablets are unscored.
## Pharmacodynamics
- Cardiac Electrophysiology
- In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either Letairis 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Letairis 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of Letairis increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving Letairis 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.
## Pharmacokinetics
- The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high- and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was a positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group.
- Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA synthesis assay).
- The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses ≥10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses ≥50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of ≥10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present.
# Clinical Studies
- Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of Letairis and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Letairis to placebo. In both studies, Letairis or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36® Health Survey were assessed.
- Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.
- Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.
- Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 2 and Figure 4.
- In both studies, treatment with Letairis resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Letairis, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Letairis were smaller for elderly patients (age ≥65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.
- The effects of Letairis on walk distances at trough drug levels are not known. Because only once-daily dosing was studied in the clinical trials, the efficacy and safety of more frequent dosing regimens for Letairis are not known. If exercise ability is not sustained throughout the day in a patient, consider other PAH treatments that have been studied with more-frequent dosing regimens.
- Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the Letairis clinical trials are shown in Table 3 and Figure 5.
- There was a significant delay in the time to clinical worsening for patients receiving Letairis compared to placebo. Results in subgroups such as the elderly were also favorable.
- In long-term follow-up of patients who were treated with Letairis (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N = 383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on Letairis for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis on mortality.
- A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Letairis (N = 329) to placebo (N = 163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on Letairis. More patients taking Letairis died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%).
# How Supplied
- Letairis film-coated tablets are supplied as follows:
- Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F).
- Store Letairis in its original packaging.
## Storage
There is limited information regarding Ambrisentan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Ambrisentan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Letairis®[1]
# Look-Alike Drug Names
- Letairis® — Letaris®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ambrisentan | |
2565ba1e2c0242f3dbd427e422ab858cc2f1eb19 | wikidoc | Naratriptan | Naratriptan
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# Overview
Naratriptan is an antimigraine and5-HT1 serotonin receptor agonist that is FDA approved for the treatment of migraine with or without aura in adults. Common adverse reactions include paresthesias, nausea, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Dosing Information
- The recommended dose of Naratriptan is 1 mg or 2.5 mg.
- If the migraine returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period.
- The safety of treating an average of more than 4 migraine attacks in a 30‑day period has not been established.
### Dosage Adjustment in Patients With Renal Impairment
- Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug.
- In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24‑hour period and a 1-mg starting dose is recommended.
### Dosage Adjustment in Patients With Hepatic Impairment
- Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance.
- In patients with mild or moderate hepatic impairment (Child-Pugh grade A or B), the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1-mg starting dose is recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naratriptan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naratriptan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Naratriptan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naratriptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naratriptan in pediatric patients.
# Contraindications
Naratriptan is contraindicated in patients with:
- Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina
- Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
- History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because such patients are at a higher risk of stroke.
- Peripheral vascular disease.
- Ischemic bowel disease.
- Uncontrolled hypertension.
- Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide)
- Hypersensitivity to Naratriptan (angioedema and anaphylaxis seen)
- Severe renal impairment or hepatic impairment.
# Warnings
### Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
- Naratriptan is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of Naratriptan. Some of these reactions occurred in patients without known CAD. Naratriptan may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD.
- Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving Naratriptan. If there is evidence of CAD or coronary artery vasospasm, Naratriptan is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of Naratriptan in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of Naratriptan. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Naratriptan.
### Arrhythmias
- Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue Naratriptan if these disturbances occur. Naratriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
### Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
- Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with Naratriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT1 agonists, including Naratriptan, are contraindicated in patients with CAD and those with Prinzmetal’s variant angina.
### Cerebrovascular Events
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue Naratriptan if a cerebrovascular event occurs.
- Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions. Naratriptan is contraindicated in patients with a history of stroke or TIA.
### Other Vasospasm Reactions
- Naratriptan may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional doses of Naratriptan.
- Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
### Medication Overuse Headache
- Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
### Serotonin Syndrome
- Serotonin syndrome may occur with Naratriptan, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAO). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue Naratriptan if serotonin syndrome is suspected.
### Increase in Blood Pressure
- Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with Naratriptan. Naratriptan is contraindicated in patients with uncontrolled hypertension.
### Anaphylactic/Anaphylactoid Reactions
- There have been reports of anaphylaxis and anaphylactoid and hypersensitivity reactions, including angioedema, in patients receiving Naratriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Naratriptan is contraindicated in patients with a history of hypersensitivity reaction to Naratriptan.
# Adverse Reactions
## Clinical Trials Experience
- Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina.
- Arrhythmias.
- Chest, throat, neck, and/or jaw pain/tightness/pressure.
- Cerebrovascular events.
- Other vasospasm reactions.
- Medication overuse headache.
- Serotonin syndrome.
- Increase in blood pressure.
- Hypersensitivity reactions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In a long-term open-label trial where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse reactions.
- In controlled clinical trials, the most common adverse reactions were paresthesias, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms, which occurred at a rate of 2% and at least 2 times placebo rate.
- Table 1 lists the adverse reactions that occurred in 5 placebo-controlled clinical trials of approximately 1,752 exposures to placebo and Naratriptan in adult patients with migraine. Only reactions that occurred at a frequency of 2% or more in groups treated with Naratriptan 2.5 mg and that occurred at a frequency greater than the placebo group in the 5 pooled trials are included in Table 1.
## Postmarketing Experience
There is limited information regarding Naratriptan Postmarketing Experience in the drug label.
# Drug Interactions
### Ergot-Containing Drugs
- Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Naratriptan within 24 hours of each other is contraindicated.
### Other 5-HT1 Agonists
- Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of treatment with Naratriptan is contraindicated because the risk of vasospastic reactions may be additive.
### Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
- Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled trials in pregnant women. Naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg.
- When naratriptan was administered to pregnant rats during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death; incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established.
- When naratriptan was administered orally (1, 5, or 30 mg/kg/day) to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose in this study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established.
- When female rats were treated orally with naratriptan (10, 60, or 340 mg/kg/day) during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Naratriptan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Naratriptan during labor and delivery.
### Nursing Mothers
- Naratriptan is excreted in rat milk. It is not known whether naratriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Naratriptan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Therefore, Naratriptan is not recommended for use in patients younger than 18 years of age.
- One controlled clinical trial evaluated Naratriptan (0.25 to 2.5 mg) in 300 adolescent migraineurs aged 12 to 17 years who received at least 1 dose of Naratriptan for an acute migraine. In this study, 54% of the patients were female and 89% were Caucasian. There were no statistically significant differences between any of the treatment groups. The headache response rates at 4 hours (n) were 65% (n = 74), 67% (n = 78), and 64% (n = 70) for placebo, 1-mg, and 2.5-mg groups, respectively. This trial did not establish the efficacy of Naratriptan compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in this clinical trial were similar in nature to those reported in clinical trials in adults.
### Geriatic Use
- Clinical trials of Naratriptan did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
- Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly.
- A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving Naratriptan
### Gender
There is no FDA guidance on the use of Naratriptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Naratriptan with respect to specific racial populations.
### Renal Impairment
- The use of Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug. In patients with mild to moderate renal impairment, the recommended starting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period.
### Hepatic Impairment
- The use of Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance. In patients with mild or moderate hepatic impairment (Child-Pugh grade A or B), the recommendedstarting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Naratriptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Naratriptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Naratriptan Administration in the drug label.
### Monitoring
There is limited information regarding Naratriptan Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Naratriptan and IV administrations.
# Overdosage
- Adverse reactions observed after overdoses of up to 25 mg included increases in blood pressure resulting in lightheadedness, neck tension, tiredness, and loss of coordination. Also, ischemic ECG changes likely due to coronary artery vasospasm have been reported.
- The elimination half-life of naratriptan is about 6 hours , and therefore monitoring of patients after overdose with Naratriptan should continue for at least 24 hours or while symptoms or signs persist. There is no specific antidote to naratriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.
# Pharmacology
## Mechanism of Action
- Naratriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of Naratriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
## Structure
- Naratriptan hydrochloride is chemically designated as N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride, and it has the following structure:
## Pharmacodynamics
- In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial bed, increases in vascular resistance of up to 30% were seen in the coronary arterial bed. Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat.
- In 10 subjects with suspected CAD undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan
## Pharmacokinetics
### Absorption
- Naratriptan is well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet, the peak concentrations are obtained in 2 to 3 hours. After administration of 1- or 2.5-mg tablets, the Cmax is somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram dose) than in men. During a migraine attack, absorption is slower, with a Tmax of 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range.
### Distribution
- The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL.
### Metabolism
- In vitro, naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites.
### Elimination
- Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
### Carcinogenesis
- In carcinogenicity studies, mice and rats were given naratriptan by oral gavage for 104 weeks. There was no evidence of an increase in tumors related to naratriptan administration in mice receiving up to 200 mg/kg/day. That dose was associated with a plasma (AUC) exposure that was 110 times the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg. Two rat studies were conducted, one using a standard diet and the other a nitrite-supplemented diet (naratriptan can be nitrosated in vitro to form a mutagenic product that has been detected in the stomachs of rats fed a high-nitrite diet). Doses of 5, 20, and 90 mg/kg were associated with AUC exposures that in the standard-diet study were 7, 40, and 236 times, respectively, and in the nitrite-supplemented diet study were 7, 29, and 180 times, respectively, the exposure in humans at the MRDD. In both studies, there was an increase in the incidence of thyroid follicular hyperplasia in high-dose males and females and in thyroid follicular adenomas in high-dose males. In the standard-diet study only, there was also an increase in the incidence of benign c-cell adenomas in the thyroid of high-dose males and females. The exposures achieved at the no-effect dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented diet) times the exposure achieved in humans at the MRDD. In the nitrite-supplemented diet study only, the incidence of benign lymphocytic thymoma was increased in all treated groups of females. It was not determined if the nitrosated product is systemically absorbed. However, no changes were seen in the stomachs of rats in that study.
### Mutagenesis
- Naratriptan was not mutagenic when tested in in vitro gene mutation (Ames and mouse lymphoma tk) assays. Naratriptan was also negative in the in vitro human lymphocyte assay and the in vivo mouse micronucleus assay. Naratriptan can be nitrosated in vitro to form a mutagenic product (WHO nitrosation assay) that has been detected in the stomachs of rats fed a nitrite-supplemented diet.
### Impairment of Fertility
- In a reproductive toxicity study in which male and female rats were administered naratriptan orally prior to and throughout the mating period (10, 60, 170, or 340 mg/kg/day; plasma exposures approximately 11, 70, 230, and 470 times, respectively, the human exposure at the MRDD), there was a treatment-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in preimplantation loss at 60 mg/kg/day or greater. In high-dose males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed preimplantation loss. The exposures achieved at the no-effect doses for preimplantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans at the MRDD.
- In a study in which rats were dosed orally with naratriptan (10, 60, or 340 mg/kg/day) for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times that in humans at the MRDD.
# Clinical Studies
- The efficacy of Naratriptan in the acute treatment of migraine headaches was evaluated in 3 randomized, double-blind, placebo-controlled trials in adult patients (Trials 1, 2, 3). These trials enrolled adult patients who were predominantly female (86%) and Caucasian (96%) with a mean age of 41 years (range: 18 to 65 years). In all studies, patients were instructed to treat at least 1 moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of Naratriptan or other rescue medication to treat migraines was allowed 4 to 24 hours after the initial treatment for recurrent headache.
- In all 3 trials, the percentage of patients achieving headache response 4 hours after treatment, the primary outcome measure, was significantly greater among patients receiving Naratriptan compared with those who received placebo. In all trials, response to 2.5 mg was numerically greater than response to 1 mg and in the largest of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 4 hours in the 2.5-mg group compared with the 1-mg group. The results are summarized in Table 2.
- Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other rescue medication. The estimated probability of patients taking a second dose or other rescue medication to treat migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
# How Supplied
There is limited information regarding Naratriptan How Supplied in the drug label.
## Storage
There is limited information regarding Naratriptan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Naratriptan Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Naratriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Amerge
# Look-Alike Drug Names
There is limited information regarding Naratriptan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Naratriptan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Naratriptan is an antimigraine and5-HT1 serotonin receptor agonist that is FDA approved for the treatment of migraine with or without aura in adults. Common adverse reactions include paresthesias, nausea, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Dosing Information
- The recommended dose of Naratriptan is 1 mg or 2.5 mg.
- If the migraine returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period.
- The safety of treating an average of more than 4 migraine attacks in a 30‑day period has not been established.
### Dosage Adjustment in Patients With Renal Impairment
- Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug.
- In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24‑hour period and a 1-mg starting dose is recommended.
### Dosage Adjustment in Patients With Hepatic Impairment
- Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance.
- In patients with mild or moderate hepatic impairment (Child-Pugh grade A or B), the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1-mg starting dose is recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naratriptan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naratriptan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Naratriptan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naratriptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naratriptan in pediatric patients.
# Contraindications
Naratriptan is contraindicated in patients with:
- Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina
- Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
- History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because such patients are at a higher risk of stroke.
- Peripheral vascular disease.
- Ischemic bowel disease.
- Uncontrolled hypertension.
- Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide)
- Hypersensitivity to Naratriptan (angioedema and anaphylaxis seen)
- Severe renal impairment or hepatic impairment.
# Warnings
### Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
- Naratriptan is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of Naratriptan. Some of these reactions occurred in patients without known CAD. Naratriptan may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD.
- Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving Naratriptan. If there is evidence of CAD or coronary artery vasospasm, Naratriptan is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of Naratriptan in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of Naratriptan. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Naratriptan.
### Arrhythmias
- Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue Naratriptan if these disturbances occur. Naratriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
### Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
- Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with Naratriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT1 agonists, including Naratriptan, are contraindicated in patients with CAD and those with Prinzmetal’s variant angina.
### Cerebrovascular Events
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue Naratriptan if a cerebrovascular event occurs.
- Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions. Naratriptan is contraindicated in patients with a history of stroke or TIA.
### Other Vasospasm Reactions
- Naratriptan may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional doses of Naratriptan.
- Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
### Medication Overuse Headache
- Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
### Serotonin Syndrome
- Serotonin syndrome may occur with Naratriptan, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAO). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue Naratriptan if serotonin syndrome is suspected.
### Increase in Blood Pressure
- Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with Naratriptan. Naratriptan is contraindicated in patients with uncontrolled hypertension.
### Anaphylactic/Anaphylactoid Reactions
- There have been reports of anaphylaxis and anaphylactoid and hypersensitivity reactions, including angioedema, in patients receiving Naratriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Naratriptan is contraindicated in patients with a history of hypersensitivity reaction to Naratriptan.
# Adverse Reactions
## Clinical Trials Experience
- Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina.
- Arrhythmias.
- Chest, throat, neck, and/or jaw pain/tightness/pressure.
- Cerebrovascular events.
- Other vasospasm reactions.
- Medication overuse headache.
- Serotonin syndrome.
- Increase in blood pressure.
- Hypersensitivity reactions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In a long-term open-label trial where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse reactions.
- In controlled clinical trials, the most common adverse reactions were ��paresthesias, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms, which occurred at a rate of 2% and at least 2 times placebo rate.
- Table 1 lists the adverse reactions that occurred in 5 placebo-controlled clinical trials of approximately 1,752 exposures to placebo and Naratriptan in adult patients with migraine. Only reactions that occurred at a frequency of 2% or more in groups treated with Naratriptan 2.5 mg and that occurred at a frequency greater than the placebo group in the 5 pooled trials are included in Table 1.
## Postmarketing Experience
There is limited information regarding Naratriptan Postmarketing Experience in the drug label.
# Drug Interactions
### Ergot-Containing Drugs
- Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Naratriptan within 24 hours of each other is contraindicated.
### Other 5-HT1 Agonists
- Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of treatment with Naratriptan is contraindicated because the risk of vasospastic reactions may be additive.
### Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
- Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled trials in pregnant women. Naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg.
- When naratriptan was administered to pregnant rats during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death; incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established.
- When naratriptan was administered orally (1, 5, or 30 mg/kg/day) to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose in this study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established.
- When female rats were treated orally with naratriptan (10, 60, or 340 mg/kg/day) during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Naratriptan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Naratriptan during labor and delivery.
### Nursing Mothers
- Naratriptan is excreted in rat milk. It is not known whether naratriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Naratriptan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Therefore, Naratriptan is not recommended for use in patients younger than 18 years of age.
- One controlled clinical trial evaluated Naratriptan (0.25 to 2.5 mg) in 300 adolescent migraineurs aged 12 to 17 years who received at least 1 dose of Naratriptan for an acute migraine. In this study, 54% of the patients were female and 89% were Caucasian. There were no statistically significant differences between any of the treatment groups. The headache response rates at 4 hours (n) were 65% (n = 74), 67% (n = 78), and 64% (n = 70) for placebo, 1-mg, and 2.5-mg groups, respectively. This trial did not establish the efficacy of Naratriptan compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in this clinical trial were similar in nature to those reported in clinical trials in adults.
### Geriatic Use
- Clinical trials of Naratriptan did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
- Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly.
- A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving Naratriptan
### Gender
There is no FDA guidance on the use of Naratriptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Naratriptan with respect to specific racial populations.
### Renal Impairment
- The use of Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug. In patients with mild to moderate renal impairment, the recommended starting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period.
### Hepatic Impairment
- The use of Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance. In patients with mild or moderate hepatic impairment (Child-Pugh grade A or B), the recommendedstarting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Naratriptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Naratriptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Naratriptan Administration in the drug label.
### Monitoring
There is limited information regarding Naratriptan Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Naratriptan and IV administrations.
# Overdosage
- Adverse reactions observed after overdoses of up to 25 mg included increases in blood pressure resulting in lightheadedness, neck tension, tiredness, and loss of coordination. Also, ischemic ECG changes likely due to coronary artery vasospasm have been reported.
- The elimination half-life of naratriptan is about 6 hours , and therefore monitoring of patients after overdose with Naratriptan should continue for at least 24 hours or while symptoms or signs persist. There is no specific antidote to naratriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.
# Pharmacology
## Mechanism of Action
- Naratriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of Naratriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
## Structure
- Naratriptan hydrochloride is chemically designated as N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride, and it has the following structure:
## Pharmacodynamics
- In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial bed, increases in vascular resistance of up to 30% were seen in the coronary arterial bed. Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat.
- In 10 subjects with suspected CAD undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan
## Pharmacokinetics
### Absorption
- Naratriptan is well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet, the peak concentrations are obtained in 2 to 3 hours. After administration of 1- or 2.5-mg tablets, the Cmax is somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram dose) than in men. During a migraine attack, absorption is slower, with a Tmax of 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range.
### Distribution
- The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL.
### Metabolism
- In vitro, naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites.
### Elimination
- Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
### Carcinogenesis
- In carcinogenicity studies, mice and rats were given naratriptan by oral gavage for 104 weeks. There was no evidence of an increase in tumors related to naratriptan administration in mice receiving up to 200 mg/kg/day. That dose was associated with a plasma (AUC) exposure that was 110 times the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg. Two rat studies were conducted, one using a standard diet and the other a nitrite-supplemented diet (naratriptan can be nitrosated in vitro to form a mutagenic product that has been detected in the stomachs of rats fed a high-nitrite diet). Doses of 5, 20, and 90 mg/kg were associated with AUC exposures that in the standard-diet study were 7, 40, and 236 times, respectively, and in the nitrite-supplemented diet study were 7, 29, and 180 times, respectively, the exposure in humans at the MRDD. In both studies, there was an increase in the incidence of thyroid follicular hyperplasia in high-dose males and females and in thyroid follicular adenomas in high-dose males. In the standard-diet study only, there was also an increase in the incidence of benign c-cell adenomas in the thyroid of high-dose males and females. The exposures achieved at the no-effect dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented diet) times the exposure achieved in humans at the MRDD. In the nitrite-supplemented diet study only, the incidence of benign lymphocytic thymoma was increased in all treated groups of females. It was not determined if the nitrosated product is systemically absorbed. However, no changes were seen in the stomachs of rats in that study.
### Mutagenesis
- Naratriptan was not mutagenic when tested in in vitro gene mutation (Ames and mouse lymphoma tk) assays. Naratriptan was also negative in the in vitro human lymphocyte assay and the in vivo mouse micronucleus assay. Naratriptan can be nitrosated in vitro to form a mutagenic product (WHO nitrosation assay) that has been detected in the stomachs of rats fed a nitrite-supplemented diet.
### Impairment of Fertility
- In a reproductive toxicity study in which male and female rats were administered naratriptan orally prior to and throughout the mating period (10, 60, 170, or 340 mg/kg/day; plasma exposures [AUC] approximately 11, 70, 230, and 470 times, respectively, the human exposure at the MRDD), there was a treatment-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in preimplantation loss at 60 mg/kg/day or greater. In high-dose males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed preimplantation loss. The exposures achieved at the no-effect doses for preimplantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans at the MRDD.
- In a study in which rats were dosed orally with naratriptan (10, 60, or 340 mg/kg/day) for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times that in humans at the MRDD.
# Clinical Studies
- The efficacy of Naratriptan in the acute treatment of migraine headaches was evaluated in 3 randomized, double-blind, placebo-controlled trials in adult patients (Trials 1, 2, 3). These trials enrolled adult patients who were predominantly female (86%) and Caucasian (96%) with a mean age of 41 years (range: 18 to 65 years). In all studies, patients were instructed to treat at least 1 moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of Naratriptan or other rescue medication to treat migraines was allowed 4 to 24 hours after the initial treatment for recurrent headache.
- In all 3 trials, the percentage of patients achieving headache response 4 hours after treatment, the primary outcome measure, was significantly greater among patients receiving Naratriptan compared with those who received placebo. In all trials, response to 2.5 mg was numerically greater than response to 1 mg and in the largest of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 4 hours in the 2.5-mg group compared with the 1-mg group. The results are summarized in Table 2.
- Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other rescue medication. The estimated probability of patients taking a second dose or other rescue medication to treat migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
# How Supplied
There is limited information regarding Naratriptan How Supplied in the drug label.
## Storage
There is limited information regarding Naratriptan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Naratriptan Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Naratriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Amerge
# Look-Alike Drug Names
There is limited information regarding Naratriptan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Amerge | |
4775fe74f82e6b5cf89e267b53c7c9f17f851efb | wikidoc | Amfepramone | Amfepramone
# Overview
Amfepramone (INN) is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant. It is used in the short-term management of obesity, along with dietary and lifestyle changes. Amfepramone is most closely chemically related to the antidepressant and smoking cessation aid bupropion (previously called amfebutamone), which has also been developed as a weight-loss medicine when in a combination product with naltrexone.
# Pharmacology
Amfepramone itself lacks any affinity for the monoamine transporters and instead functions as a prodrug to ethcathinone. Ethcathinone (and therefore amfepramone as well) is a very weak dopaminergic and serotonergic, and is approximately 10x and 20x stronger on norepinephrine in comparison, respectively. As a result, ethcathinone and amfepramone can essentially be considered a member of the class of drugs known as norepinephrine releasing agents (NRAs).
# Abuse
Amfepramone is believed to have relatively low abuse potential. but recently there have been reports of teens and adults in the UK abusing this drug, known as "tombstones" to the abusers.
# Legality
Amfepramone is classified as a Schedule IV controlled substance in the United States. It is also a Schedule IV controlled substance in Canada. In the UK Amfepramone is a class C drug and as a medicine, it is a Schedule 3 Controlled Drug which requires safe custody.
It's not US FDA approved.
# Chemistry
- Propiophenone is brominated to produce α-bromopropiophenone.
- This is reacted with diethylamine to yield the product, diethylpropion. | Amfepramone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amfepramone (INN)[note 1] is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant.[2][3] It is used in the short-term management of obesity, along with dietary and lifestyle changes.[2] Amfepramone is most closely chemically related to the antidepressant and smoking cessation aid bupropion (previously called amfebutamone), which has also been developed as a weight-loss medicine when in a combination product with naltrexone.[4]
# Pharmacology
Amfepramone itself lacks any affinity for the monoamine transporters and instead functions as a prodrug to ethcathinone.[5] Ethcathinone (and therefore amfepramone as well) is a very weak dopaminergic and serotonergic, and is approximately 10x and 20x stronger on norepinephrine in comparison, respectively.[5] As a result, ethcathinone and amfepramone can essentially be considered a member of the class of drugs known as norepinephrine releasing agents (NRAs).
# Abuse
Amfepramone is believed to have relatively low abuse potential.[6][7][8][9] but recently there have been reports of teens and adults in the UK abusing this drug, known as "tombstones" to the abusers.
# Legality
Amfepramone is classified as a Schedule IV controlled substance in the United States. It is also a Schedule IV controlled substance in Canada. In the UK Amfepramone is a class C drug [10] and as a medicine, it is a Schedule 3 Controlled Drug which requires safe custody.
It's not US FDA approved.
# Chemistry
- Propiophenone is brominated to produce α-bromopropiophenone.
- This is reacted with diethylamine to yield the product, diethylpropion.[11][12] | https://www.wikidoc.org/index.php/Amfepramone | |
80939a126ea4d23b1c43bca7364d416a4e7c2e24 | wikidoc | Amine oxide | Amine oxide
An amine oxide, also known as amine-N-oxide and N-oxide, is a chemical compound that contains the functional group R3N+-O− (sometimes written as R3N=O or R3N→O). In the strict sense the term amine oxide applies only to oxides of tertiary amines including nitrogen-containing aromatic compounds like pyridine, but is sometimes also used for the analogous derivatives of primary and secondary amines.
Amine oxides are used as protecting group for amines and as chemical intermediates. Long-chain alkyl amine oxides are used as nonionic surfactants and foam stabilizers.
Amine oxide are highly polar molecules have a high polarity close to that of quaternary ammonium salts. Small amine oxides are very hydrophilic and have an excellent water solubility and a very poor solubility in most organic solvents.
Amine oxides are weak bases with a pKa of around 4.5 that form R3N+-OH, cationic hydroxylamines, upon protonation at a pH below their pKa.
Pyridine N-oxide is a crystalline solid with melting point 62-67°C and soluble in water N-Methylmorpholine N-oxide is an oxidant.
# Synthesis
Amine oxides are prepared by oxidation of tertiary amines or pyridine analogs with hydrogen peroxide (H2O2), Caro's acid or peracids like mCPBA in N-oxidation .
# Reactions
- Pyrolytic elimination. Amine oxides, when heated to 150 to 200 ºC eliminate a hydroxylamine, resulting in an alkene. This pyrolytic syn-elimination reaction is known under the name Cope reaction. The mechanism is similar to that of the Hofmann elimination.
- Reduction to amines. Amine oxides are readily converted to the parent amine by common reduction reagents including lithium aluminum hydride, sodium borohydride, catalytic reduction, zinc / acetic acid, and iron / acetic acid. Pyridine N-oxides can be deoxygenated by phosphorus oxychloride
- O-alkylation. Pyridine N-oxides react with alkyl halides to the O-alkylated product
- In the Meisenheimer rearrangement certain N-oxides R1R2R3N+O- rearrange to hydroxylamines R2R3N-O-R1
# Metabolites
Amine oxides are common metabolites of medication and psychoactive drugs. Examples include nicotine, Zolmitriptan, and morphine.
Amine oxides of anti-cancer drugs have been developed as prodrugs that are metabolized in the oxygen deficient cancer tissue to the active drug. | Amine oxide
An amine oxide, also known as amine-N-oxide and N-oxide, is a chemical compound that contains the functional group R3N+-O− (sometimes written as R3N=O or R3N→O). In the strict sense the term amine oxide applies only to oxides of tertiary amines including nitrogen-containing aromatic compounds like pyridine, but is sometimes also used for the analogous derivatives of primary and secondary amines.
Amine oxides are used as protecting group for amines and as chemical intermediates. Long-chain alkyl amine oxides are used as nonionic surfactants and foam stabilizers.
Amine oxide are highly polar molecules have a high polarity close to that of quaternary ammonium salts. Small amine oxides are very hydrophilic and have an excellent water solubility and a very poor solubility in most organic solvents.
Amine oxides are weak bases with a pKa of around 4.5 that form R3N+-OH, cationic hydroxylamines, upon protonation at a pH below their pKa.
Pyridine N-oxide is a crystalline solid with melting point 62-67°C and soluble in water N-Methylmorpholine N-oxide is an oxidant.
# Synthesis
Amine oxides are prepared by oxidation of tertiary amines or pyridine analogs with hydrogen peroxide (H2O2), Caro's acid or peracids like mCPBA in N-oxidation [1].
# Reactions
- Pyrolytic elimination. Amine oxides, when heated to 150 to 200 ºC eliminate a hydroxylamine, resulting in an alkene. This pyrolytic syn-elimination reaction is known under the name Cope reaction. The mechanism is similar to that of the Hofmann elimination.
- Reduction to amines. Amine oxides are readily converted to the parent amine by common reduction reagents including lithium aluminum hydride, sodium borohydride, catalytic reduction, zinc / acetic acid, and iron / acetic acid. Pyridine N-oxides can be deoxygenated by phosphorus oxychloride
- O-alkylation. Pyridine N-oxides react with alkyl halides to the O-alkylated product
- In the Meisenheimer rearrangement certain N-oxides R1R2R3N+O- rearrange to hydroxylamines R2R3N-O-R1 [2] [3]
# Metabolites
Amine oxides are common metabolites of medication and psychoactive drugs. Examples include nicotine, Zolmitriptan, and morphine.
Amine oxides of anti-cancer drugs have been developed as prodrugs that are metabolized in the oxygen deficient cancer tissue to the active drug. | https://www.wikidoc.org/index.php/Amine_oxide | |
5886381a6cbf0c9d5e99b6bf0d26765a2c9055d6 | wikidoc | Amino acids | Amino acids
An amphoteric organic acid containing the amino group is an amino acid.
Amino acids make up proteins.
Amino acids and proteins are the building blocks of life.
Amino acid, any of a group of organic molecules that consist of a basic amino group (―NH2), an acidic carboxyl group (―COOH), and an organic R group (or side chain) that is unique to each amino acid. The term amino acid is short for α-amino carboxylic acid. Each molecule contains a central carbon (C) atom, called the α-carbon, to which both an amino and a carboxyl group are attached. The remaining two bonds of the α-carbon atom are generally satisfied by a hydrogen (H) atom and the R group.
When proteins are digested or broken down, amino acids are left. The human body uses amino acids to make proteins to help the body:
Proteins are of primary importance to the continuing functioning of life on Earth. Proteins catalyze the vast majority of chemical reactions that occur in the cell. They provide many of the structural elements of a cell, and they help to bind cells together into tissues. Some proteins act as contractile elements to make movement possible. Others are responsible for the transport of vital materials from the outside of the cell (“extracellular”) to its inside (“intracellular”). Proteins, in the form of antibodies, protect animals from disease and, in the form of interferon, mount an intracellular attack against viruses that have eluded destruction by the antibodies and other immune system defenses. Many hormones are proteins. Last but certainly not least, proteins control the activity of genes (“gene expression”).
This plethora of vital tasks is reflected in the incredible spectrum of known proteins that vary markedly in their overall size, shape, and charge. By the end of the 19th century, scientists appreciated that, although there exist many different kinds of proteins in nature, all proteins upon their hydrolysis yield a class of simpler compounds, the building blocks of proteins, called amino acids. The simplest amino acid is called glycine, named for its sweet taste (glyco, “sugar”). It was one of the first amino acids to be identified, having been isolated from the protein gelatin in 1820. In the mid-1950s scientists involved in elucidating the relationship between proteins and genes agreed that 20 amino acids (called standard or common amino acids) were to be considered the essential building blocks of all proteins. The last of these to be discovered, threonine, had been identified in 1935.
Amino acids are classified into three groups:
Essential amino acids cannot be made by the body. As a result, they must come from food.
The 9 essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
Nonessential means that our bodies produce an amino acid, even if we do not get it from the food we eat.
Nonessential amino acids include: alanine, asparagine, aspartic acid, and glutamic acid.
Conditional amino acids are usually not essential, except in times of illness and stress.
Conditional amino acids include: arginine, cysteine, glutamine, tyrosine, glycine, ornithine, proline, and serine.
You do not need to eat essential and nonessential amino acids at every meal, but getting a balance of them over the whole day is important. A diet based on a single plant item will not be adequate, but we no longer worry about pairing proteins (such as beans with rice) at a single meal. Instead we look at the adequacy of the diet overall throughout the day.
Standard Amino Acids:
Group I: Nonpolar amino acids,
Isoleucine is an isomer of leucine, and it contains two chiral carbon atoms. Proline is unique among the standard amino acids in that it does not have both free α-amino and free α-carboxyl groups. Instead, its side chain forms a cyclic structure as the nitrogen atom of proline is linked to two carbon atoms. (Strictly speaking, this means that proline is not an amino acid but rather an α-imino acid.) Phenylalanine, as the name implies, consists of a phenyl group attached to alanine. Methionine is one of the two amino acids that possess a sulfur atom. Methionine plays a central role in protein biosynthesis (translation) as it is almost always the initiating amino acid. Methionine also provides methyl groups for metabolism. Tryptophan contains an indole ring attached to the alanyl side chain.
Group II: Polar, uncharged amino acids
Two amino acids, serine and threonine, contain aliphatic hydroxyl groups (that is, an oxygen atom bonded to a hydrogen atom, represented as ―OH). Tyrosine possesses a hydroxyl group in the aromatic ring, making it a phenol derivative. The hydroxyl groups in these three amino acids are subject to an important type of posttranslational modification: phosphorylation (see below Nonstandard amino acids). Like methionine, cysteine contains a sulfur atom. Unlike methionine’s sulfur atom, however, cysteine’s sulfur is very chemically reactive (see below Cysteine oxidation). Asparagine, first isolated from asparagus, and glutamine both contain amide R groups. The carbonyl group can function as a hydrogen bond acceptor, and the amino group (NH2) can function as a hydrogen bond donor.
Group III: Acidic amino acids
The side chains of aspartate and glutamate can form ionic bonds (“salt bridges”), and they can also function as hydrogen bond acceptors. Many proteins that bind metal ions (“metalloproteins”) for structural or functional purposes possess metal-binding sites containing aspartate or glutamate side chains or both. Free glutamate and glutamine play a central role in amino acid metabolism. Glutamate is the most abundant excitatory neurotransmitter in the central nervous system.
Group IV: Basic amino acids
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The imidazole side chain of histidine allows it to function in both acid and base catalysis near physiological pH values. None of the other standard amino acids possesses this important chemical property. Therefore, histidine is an amino acid that most often makes up the active sites of protein enzymes.
The majority of amino acids in Groups II, III, and IV are hydrophilic (“water loving”). As a result, they are often found clustered on the surface of globular proteins in aqueous solutions.
Amino Acid Reactions:
Peptide bond:
Amino acids joined by a series of peptide bonds are said to constitute a peptide. After they are incorporated into a peptide, the individual amino acids are referred to as amino acid residues. Small polymers of amino acids (fewer than 50) are called oligopeptides, while larger ones (more than 50) are referred to as polypeptides. Hence, a protein molecule is a polypeptide chain composed of many amino acid residues, with each residue joined to the next by a peptide bond. The lengths for different proteins range from a few dozen to thousands of amino acids, and each protein contains different relative proportions of the 20 standard amino acids.
Condensation reaction in which three molecules of the amino acid glycine produce a tripeptide chain, with the elimination of two molecules of water (H2O).
Condensation reaction in which three molecules of the amino acid glycine produce a tripeptide chain, with the elimination of two molecules of water (H2O).
Encyclopædia Britannica, Inc.
Cysteine oxidation:
# Biochemistry
Def. a compound that releases at least one hydrogen ion (H+), or donates a proton, accepts an electron in reactions, when dissolved in water is called an acid.
Def. capable of reacting chemically either as an acid or a base is called amphoteric.
# Organic chemistry
Def. any of various compounds derived from ammonia (NH3) by replacement of hydrogen (H) by one or more univalent hydrocarbon radicals is called an amine.
Def. a compound derived from ammonia by replacement of a hydrogen by a metal, containing the anion NH2- is called an amide.
Def. containing the group NH2 or a substituted group NHR or NR2 united to a radical group (R) other than an acid radical is called amino.
Most organic acids (carboxylic or fatty acids) contain the carboxyl group (-COOH).
# Theoretical amino acids
Def. a simple organic compound containing both a carboxyl (-COOH) and an amino (-NH2) group is called an amino acid.
# Electromagnetics
# Chemistry
One way amino acids are classified is dextro (D) versus levo (L). This refers to the arrangement of certain radicals relative to the COOH portion.
Dextro has NH2 or the charged NH3+ on the right or on the bottom when the double bonded oxygen is on top.
# Compounds
Def. 2-aminopropanoic acid with the chemical formula: CH3 CH(NH2)COOH is called alanine.
Def. 3-aminopropanoic acid, (NH2)CH2 CH2 COOH, is called β-alanine.
Def. 2-aminobutanedioic acid, COOHCH2 CH(NH2)COOH, or symmetrically HOOCCH(NH2)CH2COOH, is called aspartic acid.
Def. 2-aminopentanedioic acid, HOOC(CH2)2 (NH2)COOH, is called glutamic acid.
Def. 2,6-Diaminohexanoic acid, CH2OH CH (NH2)COOH, is called lysine.
Def. 2-amino-3-hydroxypropanic acid, HO2CCH(NH2)CH2OH, is called serine.
# Lysine anabolisms
Lysine (Lys or K), is an α-amino acid that contains an α-amino group (−NH3+ protonated under physiologicl conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain lysyl ((CH2)4NH2), classifying it as a charged (at physiological pH), aliphatic amino acid.
Lysine is an essential amino acid, with an element formula of C6H14N2O2.
In plants and most bacteria, lysine is synthesized from aspartic acid (aspartate):
Lysine is a base. The ε-amino group often participates in hydrogen bonding and as a general base in catalysis. The ε-ammonium group (NH3+) is attached to the fourth carbon from the α-carbon, which is attached to the carboxyl (C=OOH) group.
Enzymes involved in this biosynthesis include:
- Aspartokinase
- Aspartate-semialdehyde dehydrogenase
- 4-hydroxy-tetrahydrodipicolinate synthase
- dihydrodipicolinate reductase or 4-hydroxy-tetrahydrodipicolinate reductase
- 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase
- Succinyldiaminopimelate transaminase
- Succinyl-diaminopimelate desuccinylase
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase
- L-aspartate is first converted to L-aspartyl-4-phosphate by aspartokinase (or aspartate kinase). Adenosine triphosphate (ATP) is needed as an energy source for this step.
- β-Aspartate semialdehyde dehydrogenase converts this into β-aspartyl-4-semialdehyde (or β-aspartate-4-semialdehyde). Energy from Nicotinamide adenine dinucleotide phosphate (NADPH) is used in this conversion.
- 4-hydroxy-tetrahydrodipicolinate synthase adds a pyruvate group to the β-aspartyl-4-semialdehyde, and a water molecule is removed. This causes cyclization and gives rise to (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate.
- This product is reduced to 2,3,4,5-tetrahydrodipicolinate (or Δ1-piperidine-2,6-dicarboxylate, in the figure: (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate) by dihydrodipicolinate reductase or 4-hydroxy-tetrahydrodipicolinate reductase. This reaction consumes an NADPH molecule and releases a second water molecule.
- Tetrahydrodipicolinate N-acetyltransferase opens this ring and gives rise to N-succinyl-L-2-amino-6-oxoheptanedionate (or N-acyl-2-amino-6-oxopimelate). Two water molecules and one acyl-CoA (succinyl-CoA) enzyme are used in this reaction.
- N-succinyl-L-2-amino-6-oxoheptanedionate is converted into N-succinyl-LL-2,6-diaminoheptanedionate (N-acyl-2,6-diaminopimelate). This reaction is catalyzed by the enzyme succinyl diaminopimelate aminotransferase. A glutamic acid molecule is used in this reaction and an oxoacid is produced as a byproduct.
- N-succinyl-LL-2,6-diaminoheptanedionate (N-acyl-2,6-diaminopimelate) is converted into LL-2,6-diaminoheptanedionate (L,L-2,6-diaminopimelate) by succinyl diaminopimelate desuccinylase (acyldiaminopimelate deacylase). A water molecule is consumed in this reaction and a succinate is produced as a by-product.
- LL-2,6-diaminoheptanedionate is converted by diaminopimelate epimerase into meso-2,6-diamino-heptanedionate (meso-2,6-diaminopimelate).
- Finally, meso-2,6-diamino-heptanedionate is converted into L-lysine by diaminopimelate decarboxylase.
In fungi, euglenoids and some prokaryotes lysine is synthesized via the alpha-aminoadipate pathway.
Homocitrate is initially synthesised from acetyl-CoA and 2-oxoglutarate by homocitrate synthase. This is then converted to homoaconitate by homoaconitate hydratase (homoaconitase) and then to homoisocitrate by homoisocitrate dehydrogenase. A nitrogen atom is added from glutamate by aminoadipate aminotransferase to form the alpha-aminoadipic acid (α-aminoadipate) from which this pathway gets its name. This is then reduced by L-aminoadipate-semialdehyde dehydrogenase (aminoadipate reductase) via an acyl-enzyme intermediate to a semialdehyde. Reaction with glutamate by one class of saccharopine dehydrogenase yields saccharopine which is then cleaved by a second saccharopine dehydrogenase to yield lysine and oxoglutarate.
# Metallosphaera cuprina
"The genome of the metal sulfide-oxidizing, thermoacidophilic strain Metallosphaera cuprina Ar-4 has been completely sequenced and annotated."
Lysine biosynthesis enzymes are
- Aspartokinase Gene ID: 10492721.
- Aspartate-semialdehyde dehydrogenase Gene ID: 10492720.
- 4-hydroxy-tetrahydrodipicolinate synthase Gene ID: 10492422.
- dihydrodipicolinate reductase or 4-hydroxy-tetrahydrodipicolinate reductase
- 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase
- Succinyldiaminopimelate transaminase
- Succinyl-diaminopimelate desuccinylase
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase
# Metallosphaera cuprina gene to enzyme match-up
E.C. numbers can be searched using KEGG Enzyme.
- Gene ID: 10492201 is MCUP_RS00020 nicotinamide-nucleotide adenylyltransferase Mcup_0004 .
- Gene ID: 10492208 is MCUP_RS00055 threonine ammonia-lyase Mcup_0011 .
- Gene ID: 10492218 is MCUP_RS00115 diaminohydroxyphosphoribosylaminopyrimidine reductase Mcup_0021 .
- Gene ID: 10492243 is MCUP_RS00245 riboflavin synthase Mcup_0046 .
- Gene ID: 10492277 is MCUP_RS00425 aldo/keto reductase Mcup_0081.
- Gene ID: 10492364 is MCUP_RS00875 alcohol dehydrogenase Mcup_0169 (NADP+) .
- Gene ID: 10492386 is MCUP_RS00980 hypothetical protein Mcup_0191.
- Gene ID: 10492404 is MCUP_RS01065 CoA-disulfide reductase Mcup_0209 .
- Gene ID: 10492412 is MCUP_RS01105 3-oxoacyl-ACP reductase Mcup_0217 .
- Gene ID: 10492422 is MCUP_RS01150 dihydrodipicolinate synthase family protein or 4-hydroxy-tetrahydrodipicolinate synthase Mcup_0227 .
- Gene ID: 10492489 is MCUP_RS01510 lysine biosynthesis enzyme LysX Mcup_0295 .
- Gene ID: 10492516 is MCUP_RS01655 2-polyprenylphenol hydroxylase Mcup_0322 .
- Gene ID: 10492603 is aroE shikimate dehydrogenase Mcup_0409 .
- Gene ID: 10492647 is MCUP_RS02325 3-oxoacyl-ACP reductase Mcup_0453 .
- Gene ID: 10492660 is MCUP_RS02390 3-oxoacyl-ACP reductase Mcup_0467 .
- Gene ID: 10492705 is MCUP_RS02610 ribonucleoside-diphosphate reductase , adenosylcobalamin-dependent Mcup_0512.
- Gene ID: 10492720 is MCUP_RS02695 aspartate-semialdehyde dehydrogenase Mcup_0527 ; PRK08664 Location:1 → 348: PRK08664; aspartate-semialdehyde dehydrogenase; Reviewed.
- Gene ID: 10492721 is MCUP_RS02700 aspartate kinase Mcup_0528 ; COG0527 Location:1 → 438: LysC; Aspartokinase .
- Gene ID: 10492728 is MCUP_RS02735 acylphosphatase Mcup_0535 .
- Gene ID: 10492734 is MCUP_RS02765 anthranilate synthase component I Mcup_0541 .
- Gene ID: 10492739 is MCUP_RS02790 dehydrogenase Mcup_0546.
- Gene ID: 10492755 is MCUP_RS02865 S26 family signal peptidase Mcup_0562 .
- Gene ID: 10492771 is MCUP_RS02970 hydroxymethylglutaryl-CoA reductase (NADPH) Mcup_0580 .
- Gene ID: 10492799 is MCUP_RS03115 hypothetical protein Mcup_0608.
- Gene ID: 10492806 is MCUP_RS03150 thiol reductase thioredoxin Mcup_0615 .
- Gene ID: 10492838 is MCUP_RS03335 threonine--tRNA ligase Mcup_0647 .
- Gene ID: 10492872 is MCUP_RS03505 DsrE family protein Mcup_0681.
- Gene ID: 10492875 is MCUP_RS03520 heterodisulfide reductase Mcup_0684 .
- Gene ID: 10492876 is MCUP_RS03525 heterodisulfide reductase subunit B Mcup_0685 .
- Gene ID: 10492879 is MCUP_RS03540 heterodisulfide reductase subunit C Mcup_0688 .
- Gene ID: 10492880 is MCUP_RS03545 disulfide reductase Mcup_0689.
- Gene ID: 10492918 is MCUP_RS03695 oxidoreductase Mcup_0727.
- Gene ID: 10493002 is MCUP_RS04100 succinate-semialdehyde dehydrogenase Mcup_0811 .
- Gene ID: 10493114 is MCUP_RS04635 NAD(P)-dependent oxidoreductase Mcup_0923 .
- Gene ID: 10493216 is MCUP_RS05050 FAD-dependent oxidoreductase Mcup_1025 .
- Gene ID: 10493261 is MCUP_RS05240 pyridine nucleotide-disulfide oxidoreductase Mcup_1070 .
- Gene ID: 10493372 is MCUP_RS05540 beta-ketoacyl-ACP reductase Mcup_1181 .
- Gene ID: 10493374 is MCUP_RS05550 rubredoxin Mcup_1183 .
- Gene ID: 10493379 is MCUP_RS05575 flavin reductase Mcup_1188 .
- Gene ID: 10493392 is MCUP_RS05635 pyrroline-5-carboxylate reductase Mcup_1201 .
- Gene ID: 10493407 is MCUP_RS05700 alcohol dehydrogenase Mcup_1216 (NADP+) .
- Gene ID: 10493417 is MCUP_RS05750 thiol reductase thioredoxin Mcup_1226 .
- Gene ID: 10493454 is fabG 3-ketoacyl-ACP reductase Mcup_1263 .
- Gene ID: 10493470 is MCUP_RS06010 vitamin K epoxide reductase Mcup_1279 .
- Gene ID: 10493478 is MCUP_RS06050 nitrite reductase Mcup_1288 .
- Gene ID: 10493482 is MCUP_RS06070 component of anaerobic dehydrogenase Mcup_1292.
- Gene ID: 10493515 is MCUP_RS06215 mercury(II) reductase Mcup_1326 .
- Gene ID: 10493544 is MCUP_RS06335 ferredoxin--NADP(+) reductase Mcup_1355 .
- Gene ID: 10493553 is MCUP_RS06375 dTDP-4-dehydrorhamnose reductase Mcup_1364 .
- Gene ID: 10493582 is MCUP_RS06525 disulfide reductase Mcup_1393 .
- Gene ID: 10493583 is MCUP_RS06530 succinate dehydrogenase Mcup_1394 .
- Gene ID: 10493584 is MCUP_RS06535 succinate dehydrogenase flavoprotein subunit Mcup_1395 .
- Gene ID: 10493616 is MCUP_RS06695 aspartate-semialdehyde dehydrogenase Mcup_1427 malonyl-CoA reductase (malonate semialdehyde-forming) 1.2.1.76 succinate-semialdehyde dehydrogenase (acylating); PRK08664 Location:2 → 354: PRK08664; aspartate-semialdehyde dehydrogenase; Reviewed.
- Gene ID: 10493619 is MCUP_RS06710 peptide-methionine (S)-S-oxide reductase Mcup_1430 .
- Gene ID: 10493642 is MCUP_RS06820 DNA-binding protein Mcup_1453.
- Gene ID: 10493691 is MCUP_RS07050 alcohol dehydrogenase Mcup_1502 (NADP+) .
- Gene ID: 10493694 is MCUP_RS07065 DNA polymerase IV Mcup_1505 .
- Gene ID: 10493700 is MCUP_RS07095 thioredoxin-disulfide reductase Mcup_1511 .
- Gene ID: 10493802 is MCUP_RS07585 FAD-dependent oxidoreductase Mcup_1613 .
- Gene ID: 10493824 is MCUP_RS07690 aldo/keto reductase Mcup_1635.
- Gene ID: 10493838 is MCUP_RS07760 alcohol dehydrogenase (NADP+) Mcup_1649 .
- Gene ID: 10493847 is MCUP_RS07805 flavoprotein Mcup_1658 .
- Gene ID: 10493859 is MCUP_RS07865 NADH oxidase Mcup_1670 .
- Gene ID: 10493870 is MCUP_RS07920 alcohol dehydrogenase Mcup_1681 (NADP+) .
- Gene ID: 10493881 is MCUP_RS07975 enoyl-CoA hydratase Mcup_1692 .
- Gene ID: 10493903 is MCUP_RS08085 oxidoreductase Mcup_1714 .
- Gene ID: 10493920 is MCUP_RS08170 hypothetical protein Mcup_1731.
- Gene ID: 10493946 is MCUP_RS08300 2-ketoisovalerate ferredoxin oxidoreductase Mcup_1758 .
- Gene ID: 10493950 is MCUP_RS08320 4Fe-4S ferredoxin Mcup_1762 .
- Gene ID: 10494003 is MCUP_RS08555 D-glycerate dehydrogenase Mcup_1815.
- Gene ID: 10494014 is MCUP_RS08605 nucleotide pyrophosphohydrolase Mcup_1826 .
- Gene ID: 10494032 is pyrG CTP synthetase Mcup_1844 .
- Gene ID: 10494046 is MCUP_RS08765 glutamyl-tRNA reductase Mcup_1858 .
- Gene ID: 10494054 is MCUP_RS08800 peptidyl-tRNA hydrolase Mcup_1866 .
- Gene ID: 10494093 is MCUP_RS09005 lysine biosynthesis enzyme LysX Mcup_1905 .
- Gene ID: 10494094 is MCUP_RS09010 sulfonate ABC transporter Mcup_1906 .
- Gene ID: 10494097 is MCUP_RS09025 N-acetyl-gamma-glutamyl-phosphate reductase Mcup_1909 .
- Gene ID: 10494159 is MCUP_RS09350 hypothetical protein Mcup_1971.
- Gene ID: 32167125 is MCUP_RS09805 DNA-directed RNA polymerase subunit P Mcup_0095 .
- Gene ID: 32167145 is MCUP_RS09905 YHS domain-containing protein Mcup_1601.
- Gene ID: 32167149 is MCUP_RS09925 30S ribosomal protein S14 Mcup_1953.
- Gene ID: 32167150 is MCUP_RS09930 50S ribosomal protein L37e Mcup_1997.
# Hypotheses
- Genes are used to produce amino acids.
- Archaea have a different pathway to produce lysine than bacteria, fungi, or plants.
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | Amino acids
Editor-In-Chief: Henry A. Hoff
An amphoteric organic acid containing the amino group is an amino acid.
Amino acids make up proteins.
Amino acids and proteins are the building blocks of life.
Amino acid, any of a group of organic molecules that consist of a basic amino group (―NH2), an acidic carboxyl group (―COOH), and an organic R group (or side chain) that is unique to each amino acid. The term amino acid is short for α-amino [alpha-amino] carboxylic acid. Each molecule contains a central carbon (C) atom, called the α-carbon, to which both an amino and a carboxyl group are attached. The remaining two bonds of the α-carbon atom are generally satisfied by a hydrogen (H) atom and the R group.
When proteins are digested or broken down, amino acids are left. The human body uses amino acids to make proteins to help the body:
Proteins are of primary importance to the continuing functioning of life on Earth. Proteins catalyze the vast majority of chemical reactions that occur in the cell. They provide many of the structural elements of a cell, and they help to bind cells together into tissues. Some proteins act as contractile elements to make movement possible. Others are responsible for the transport of vital materials from the outside of the cell (“extracellular”) to its inside (“intracellular”). Proteins, in the form of antibodies, protect animals from disease and, in the form of interferon, mount an intracellular attack against viruses that have eluded destruction by the antibodies and other immune system defenses. Many hormones are proteins. Last but certainly not least, proteins control the activity of genes (“gene expression”).
This plethora of vital tasks is reflected in the incredible spectrum of known proteins that vary markedly in their overall size, shape, and charge. By the end of the 19th century, scientists appreciated that, although there exist many different kinds of proteins in nature, all proteins upon their hydrolysis yield a class of simpler compounds, the building blocks of proteins, called amino acids. The simplest amino acid is called glycine, named for its sweet taste (glyco, “sugar”). It was one of the first amino acids to be identified, having been isolated from the protein gelatin in 1820. In the mid-1950s scientists involved in elucidating the relationship between proteins and genes agreed that 20 amino acids (called standard or common amino acids) were to be considered the essential building blocks of all proteins. The last of these to be discovered, threonine, had been identified in 1935.
Amino acids are classified into three groups:
Essential amino acids cannot be made by the body. As a result, they must come from food.
The 9 essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
Nonessential means that our bodies produce an amino acid, even if we do not get it from the food we eat.
Nonessential amino acids include: alanine, asparagine, aspartic acid, and glutamic acid.
Conditional amino acids are usually not essential, except in times of illness and stress.
Conditional amino acids include: arginine, cysteine, glutamine, tyrosine, glycine, ornithine, proline, and serine.
You do not need to eat essential and nonessential amino acids at every meal, but getting a balance of them over the whole day is important. A diet based on a single plant item will not be adequate, but we no longer worry about pairing proteins (such as beans with rice) at a single meal. Instead we look at the adequacy of the diet overall throughout the day.
Standard Amino Acids:
Group I: Nonpolar amino acids,
Isoleucine is an isomer of leucine, and it contains two chiral carbon atoms. Proline is unique among the standard amino acids in that it does not have both free α-amino and free α-carboxyl groups. Instead, its side chain forms a cyclic structure as the nitrogen atom of proline is linked to two carbon atoms. (Strictly speaking, this means that proline is not an amino acid but rather an α-imino acid.) Phenylalanine, as the name implies, consists of a phenyl group attached to alanine. Methionine is one of the two amino acids that possess a sulfur atom. Methionine plays a central role in protein biosynthesis (translation) as it is almost always the initiating amino acid. Methionine also provides methyl groups for metabolism. Tryptophan contains an indole ring attached to the alanyl side chain.
Group II: Polar, uncharged amino acids
Two amino acids, serine and threonine, contain aliphatic hydroxyl groups (that is, an oxygen atom bonded to a hydrogen atom, represented as ―OH). Tyrosine possesses a hydroxyl group in the aromatic ring, making it a phenol derivative. The hydroxyl groups in these three amino acids are subject to an important type of posttranslational modification: phosphorylation (see below Nonstandard amino acids). Like methionine, cysteine contains a sulfur atom. Unlike methionine’s sulfur atom, however, cysteine’s sulfur is very chemically reactive (see below Cysteine oxidation). Asparagine, first isolated from asparagus, and glutamine both contain amide R groups. The carbonyl group can function as a hydrogen bond acceptor, and the amino group (NH2) can function as a hydrogen bond donor.
Group III: Acidic amino acids
The side chains of aspartate and glutamate can form ionic bonds (“salt bridges”), and they can also function as hydrogen bond acceptors. Many proteins that bind metal ions (“metalloproteins”) for structural or functional purposes possess metal-binding sites containing aspartate or glutamate side chains or both. Free glutamate and glutamine play a central role in amino acid metabolism. Glutamate is the most abundant excitatory neurotransmitter in the central nervous system.
Group IV: Basic amino acids
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The imidazole side chain of histidine allows it to function in both acid and base catalysis near physiological pH values. None of the other standard amino acids possesses this important chemical property. Therefore, histidine is an amino acid that most often makes up the active sites of protein enzymes.
The majority of amino acids in Groups II, III, and IV are hydrophilic (“water loving”). As a result, they are often found clustered on the surface of globular proteins in aqueous solutions.
Amino Acid Reactions:
Peptide bond:
Amino acids joined by a series of peptide bonds are said to constitute a peptide. After they are incorporated into a peptide, the individual amino acids are referred to as amino acid residues. Small polymers of amino acids (fewer than 50) are called oligopeptides, while larger ones (more than 50) are referred to as polypeptides. Hence, a protein molecule is a polypeptide chain composed of many amino acid residues, with each residue joined to the next by a peptide bond. The lengths for different proteins range from a few dozen to thousands of amino acids, and each protein contains different relative proportions of the 20 standard amino acids.
Condensation reaction in which three molecules of the amino acid glycine produce a tripeptide chain, with the elimination of two molecules of water (H2O).
Condensation reaction in which three molecules of the amino acid glycine produce a tripeptide chain, with the elimination of two molecules of water (H2O).
Encyclopædia Britannica, Inc.
Cysteine oxidation:
# Biochemistry
Def. a compound that releases at least one hydrogen ion (H+), or donates a proton, accepts an electron in reactions, when dissolved in water is called an acid.
Def. capable of reacting chemically either as an acid or a base is called amphoteric.
# Organic chemistry
Def. any of various compounds derived from ammonia (NH3) by replacement of hydrogen (H) by one or more univalent hydrocarbon radicals is called an amine.
Def. a compound derived from ammonia by replacement of a hydrogen by a metal, containing the anion NH2- is called an amide.
Def. containing the group NH2 or a substituted group NHR or NR2 united to a radical group (R) other than an acid radical is called amino.
Most organic acids (carboxylic or fatty acids) contain the carboxyl group (-COOH).
# Theoretical amino acids
Def. a simple organic compound containing both a carboxyl (-COOH) and an amino (-NH2) group is called an amino acid.
# Electromagnetics
# Chemistry
One way amino acids are classified is dextro (D) versus levo (L). This refers to the arrangement of certain radicals relative to the COOH portion.
Dextro has NH2 or the charged NH3+ on the right or on the bottom when the double bonded oxygen is on top.
# Compounds
Def. 2-aminopropanoic acid with the chemical formula: CH3 CH(NH2)COOH is called alanine.
Def. 3-aminopropanoic acid, (NH2)CH2 CH2 COOH, is called β-alanine.
Def. 2-aminobutanedioic acid, COOHCH2 CH(NH2)COOH, or symmetrically HOOCCH(NH2)CH2COOH, is called aspartic acid.
Def. 2-aminopentanedioic acid, HOOC(CH2)2 (NH2)COOH, is called glutamic acid.
Def. 2,6-Diaminohexanoic acid, CH2OH CH (NH2)COOH, is called lysine.
Def. 2-amino-3-hydroxypropanic acid, HO2CCH(NH2)CH2OH, is called serine.
# Lysine anabolisms
Lysine (Lys or K),[1] is an α-amino acid that contains an α-amino group (−NH3+ protonated under physiologicl conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain lysyl ((CH2)4NH2), classifying it as a charged (at physiological pH), aliphatic amino acid.
Lysine is an essential amino acid, with an element formula of C6H14N2O2.
In plants and most bacteria, lysine is synthesized from aspartic acid (aspartate):[2]
Lysine is a base. The ε-amino group often participates in hydrogen bonding and as a general base in catalysis. The ε-ammonium group (NH3+) is attached to the fourth carbon from the α-carbon, which is attached to the carboxyl (C=OOH) group.[3]
Enzymes involved in this biosynthesis include:[2]
- Aspartokinase
- Aspartate-semialdehyde dehydrogenase
- 4-hydroxy-tetrahydrodipicolinate synthase
- dihydrodipicolinate reductase or 4-hydroxy-tetrahydrodipicolinate reductase
- 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase
- Succinyldiaminopimelate transaminase
- Succinyl-diaminopimelate desuccinylase
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase
- L-aspartate is first converted to L-aspartyl-4-phosphate by aspartokinase (or aspartate kinase). Adenosine triphosphate (ATP) is needed as an energy source for this step.
- β-Aspartate semialdehyde dehydrogenase converts this into β-aspartyl-4-semialdehyde (or β-aspartate-4-semialdehyde). Energy from Nicotinamide adenine dinucleotide phosphate (NADPH) is used in this conversion.
- 4-hydroxy-tetrahydrodipicolinate synthase adds a pyruvate group to the β-aspartyl-4-semialdehyde, and a water molecule is removed. This causes cyclization and gives rise to (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate.
- This product is reduced to 2,3,4,5-tetrahydrodipicolinate (or Δ1-piperidine-2,6-dicarboxylate, in the figure: (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate) by dihydrodipicolinate reductase or 4-hydroxy-tetrahydrodipicolinate reductase. This reaction consumes an NADPH molecule and releases a second water molecule.
- Tetrahydrodipicolinate N-acetyltransferase opens this ring and gives rise to N-succinyl-L-2-amino-6-oxoheptanedionate (or N-acyl-2-amino-6-oxopimelate). Two water molecules and one acyl-CoA (succinyl-CoA) enzyme are used in this reaction.
- N-succinyl-L-2-amino-6-oxoheptanedionate is converted into N-succinyl-LL-2,6-diaminoheptanedionate (N-acyl-2,6-diaminopimelate). This reaction is catalyzed by the enzyme succinyl diaminopimelate aminotransferase. A glutamic acid molecule is used in this reaction and an oxoacid is produced as a byproduct.
- N-succinyl-LL-2,6-diaminoheptanedionate (N-acyl-2,6-diaminopimelate) is converted into LL-2,6-diaminoheptanedionate (L,L-2,6-diaminopimelate) by succinyl diaminopimelate desuccinylase (acyldiaminopimelate deacylase). A water molecule is consumed in this reaction and a succinate is produced as a by-product.
- LL-2,6-diaminoheptanedionate is converted by diaminopimelate epimerase into meso-2,6-diamino-heptanedionate (meso-2,6-diaminopimelate).
- Finally, meso-2,6-diamino-heptanedionate is converted into L-lysine by diaminopimelate decarboxylase.
In fungi, euglenoids and some prokaryotes lysine is synthesized via the alpha-aminoadipate pathway.
Homocitrate is initially synthesised from acetyl-CoA and 2-oxoglutarate by homocitrate synthase. This is then converted to homoaconitate by homoaconitate hydratase (homoaconitase) and then to homoisocitrate by homoisocitrate dehydrogenase. A nitrogen atom is added from glutamate by aminoadipate aminotransferase to form the alpha-aminoadipic acid (α-aminoadipate) from which this pathway gets its name. This is then reduced by L-aminoadipate-semialdehyde dehydrogenase (aminoadipate reductase) via an acyl-enzyme intermediate to a semialdehyde. Reaction with glutamate by one class of saccharopine dehydrogenase yields saccharopine which is then cleaved by a second saccharopine dehydrogenase to yield lysine and oxoglutarate.[4]
# Metallosphaera cuprina
"The genome of the metal sulfide-oxidizing, thermoacidophilic strain Metallosphaera cuprina Ar-4 has been completely sequenced and annotated."[5]
Lysine biosynthesis enzymes are
- Aspartokinase Gene ID: 10492721.
- Aspartate-semialdehyde dehydrogenase Gene ID: 10492720.
- 4-hydroxy-tetrahydrodipicolinate synthase Gene ID: 10492422.
- dihydrodipicolinate reductase or 4-hydroxy-tetrahydrodipicolinate reductase [EC 1.17.1.8]
- 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase [EC:2.3.1.117]
- Succinyldiaminopimelate transaminase [EC:2.6.1.11 2.6.1.17]
- Succinyl-diaminopimelate desuccinylase [EC:3.5.1.18]
- Diaminopimelate epimerase [EC:5.1.1.7]
- Diaminopimelate decarboxylase [EC:4.1.1.20]
# Metallosphaera cuprina gene to enzyme match-up
E.C. numbers can be searched using KEGG Enzyme.
- Gene ID: 10492201 is MCUP_RS00020 nicotinamide-nucleotide adenylyltransferase Mcup_0004 [EC:2.7.7.1].
- Gene ID: 10492208 is MCUP_RS00055 threonine ammonia-lyase Mcup_0011 [EC:4.3.1.17 4.3.1.19].
- Gene ID: 10492218 is MCUP_RS00115 diaminohydroxyphosphoribosylaminopyrimidine reductase Mcup_0021 [EC:3.5.4.26 1.1.1.193].
- Gene ID: 10492243 is MCUP_RS00245 riboflavin synthase Mcup_0046 [EC:2.5.1.9].
- Gene ID: 10492277 is MCUP_RS00425 aldo/keto reductase Mcup_0081.
- Gene ID: 10492364 is MCUP_RS00875 alcohol dehydrogenase Mcup_0169 (NADP+) [EC:1.1.1.2].
- Gene ID: 10492386 is MCUP_RS00980 hypothetical protein Mcup_0191.
- Gene ID: 10492404 is MCUP_RS01065 CoA-disulfide reductase Mcup_0209 [EC:1.8.1.14].
- Gene ID: 10492412 is MCUP_RS01105 3-oxoacyl-ACP reductase Mcup_0217 [EC:1.1.1.100].
- Gene ID: 10492422 is MCUP_RS01150 dihydrodipicolinate synthase family protein or 4-hydroxy-tetrahydrodipicolinate synthase Mcup_0227 [EC:4.3.3.7].
- Gene ID: 10492489 is MCUP_RS01510 lysine biosynthesis enzyme LysX Mcup_0295 [EC:6.3.2.43].
- Gene ID: 10492516 is MCUP_RS01655 2-polyprenylphenol hydroxylase Mcup_0322 .
- Gene ID: 10492603 is aroE shikimate dehydrogenase Mcup_0409 [EC:4.2.1.10 1.1.1.25].
- Gene ID: 10492647 is MCUP_RS02325 3-oxoacyl-ACP reductase Mcup_0453 [EC:1.1.1.100].
- Gene ID: 10492660 is MCUP_RS02390 3-oxoacyl-ACP reductase Mcup_0467 [EC:1.1.1.100].
- Gene ID: 10492705 is MCUP_RS02610 ribonucleoside-diphosphate reductase [EC:1.17.4.1], adenosylcobalamin-dependent [EC:1.17.4.1] Mcup_0512.
- Gene ID: 10492720 is MCUP_RS02695 aspartate-semialdehyde dehydrogenase Mcup_0527 [EC:1.2.1.11]; PRK08664 Location:1 → 348: PRK08664; aspartate-semialdehyde dehydrogenase; Reviewed.
- Gene ID: 10492721 is MCUP_RS02700 aspartate kinase Mcup_0528 [EC:2.7.2.4]; COG0527 Location:1 → 438: LysC; Aspartokinase [Amino acid transport and metabolism].
- Gene ID: 10492728 is MCUP_RS02735 acylphosphatase Mcup_0535 [EC:3.6.1.7].
- Gene ID: 10492734 is MCUP_RS02765 anthranilate synthase component I Mcup_0541 [EC:4.1.3.27].
- Gene ID: 10492739 is MCUP_RS02790 dehydrogenase Mcup_0546.
- Gene ID: 10492755 is MCUP_RS02865 S26 family signal peptidase Mcup_0562 [EC:3.4.21.89].
- Gene ID: 10492771 is MCUP_RS02970 hydroxymethylglutaryl-CoA reductase (NADPH) Mcup_0580 [EC:1.1.1.34].
- Gene ID: 10492799 is MCUP_RS03115 hypothetical protein Mcup_0608.
- Gene ID: 10492806 is MCUP_RS03150 thiol reductase thioredoxin Mcup_0615 [EC:1.8.1.8].
- Gene ID: 10492838 is MCUP_RS03335 threonine--tRNA ligase Mcup_0647 [EC:6.1.1.3].
- Gene ID: 10492872 is MCUP_RS03505 DsrE family protein Mcup_0681.
- Gene ID: 10492875 is MCUP_RS03520 heterodisulfide reductase Mcup_0684 [EC:1.8.98.1].
- Gene ID: 10492876 is MCUP_RS03525 heterodisulfide reductase subunit B Mcup_0685 [EC:1.8.98.1].
- Gene ID: 10492879 is MCUP_RS03540 heterodisulfide reductase subunit C Mcup_0688 [EC:1.8.98.1].
- Gene ID: 10492880 is MCUP_RS03545 disulfide reductase Mcup_0689.
- Gene ID: 10492918 is MCUP_RS03695 oxidoreductase Mcup_0727.
- Gene ID: 10493002 is MCUP_RS04100 succinate-semialdehyde dehydrogenase Mcup_0811 [EC:1.2.1.16 1.2.1.79 1.2.1.20].
- Gene ID: 10493114 is MCUP_RS04635 NAD(P)-dependent oxidoreductase Mcup_0923 [EC:1.1.1.30].
- Gene ID: 10493216 is MCUP_RS05050 FAD-dependent oxidoreductase Mcup_1025 [EC:1.8.5.4].
- Gene ID: 10493261 is MCUP_RS05240 pyridine nucleotide-disulfide oxidoreductase Mcup_1070 [EC:1.2.1.43].
- Gene ID: 10493372 is MCUP_RS05540 beta-ketoacyl-ACP reductase Mcup_1181 [EC:1.1.1.62 1.1.1.239].
- Gene ID: 10493374 is MCUP_RS05550 rubredoxin Mcup_1183 [EC:1.18.1.1].
- Gene ID: 10493379 is MCUP_RS05575 flavin reductase Mcup_1188 [EC:1.5.1.36].
- Gene ID: 10493392 is MCUP_RS05635 pyrroline-5-carboxylate reductase Mcup_1201 [EC:1.5.1.2].
- Gene ID: 10493407 is MCUP_RS05700 alcohol dehydrogenase Mcup_1216 (NADP+) [EC:1.1.1.2].
- Gene ID: 10493417 is MCUP_RS05750 thiol reductase thioredoxin Mcup_1226 [EC:1.11.1.15].
- Gene ID: 10493454 is fabG 3-ketoacyl-ACP reductase Mcup_1263 [EC:1.1.1.100].
- Gene ID: 10493470 is MCUP_RS06010 vitamin K epoxide reductase Mcup_1279 [EC:1.17.4.4].
- Gene ID: 10493478 is MCUP_RS06050 nitrite reductase Mcup_1288 [EC:1.7.1.15].
- Gene ID: 10493482 is MCUP_RS06070 component of anaerobic dehydrogenase Mcup_1292.
- Gene ID: 10493515 is MCUP_RS06215 mercury(II) reductase Mcup_1326 [EC:1.16.1.1].
- Gene ID: 10493544 is MCUP_RS06335 ferredoxin--NADP(+) reductase Mcup_1355 [EC:1.18.1.2].
- Gene ID: 10493553 is MCUP_RS06375 dTDP-4-dehydrorhamnose reductase Mcup_1364 [EC:1.1.1.133].
- Gene ID: 10493582 is MCUP_RS06525 disulfide reductase Mcup_1393 [EC:1.8.4.-].
- Gene ID: 10493583 is MCUP_RS06530 succinate dehydrogenase Mcup_1394 [EC:1.8.99.2].
- Gene ID: 10493584 is MCUP_RS06535 succinate dehydrogenase flavoprotein subunit Mcup_1395 [EC:1.3.5.1 1.3.5.4].
- Gene ID: 10493616 is MCUP_RS06695 aspartate-semialdehyde dehydrogenase Mcup_1427 [EC:1.2.1.75] malonyl-CoA reductase (malonate semialdehyde-forming) 1.2.1.76 succinate-semialdehyde dehydrogenase (acylating); PRK08664 Location:2 → 354: PRK08664; aspartate-semialdehyde dehydrogenase; Reviewed.
- Gene ID: 10493619 is MCUP_RS06710 peptide-methionine (S)-S-oxide reductase Mcup_1430 [EC:1.8.4.11].
- Gene ID: 10493642 is MCUP_RS06820 DNA-binding protein Mcup_1453.
- Gene ID: 10493691 is MCUP_RS07050 alcohol dehydrogenase Mcup_1502 (NADP+) [EC:1.1.1.2].
- Gene ID: 10493694 is MCUP_RS07065 DNA polymerase IV Mcup_1505 [EC:2.7.7.7].
- Gene ID: 10493700 is MCUP_RS07095 thioredoxin-disulfide reductase Mcup_1511 [EC:1.8.1.9].
- Gene ID: 10493802 is MCUP_RS07585 FAD-dependent oxidoreductase Mcup_1613 [EC:1.8.5.4].
- Gene ID: 10493824 is MCUP_RS07690 aldo/keto reductase Mcup_1635.
- Gene ID: 10493838 is MCUP_RS07760 alcohol dehydrogenase (NADP+) Mcup_1649 [EC:1.1.1.2].
- Gene ID: 10493847 is MCUP_RS07805 flavoprotein Mcup_1658 [EC:1.5.5.1].
- Gene ID: 10493859 is MCUP_RS07865 NADH oxidase Mcup_1670 [EC:1.6.3.3].
- Gene ID: 10493870 is MCUP_RS07920 alcohol dehydrogenase Mcup_1681 (NADP+) [EC:1.1.1.2].
- Gene ID: 10493881 is MCUP_RS07975 enoyl-CoA hydratase Mcup_1692 [EC:5.3.3.18].
- Gene ID: 10493903 is MCUP_RS08085 oxidoreductase Mcup_1714 [EC:1.3.1.34].
- Gene ID: 10493920 is MCUP_RS08170 hypothetical protein Mcup_1731.
- Gene ID: 10493946 is MCUP_RS08300 2-ketoisovalerate ferredoxin oxidoreductase Mcup_1758 [EC:1.2.7.1].
- Gene ID: 10493950 is MCUP_RS08320 4Fe-4S ferredoxin Mcup_1762 [EC:1.8.7.1].
- Gene ID: 10494003 is MCUP_RS08555 D-glycerate dehydrogenase Mcup_1815.
- Gene ID: 10494014 is MCUP_RS08605 nucleotide pyrophosphohydrolase Mcup_1826 [EC:3.6.1.11 3.6.1.40].
- Gene ID: 10494032 is pyrG CTP synthetase Mcup_1844 [EC:6.3.4.2].
- Gene ID: 10494046 is MCUP_RS08765 glutamyl-tRNA reductase Mcup_1858 [EC:1.2.1.70].
- Gene ID: 10494054 is MCUP_RS08800 peptidyl-tRNA hydrolase Mcup_1866 [EC:3.1.1.29].
- Gene ID: 10494093 is MCUP_RS09005 lysine biosynthesis enzyme LysX Mcup_1905 [EC:6.3.2.43].
- Gene ID: 10494094 is MCUP_RS09010 sulfonate ABC transporter Mcup_1906 [EC:3.6.3.-].
- Gene ID: 10494097 is MCUP_RS09025 N-acetyl-gamma-glutamyl-phosphate reductase Mcup_1909 [EC:1.2.1.38].
- Gene ID: 10494159 is MCUP_RS09350 hypothetical protein Mcup_1971.
- Gene ID: 32167125 is MCUP_RS09805 DNA-directed RNA polymerase subunit P Mcup_0095 [EC:2.7.7.6].
- Gene ID: 32167145 is MCUP_RS09905 YHS domain-containing protein Mcup_1601.
- Gene ID: 32167149 is MCUP_RS09925 30S ribosomal protein S14 Mcup_1953.
- Gene ID: 32167150 is MCUP_RS09930 50S ribosomal protein L37e Mcup_1997.
# Hypotheses
- Genes are used to produce amino acids.
- Archaea have a different pathway to produce lysine than bacteria, fungi, or plants.
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | https://www.wikidoc.org/index.php/Amino_acids | |
744aa56f96cc62618de052f1065fe9c1eed29f08 | wikidoc | Aminopterin | Aminopterin
# Overview
Aminopterin (4-aminopteroic acid), a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis.
# Uses
The antifolate activity of aminopterin was first used by Sidney Farber in 1947 to induce remissions among children with leukemia. Aminopterin was later marketed by Lederle Laboratories (Pearl River, New York) in the United States from 1953 to 1964 for the indication of pediatric leukemia. The closely related antifolate methotrexate was simultaneously marketed by the company during the same period. Aminopterin was discontinued by Lederle Laboratories in favor of methotrexate due to manufacturing difficulties of the former.
During the period Aminopterin was marketed, the agent was used off-label to safely treat over 4,000 patients with psoriasis in the United States, producing dramatic clearing of lesions.
The use of aminopterin in cancer treatment was supplanted in the 1950s by methotrexate due to the latter's better therapeutic index in a rodent tumor model. Now in a more pure preparation and supported by laboratory evidence of superior tumor cell uptake in vitro, aminopterin is being investigated in clinical trials in leukemia as a potentially superior antifolate to methotrexate.
The compound was explored as an abortifacient in the 1960s and earlier, but was associated with congenital malformations. Similar congenital abnormalities have been documented with methotrexate, and collectively their teratogenic effects have become known as the fetal aminopterin syndrome. When a similar cluster of abnormalies appears in the absence of exposure to antifolates it is referred to as aminopterin-like syndrome without aminopterin.
Although the use of aminopterin as a rodenticide is widely asserted on the web and elsewhere, there is no evidence that it has ever been used for that purpose either in the United States or elsewhere in the world. The preparation of the molecule is complex and expensive. It is also unstable in the environment due to degradation by light and heat. The apparently mistaken association of aminopterin with its use as a rodenticide likely dates back to a 1951 patent issued to the American Cyanamid Company (then the holding company of Lederle Laboratories) that is commonly cited by a variety of reference textbooks. Aminopterin has a single-dose LDLo of 2.5 mg/kg when orally administered to rats.
Aminopterin and methotrexate are widely used in selection media (such as HAT medium) for cell culture.
# Implication in 2007 Menu Foods recall
On March 23 2007, ABC News reported
that aminopterin was the chemical linked to the 2007 Menu Foods pet food contamination incident. The incident resulted in a massive recall of the affected foods. The link to aminopterin was confirmed by New York State Agriculture Commissioner Patrick Hooker and Dr. Donald Smith, Dean of Cornell University's College of Veterinary Medicine, in a statement released on the same day.
On March 27, the ASPCA Animal Poison Control Center expressed concern that the problem may not yet be fully understood and that other contaminants may be involved, noting that "clinical signs reported in cats affected by the contaminated foods are not fully consistent with the ingestion of rat poison containing aminopterin".
On March 30 it was widely reported that the United States Food and Drug Administration had found melamine in wheat gluten that was used in the pet foods in question. These same reports stated that the FDA had failed to find evidence of aminopterin in the wheat gluten. Tests at the University of Guelph in Ontario, Canada detected aminopterin in some pet food samples, but only in concentrations of parts per billion or parts per trillon, amounts too low to cause the symptoms seen.
# Exposure and treatment
Symptoms of exposure in humans include:
- nausea
- vomiting
- anorexia
- weight loss
- chills
- fever
- stomatitis – inflammation of the oral mucosa
- pharyngitis – inflammation of the pharynx
- erythematous rashes – red rashes on the skin
- hyperpigmentation – increased pigmentation associated with cleared psoriatic lesions
- gastrointestinal hemorrhage
- renal failure – in high doses necessarily involving concomitant leucovorin rescue
- abortions in pregnant women
Supralethal doses of aminopterin may be rescued with the antidote leucovorin (also known as folinic acid), a reduced form of folic acid which bypasses dihydrofolate reductase, the enzyme inhibited by aminopterin. Leucovorin has been used in rats, dogs and humans to rescue aminopterin toxicity. Leucovorin rescue is a therapeutic maneuver intentionally employed with antifolates to achieve tumoricidal drug concentrations that would otherwise be lethal to the patient.
In humans, leucovorin rescue at overdosages lower than 10 mg aminopterin in an average 70 kg adult should comprise an initial leucovorin dose of at least 20 mg (10.0 mg/m2), given intravenously (preferably), or orally. Subsequent doses of 20 mg (which may be taken orally) should be given at 6 hour intervals until hematological abnormalities are improved.
Massive aminopterin overdosage in humans (i.e. > 40 mg AMT in an average 70 kg adult), should be approached with an initial leucovorin dose of 100 mg (50 mg/m2), given intravenously and continued at 6 hour intervals until the hematological abnormalities are improved (likely 8-12 courses or more). Additionally, to prevent reversible aminopterin-mediated nephrotoxicity manifesting as increases in serum creatinine and which further delays drug elimination, urinary alkalinization with NaHCO3 and volume expansion should be considered in cases of massive aminopterin overdosage, particularly those involving greater than 100 mg AMT in an average 70 kg adult human.
Consistent with the known enterohepatic cycling of the related antifolate methotrexate, oral activated charcoal, and saline cathartic or sorbitol may promote excretion if an overdose of aminopterin is suspected. However, rescue with leucovorin should form the backbone of treatment.
The vitamin folic acid is an oxidized precursor to reduced folates that is upstream of the blockade at dihydrofolate reductase, and compared to leucovrin is recognized as a very weak antidote to the toxic effects of antifolates that is inappropriate for use in cases of acute intoxication. Minnich et al. dosed mongrel dogs subcutaneously with aminopterin and folic acid simultaneously to test whether folic acid can rescue animals from the lethality and toxicity of aminopterin Dogs were given 0.020, 0.046, 0.044 escalated to 0.088, and 0.097 mg/kg aminopterin each day for 7 to 12 days. Folic acid was given in a weight ratio to aminopterin of 200:1 to 800:1. All animals survived. In contrast, animals given aminopterin in an amount of 0.041 mg/kg/day x 6 days without folic acid died. Thus, when the ratio of folic acid to aminopterin was 200:1 and greater, all of the subjects survived on regimens that would have otherwise been uniformly fatal to all subjects.
Similar effects have been noted in rodent species as well, were the range for rescue by folic acid was fairly narrow and highly dependent on the timing (optimal of 1 hour prior to aminopterin) of administration in relation to aminopterin. The temporal relationship between folic acid administration and rescue has been interpreted as the necessary period of time required for the vitamin to be converted in vivo to reduced forms. | Aminopterin
Template:Chembox new
# Overview
Aminopterin (4-aminopteroic acid), a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis.
# Uses
The antifolate activity of aminopterin was first used by Sidney Farber in 1947 to induce remissions among children with leukemia.[1][2] Aminopterin was later marketed by Lederle Laboratories (Pearl River, New York) in the United States from 1953 to 1964 for the indication of pediatric leukemia. The closely related antifolate methotrexate was simultaneously marketed by the company during the same period. Aminopterin was discontinued by Lederle Laboratories in favor of methotrexate due to manufacturing difficulties of the former.
During the period Aminopterin was marketed, the agent was used off-label to safely treat over 4,000 patients with psoriasis in the United States, producing dramatic clearing of lesions.[3]
The use of aminopterin in cancer treatment was supplanted in the 1950s by methotrexate due to the latter's better therapeutic index in a rodent tumor model.[4] Now in a more pure preparation and supported by laboratory evidence of superior tumor cell uptake in vitro, aminopterin is being investigated in clinical trials in leukemia as a potentially superior antifolate to methotrexate.[5]
The compound was explored as an abortifacient in the 1960s and earlier, but was associated with congenital malformations.[6] Similar congenital abnormalities have been documented with methotrexate, and collectively their teratogenic effects have become known as the fetal aminopterin syndrome. When a similar cluster of abnormalies appears in the absence of exposure to antifolates it is referred to as aminopterin-like syndrome without aminopterin.[7]
Although the use of aminopterin as a rodenticide is widely asserted on the web and elsewhere, there is no evidence that it has ever been used for that purpose either in the United States or elsewhere in the world.[8] The preparation of the molecule is complex and expensive. It is also unstable in the environment due to degradation by light and heat. The apparently mistaken association of aminopterin with its use as a rodenticide likely dates back to a 1951 patent issued to the American Cyanamid Company (then the holding company of Lederle Laboratories) that is commonly cited by a variety of reference textbooks.[9] Aminopterin has a single-dose LDLo of 2.5 mg/kg when orally administered to rats.[10]
Aminopterin and methotrexate are widely used in selection media (such as HAT medium) for cell culture.
# Implication in 2007 Menu Foods recall
On March 23 2007, ABC News reported[11]
that aminopterin was the chemical linked to the 2007 Menu Foods pet food contamination incident. The incident resulted in a massive recall of the affected foods.[12] The link to aminopterin was confirmed by New York State Agriculture Commissioner Patrick Hooker and Dr. Donald Smith, Dean of Cornell University's College of Veterinary Medicine, in a statement released on the same day.[13][14]
On March 27, the ASPCA Animal Poison Control Center expressed concern that the problem may not yet be fully understood and that other contaminants may be involved, noting that "clinical signs reported in cats affected by the contaminated foods are not fully consistent with the ingestion of rat poison containing aminopterin".[15]
On March 30 it was widely reported that the United States Food and Drug Administration had found melamine in wheat gluten that was used in the pet foods in question. These same reports stated that the FDA had failed to find evidence of aminopterin in the wheat gluten. Tests at the University of Guelph in Ontario, Canada detected aminopterin in some pet food samples, but only in concentrations of parts per billion or parts per trillon, amounts too low to cause the symptoms seen.[16]
# Exposure and treatment
Symptoms of exposure in humans include:[17]
[18]
- nausea
- vomiting
- anorexia
- weight loss
- chills
- fever
- stomatitis – inflammation of the oral mucosa
- pharyngitis – inflammation of the pharynx
- erythematous rashes – red rashes on the skin
- hyperpigmentation – increased pigmentation associated with cleared psoriatic lesions
- gastrointestinal hemorrhage
- renal failure – in high doses necessarily involving concomitant leucovorin rescue
- abortions in pregnant women
Supralethal doses of aminopterin may be rescued with the antidote leucovorin (also known as folinic acid), a reduced form of folic acid which bypasses dihydrofolate reductase, the enzyme inhibited by aminopterin. Leucovorin has been used in rats, dogs and humans to rescue aminopterin toxicity.[19][20][21][22] Leucovorin rescue is a therapeutic maneuver intentionally employed with antifolates to achieve tumoricidal drug concentrations that would otherwise be lethal to the patient.[5]
In humans, leucovorin rescue at overdosages lower than 10 mg aminopterin in an average 70 kg adult should comprise an initial leucovorin dose of at least 20 mg (10.0 mg/m2), given intravenously (preferably), or orally.[22] Subsequent doses of 20 mg (which may be taken orally) should be given at 6 hour intervals until hematological abnormalities are improved.
Massive aminopterin overdosage in humans (i.e. > 40 mg AMT in an average 70 kg adult), should be approached with an initial leucovorin dose of 100 mg (50 mg/m2), given intravenously and continued at 6 hour intervals until the hematological abnormalities are improved (likely 8-12 courses or more).[21] Additionally, to prevent reversible aminopterin-mediated nephrotoxicity manifesting as increases in serum creatinine and which further delays drug elimination, urinary alkalinization with NaHCO3 and volume expansion should be considered in cases of massive aminopterin overdosage, particularly those involving greater than 100 mg AMT in an average 70 kg adult human.
Consistent with the known enterohepatic cycling of the related antifolate methotrexate, oral activated charcoal, and saline cathartic or sorbitol may promote excretion if an overdose of aminopterin is suspected. However, rescue with leucovorin should form the backbone of treatment.
The vitamin folic acid is an oxidized precursor to reduced folates that is upstream of the blockade at dihydrofolate reductase, and compared to leucovrin is recognized as a very weak antidote to the toxic effects of antifolates that is inappropriate for use in cases of acute intoxication. Minnich et al. dosed mongrel dogs subcutaneously with aminopterin and folic acid simultaneously to test whether folic acid can rescue animals from the lethality and toxicity of aminopterin[23] Dogs were given 0.020, 0.046, 0.044 escalated to 0.088, and 0.097 mg/kg aminopterin each day for 7 to 12 days. Folic acid was given in a weight ratio to aminopterin of 200:1 to 800:1. All animals survived. In contrast, animals given aminopterin in an amount of 0.041 mg/kg/day x 6 days without folic acid died. Thus, when the ratio of folic acid to aminopterin was 200:1 and greater, all of the subjects survived on regimens that would have otherwise been uniformly fatal to all subjects.
Similar effects have been noted in rodent species as well, were the range for rescue by folic acid was fairly narrow and highly dependent on the timing (optimal of 1 hour prior to aminopterin) of administration in relation to aminopterin.[24][25] The temporal relationship between folic acid administration and rescue has been interpreted as the necessary period of time required for the vitamin to be converted in vivo to reduced forms. | https://www.wikidoc.org/index.php/Aminopterin | |
021a4f4d23ca4fd61c94422f07e39c8e5651cb33 | wikidoc | Aminosyn II | Aminosyn II
Aminosyn® II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection with electrolytes) is a sterile, nonpyrogenic solution for intravenous infusion. Aminosyn II 8.5% WITH ELECTROLYTES is oxygen sensitive.
The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.
Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.
Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.
# Clinical Pharmacology
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection with electrolytes) provides crystalline amino acids to promote protein synthesis and wound healing, and to reduce the rate of endogenous protein catabolism. Aminosyn II 8.5% WITH ELECTROLYTES, given by central venous infusion in combination with concentrated dextrose, electrolytes, vitamins, trace metals, and ancillary fat supplements, constitutes total parenteral nutrition (TPN). Aminosyn II 8.5% WITH ELECTROLYTES can also be administered by peripheral vein with dextrose and maintenance electrolytes. Intravenous fat emulsion may be substituted for part of the carbohydrate calories during either TPN or peripheral vein administration of Aminosyn II 8.5% WITH ELECTROLYTES.
# Indications and Usage
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection) infused with dextrose by peripheral vein infusion is indicated as a source of nitrogen in the nutritional support of patients in whom, for short periods of time, oral nutrition cannot be tolerated, is undesirable, or inadequate.
Aminosyn II 8.5% WITH ELECTROLYTES can be administered peripherally with dilute (5 to 10%) dextrose solution and I.V. fat emulsion as a source of nutritional support. This form of nutritional support can help to preserve protein and reduce catabolism in stress conditions where oral intake is inadequate.
When administered with concentrated dextrose solution with or without fat emulsions, Aminosyn II 8.5% WITH ELECTROLYTES is also indicated for central vein infusion to prevent or reverse negative nitrogen balance in patients where: (a) the alimentary tract, by the oral, gastrostomy or jejunostomy route cannot or should not be used; (b) gastrointestinal absorption of protein is impaired; (c) metabolic requirements for protein are substantially increased as with extensive burns and (d) morbidity and mortality may be reduced by replacing amino acids lost from tissue breakdown, thereby preserving tissue reserves, as in acute renal failure.
# Contraindications
This preparation should not be used in patients with hepatic coma or metabolic disorders involving impaired nitrogen utilization.
# Warnings
Intravenous infusion of amino acids may induce a rise in blood urea nitrogen (BUN), especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limitsand continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake.
Administration of amino acid solutions to a patient with hepatic insufficiency may result in serum amino acid imbalances, metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma.
Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does any protein dietary component.
Solutions containing sodium ion should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention.
Solutions which contain potassium ion should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present.
Solutions containing acetate ion should be used with great care in patients with metabolic or respiratory alkalosis. Acetate should be administered with great care in those conditions in which there is an increased level or an impaired utilization of this ion, such as severe hepatic insufficiency.
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection) may not be suitable for use in infants who require individualized electrolyte therapy.
Hyperammonemia is of special significance in infants, as it can result in mental retardation. Therefore, it is essential that blood ammonia levels be measured frequently in infants.
Instances of asymptomatic hyperammonemia have been reported in patients without overt liver dysfunction. The mechanisms of this reaction are not clearly defined, but may involve genetic defects and immature or subclinically impaired liver function.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
# Precautions
Special care must be taken when administering glucose to provide calories in diabetic or prediabetic patients.
Feeding regimens which include amino acids should be used with caution in patients with history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation.
The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time.
Nitrogen intake should be carefully monitored in patients with impaired renal function.
For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.
## SPECIAL PRECAUTIONS FOR CENTRAL VENOUS INFUSIONS
ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS.
Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL BASED ON CURRENT MEDICAL PRACTICES BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.
As a summary:
- Technical
The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.
- Septic
The constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.
Solutions should ideally be prepared in the hospital pharmacy under a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours.
Administration time for a single container and set should never exceed 24 hours.
- Metabolic
The following metabolic complications have been reported with TPN administration: metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia, hyperosmolar nonketotic states and dehydration, glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.
Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma and death.
Pregnancy Category C
Animal reproduction studies have not been conducted with Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection). It is not known whether Aminosyn II 8.5% WITH ELECTROLYTES can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn II 8.5% WITH ELECTROLYTES should be given to a pregnant woman only if clearly needed.
# Geriatric Use
Clinical studies of Aminosyn II 8.5% WITH ELECTROLYTES have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions.
CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN, ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.
Aminosyn II 8.5% WITH ELECTROLYTES contains no more than 25 mcg/L of aluminum.
# Drug Interactions
Because of its antianabolic activity, concurrent administration of tetracycline may reduce the potential anabolic effects of amino acids infused with dextrose as part of a parenteral feeding regimen.
Additives may be incompatible. Consult with pharmacist if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.
# Adverse Reactions
## Peripheral Infusions
A 3.5% to 5% solution of amino acids (without additives) is slightly hypertonic. Local reactions consisting of a warm sensation, erythema, phlebitis and thrombosis at the infusion site have occurred with peripheral intravenous infusion of amino acids particularly if other substances, such as antibiotics, are also administered through the same site. In such cases the infusion site should be changed promptly to another vein. Use of large peripheral veins, inline filters, and slowing the rate of infusion may reduce the incidence of local venous irritation. Electrolyte additives should be spread throughout the day.Irritating additive medications may need to be infused at another venous site.
Generalized flushing, fever and nausea also have been reported during peripheral infusions of amino acid solutions.
# Overdosage
In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.
# Dosage and Administration
The total daily dose of the solution depends on the daily protein requirements and on the patient’s metabolic and clinical response. In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose infusions are abruptly discontinued.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
# Central Vein Total Parenteral Nutrition
For central vein infusion with concentrated dextrose solution, alone or with I.V. lipid,the total daily dose of the amino acid solution depends upon daily protein requirements and the patient’s metabolic and clinical response. The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements.
## Adults
Admixtures of 3.5 to 4.25% amino acids with 5 to 10% dextrose may be infused with a fat emulsion by peripheral vein to provide approximately 1400 to 2000 kcal/day. Fat emulsion administration should be considered when prolonged parenteral nutrition is required in order to prevent essential fatty acid deficiency (E.F.A.D.). Serum lipids should be monitored for evidence of E.F.A.D. in patients maintained on fat-free TPN.
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection) should only be infused via a central vein when admixed with sufficient dextrose to provide full caloric requirements in patients who require prolonged total parenteral nutrition. I.V. lipid may be administered to provide part of the calories, if desired. Serum lipids should be monitored for evidence of essential fatty acid deficiency in patients maintained on fat-free TPN.
Total parenteral nutrition (TPN) may be started with 10% dextrose added to the calculated daily requirement of amino acids (1.5 g/kg for a metabolically stable patient). Dextrose content is gradually increased over the next few days to the estimated daily caloric need as the patient adapts to the increasing amounts of dextrose. Each gram of dextrose provides approximately 3.4 kcal. Each gram of fat provides 9 kcal.
The average depleted major surgical patient with complications requires between 2500 and 4000 kcal and between 12 and 24 grams of nitrogen per day. An adult patient in an acceptable weight range with restricted activity who is not hypermetabolic, requires about 30 kcal/kg of body weight/day. Average daily adult fluid requirements are between 2500 and 3000 mL and may be much higher with losses from fistula drainage or in severe burns. Typically, a hospitalized patient may lose 12 to 18 grams of nitrogen a day, and in severe trauma the daily loss may be 20 to 25 grams or more.
Aminosyn II 8.5% WITH ELECTROLYTES is designed to supply necessary electrolytes to patients in a stable metabolic state (about three-fourths of all patients on total parenteral nutrition). Other patients may require more or less of the electrolytes present, e.g., cardiac patients who should not receive sodium. Aminosyn II 8.5% WITH ELECTROLYTES does not contain calcium, and this should be added as indicated.
SERUM ELECTROLYTES SHOULD BE MONITORED AS INDICATED. Electrolytes may be added to the nutrient solution as indicated by the patient’s clinical condition and laboratory determinations of plasma values. Major electrolytes are sodium, chloride, potassium, phosphate, magnesium and calcium. Vitamins, including folic acid and vitamin K are required additives. The trace element supplements should be given when long-term parenteral nutrition is undertaken.
Calcium and phosphorus are added to the solution as indicated. The usual dose of phosphorus added to a liter of TPN solution (containing 25% dextrose) is 12 mM. This requirement is related to the carbohydrate calories delivered. Iron is added to the solution or given intramuscularly in depot form as indicated. Vitamin B12, vitamin K and folic acid are given intramuscularly or added to the solution as desired.
Calcium and phosphorus additives are potentially incompatible when added to the TPN admixture. However, if one additive is added to the amino acid container, and the other to the container of concentrated dextrose, and if the contents of both containers are swirled before they are combined, then the likelihood of physical incompatibility is reduced.
In patients with hyperchloremic or other metabolic acidosis, sodium and potassium may be added as the acetate or lactate salts to provide bicarbonate alternates.
In adults, hypertonic mixtures of amino acids and dextrose may be safely administered by continuous infusion through a central venous catheter with the tip located in the vena cava. Typically, the 8.5% solution is used in equal volume with 50% or 70% dextrose to provide an admixture containing 4.25% amino acids and 25% or 35% dextrose respectively.
The rate of intravenous infusion initially should be 2 mL/min and may be increased gradually. If administration should fall behind schedule, no attempt to “catch up” to planned intake should be made. In addition to meeting protein needs, the rate of administration is governed by the patient’s glucose tolerance estimated by glucose levels in blood and urine.
Aminosyn II 8.5% WITH ELECTROLYTES solution, when mixed with an appropriate volume of concentrated dextrose, offers a higher concentration of calories and nitrogen per unit volume. This solution is indicated for patients requiring larger amounts of nitrogen than could otherwise be provided or where total fluid load must be kept to a minimum, for example, patients with renal failure.
Provision of adequate calories in the form of hypertonic dextrose may require exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, do not abruptly discontinue administration of nutritional solutions.
## Pediatric
Aminosyn II 8.5% WITH ELECTROLYTES may not be suitable for use in infants whose electrolyte requirements must be “custom tailored” based on serial blood chemistry determinations.
Pediatric requirements for parenteral nutrition are constrained by the greater relative fluid requirements of the infant and greater caloric requirements per kilogram. Amino acids are probably best administered in a 2.5% concentration. For most pediatric patients on intravenous nutrition, 2.5 grams amino acids/kg/day with dextrose alone or with I.V. lipid calories of 100 to130 kcal/kg/day is recommended. In cases of malnutrition or stress, these requirements may be increased. It is acceptable in pediatrics to start with a nutritional solution of half strength at a rate of about 60 to 70 mL/kg/day. Within 24 to 48 hours the volume and concentration of the solution can be increased until the full strength pediatric solution (amino acids and dextrose) is given at a rate of 125 to 150 mL/kg/day.
Supplemental electrolytes and vitamin additives should be administered as deemed necessary by careful monitoring of blood chemistries and nutritional status. Addition of iron is more critical in the infant than the adult because of the increasing red cell mass required for the growing infant. Serum lipids should be monitored for evidence of essential fatty acid deficiency in patients maintained on fat-free TPN. Bicarbonate should not be administered during infusion of the nutritional solution unless deemed absolutely necessary.
To ensure the precise delivery of the small volumes of fluid necessary for total parenteral nutrition in infants, accurately calibrated and reliable infusion systems should be used.
A basic solution for pediatric use should contain 25 grams of amino acids and 200 to 250 grams of glucose per 1000 mL, administered from containers containing 250 or 500 mL. Such a solution given at the rate of 145 mL/kg/day provides 130 kcal/kg/day.
WARNING: Do not use flexible container in series connections. | Aminosyn II
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Aminosyn® II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection with electrolytes) is a sterile, nonpyrogenic solution for intravenous infusion. Aminosyn II 8.5% WITH ELECTROLYTES is oxygen sensitive.
The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.
Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.
Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.
# Clinical Pharmacology
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection with electrolytes) provides crystalline amino acids to promote protein synthesis and wound healing, and to reduce the rate of endogenous protein catabolism. Aminosyn II 8.5% WITH ELECTROLYTES, given by central venous infusion in combination with concentrated dextrose, electrolytes, vitamins, trace metals, and ancillary fat supplements, constitutes total parenteral nutrition (TPN). Aminosyn II 8.5% WITH ELECTROLYTES can also be administered by peripheral vein with dextrose and maintenance electrolytes. Intravenous fat emulsion may be substituted for part of the carbohydrate calories during either TPN or peripheral vein administration of Aminosyn II 8.5% WITH ELECTROLYTES.
# Indications and Usage
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection) infused with dextrose by peripheral vein infusion is indicated as a source of nitrogen in the nutritional support of patients in whom, for short periods of time, oral nutrition cannot be tolerated, is undesirable, or inadequate.
Aminosyn II 8.5% WITH ELECTROLYTES can be administered peripherally with dilute (5 to 10%) dextrose solution and I.V. fat emulsion as a source of nutritional support. This form of nutritional support can help to preserve protein and reduce catabolism in stress conditions where oral intake is inadequate.
When administered with concentrated dextrose solution with or without fat emulsions, Aminosyn II 8.5% WITH ELECTROLYTES is also indicated for central vein infusion to prevent or reverse negative nitrogen balance in patients where: (a) the alimentary tract, by the oral, gastrostomy or jejunostomy route cannot or should not be used; (b) gastrointestinal absorption of protein is impaired; (c) metabolic requirements for protein are substantially increased as with extensive burns and (d) morbidity and mortality may be reduced by replacing amino acids lost from tissue breakdown, thereby preserving tissue reserves, as in acute renal failure.
# Contraindications
This preparation should not be used in patients with hepatic coma or metabolic disorders involving impaired nitrogen utilization.
# Warnings
Intravenous infusion of amino acids may induce a rise in blood urea nitrogen (BUN), especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limitsand continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake.
Administration of amino acid solutions to a patient with hepatic insufficiency may result in serum amino acid imbalances, metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma.
Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does any protein dietary component.
Solutions containing sodium ion should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention.
Solutions which contain potassium ion should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present.
Solutions containing acetate ion should be used with great care in patients with metabolic or respiratory alkalosis. Acetate should be administered with great care in those conditions in which there is an increased level or an impaired utilization of this ion, such as severe hepatic insufficiency.
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection) may not be suitable for use in infants who require individualized electrolyte therapy.
Hyperammonemia is of special significance in infants, as it can result in mental retardation. Therefore, it is essential that blood ammonia levels be measured frequently in infants.
Instances of asymptomatic hyperammonemia have been reported in patients without overt liver dysfunction. The mechanisms of this reaction are not clearly defined, but may involve genetic defects and immature or subclinically impaired liver function.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
# Precautions
Special care must be taken when administering glucose to provide calories in diabetic or prediabetic patients.
Feeding regimens which include amino acids should be used with caution in patients with history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation.
The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time.
Nitrogen intake should be carefully monitored in patients with impaired renal function.
For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.
## SPECIAL PRECAUTIONS FOR CENTRAL VENOUS INFUSIONS
ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS.
Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL BASED ON CURRENT MEDICAL PRACTICES BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.
As a summary:
- Technical
The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.
- Septic
The constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.
Solutions should ideally be prepared in the hospital pharmacy under a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours.
Administration time for a single container and set should never exceed 24 hours.
- Metabolic
The following metabolic complications have been reported with TPN administration: metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia, hyperosmolar nonketotic states and dehydration, glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.
Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma and death.
Pregnancy Category C
Animal reproduction studies have not been conducted with Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection). It is not known whether Aminosyn II 8.5% WITH ELECTROLYTES can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn II 8.5% WITH ELECTROLYTES should be given to a pregnant woman only if clearly needed.
# Geriatric Use
Clinical studies of Aminosyn II 8.5% WITH ELECTROLYTES have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions.
CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN, ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.
Aminosyn II 8.5% WITH ELECTROLYTES contains no more than 25 mcg/L of aluminum.
# Drug Interactions
Because of its antianabolic activity, concurrent administration of tetracycline may reduce the potential anabolic effects of amino acids infused with dextrose as part of a parenteral feeding regimen.
Additives may be incompatible. Consult with pharmacist if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.
# Adverse Reactions
## Peripheral Infusions
A 3.5% to 5% solution of amino acids (without additives) is slightly hypertonic. Local reactions consisting of a warm sensation, erythema, phlebitis and thrombosis at the infusion site have occurred with peripheral intravenous infusion of amino acids particularly if other substances, such as antibiotics, are also administered through the same site. In such cases the infusion site should be changed promptly to another vein. Use of large peripheral veins, inline filters, and slowing the rate of infusion may reduce the incidence of local venous irritation. Electrolyte additives should be spread throughout the day.Irritating additive medications may need to be infused at another venous site.
Generalized flushing, fever and nausea also have been reported during peripheral infusions of amino acid solutions.
# Overdosage
In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.
# Dosage and Administration
The total daily dose of the solution depends on the daily protein requirements and on the patient’s metabolic and clinical response. In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose infusions are abruptly discontinued.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
# Central Vein Total Parenteral Nutrition
For central vein infusion with concentrated dextrose solution, alone or with I.V. lipid,the total daily dose of the amino acid solution depends upon daily protein requirements and the patient’s metabolic and clinical response. The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements.
## Adults
Admixtures of 3.5 to 4.25% amino acids with 5 to 10% dextrose may be infused with a fat emulsion by peripheral vein to provide approximately 1400 to 2000 kcal/day. Fat emulsion administration should be considered when prolonged parenteral nutrition is required in order to prevent essential fatty acid deficiency (E.F.A.D.). Serum lipids should be monitored for evidence of E.F.A.D. in patients maintained on fat-free TPN.
Aminosyn II 8.5% WITH ELECTROLYTES, Sulfite-Free, (an amino acid injection) should only be infused via a central vein when admixed with sufficient dextrose to provide full caloric requirements in patients who require prolonged total parenteral nutrition. I.V. lipid may be administered to provide part of the calories, if desired. Serum lipids should be monitored for evidence of essential fatty acid deficiency in patients maintained on fat-free TPN.
Total parenteral nutrition (TPN) may be started with 10% dextrose added to the calculated daily requirement of amino acids (1.5 g/kg for a metabolically stable patient). Dextrose content is gradually increased over the next few days to the estimated daily caloric need as the patient adapts to the increasing amounts of dextrose. Each gram of dextrose provides approximately 3.4 kcal. Each gram of fat provides 9 kcal.
The average depleted major surgical patient with complications requires between 2500 and 4000 kcal and between 12 and 24 grams of nitrogen per day. An adult patient in an acceptable weight range with restricted activity who is not hypermetabolic, requires about 30 kcal/kg of body weight/day. Average daily adult fluid requirements are between 2500 and 3000 mL and may be much higher with losses from fistula drainage or in severe burns. Typically, a hospitalized patient may lose 12 to 18 grams of nitrogen a day, and in severe trauma the daily loss may be 20 to 25 grams or more.
Aminosyn II 8.5% WITH ELECTROLYTES is designed to supply necessary electrolytes to patients in a stable metabolic state (about three-fourths of all patients on total parenteral nutrition). Other patients may require more or less of the electrolytes present, e.g., cardiac patients who should not receive sodium. Aminosyn II 8.5% WITH ELECTROLYTES does not contain calcium, and this should be added as indicated.
SERUM ELECTROLYTES SHOULD BE MONITORED AS INDICATED. Electrolytes may be added to the nutrient solution as indicated by the patient’s clinical condition and laboratory determinations of plasma values. Major electrolytes are sodium, chloride, potassium, phosphate, magnesium and calcium. Vitamins, including folic acid and vitamin K are required additives. The trace element supplements should be given when long-term parenteral nutrition is undertaken.
Calcium and phosphorus are added to the solution as indicated. The usual dose of phosphorus added to a liter of TPN solution (containing 25% dextrose) is 12 mM. This requirement is related to the carbohydrate calories delivered. Iron is added to the solution or given intramuscularly in depot form as indicated. Vitamin B12, vitamin K and folic acid are given intramuscularly or added to the solution as desired.
Calcium and phosphorus additives are potentially incompatible when added to the TPN admixture. However, if one additive is added to the amino acid container, and the other to the container of concentrated dextrose, and if the contents of both containers are swirled before they are combined, then the likelihood of physical incompatibility is reduced.
In patients with hyperchloremic or other metabolic acidosis, sodium and potassium may be added as the acetate or lactate salts to provide bicarbonate alternates.
In adults, hypertonic mixtures of amino acids and dextrose may be safely administered by continuous infusion through a central venous catheter with the tip located in the vena cava. Typically, the 8.5% solution is used in equal volume with 50% or 70% dextrose to provide an admixture containing 4.25% amino acids and 25% or 35% dextrose respectively.
The rate of intravenous infusion initially should be 2 mL/min and may be increased gradually. If administration should fall behind schedule, no attempt to “catch up” to planned intake should be made. In addition to meeting protein needs, the rate of administration is governed by the patient’s glucose tolerance estimated by glucose levels in blood and urine.
Aminosyn II 8.5% WITH ELECTROLYTES solution, when mixed with an appropriate volume of concentrated dextrose, offers a higher concentration of calories and nitrogen per unit volume. This solution is indicated for patients requiring larger amounts of nitrogen than could otherwise be provided or where total fluid load must be kept to a minimum, for example, patients with renal failure.
Provision of adequate calories in the form of hypertonic dextrose may require exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, do not abruptly discontinue administration of nutritional solutions.
## Pediatric
Aminosyn II 8.5% WITH ELECTROLYTES may not be suitable for use in infants whose electrolyte requirements must be “custom tailored” based on serial blood chemistry determinations.
Pediatric requirements for parenteral nutrition are constrained by the greater relative fluid requirements of the infant and greater caloric requirements per kilogram. Amino acids are probably best administered in a 2.5% concentration. For most pediatric patients on intravenous nutrition, 2.5 grams amino acids/kg/day with dextrose alone or with I.V. lipid calories of 100 to130 kcal/kg/day is recommended. In cases of malnutrition or stress, these requirements may be increased. It is acceptable in pediatrics to start with a nutritional solution of half strength at a rate of about 60 to 70 mL/kg/day. Within 24 to 48 hours the volume and concentration of the solution can be increased until the full strength pediatric solution (amino acids and dextrose) is given at a rate of 125 to 150 mL/kg/day.
Supplemental electrolytes and vitamin additives should be administered as deemed necessary by careful monitoring of blood chemistries and nutritional status. Addition of iron is more critical in the infant than the adult because of the increasing red cell mass required for the growing infant. Serum lipids should be monitored for evidence of essential fatty acid deficiency in patients maintained on fat-free TPN. Bicarbonate should not be administered during infusion of the nutritional solution unless deemed absolutely necessary.
To ensure the precise delivery of the small volumes of fluid necessary for total parenteral nutrition in infants, accurately calibrated and reliable infusion systems should be used.
A basic solution for pediatric use should contain 25 grams of amino acids and 200 to 250 grams of glucose per 1000 mL, administered from containers containing 250 or 500 mL. Such a solution given at the rate of 145 mL/kg/day provides 130 kcal/kg/day.
WARNING: Do not use flexible container in series connections.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Aminosyn_II | |
8b66f256258d831ed0918918b14306d5c5f29e26 | wikidoc | Amisulpride | Amisulpride
Amisulpride (brand-name Solian) is an antipsychotic drug sold by Sanofi-Aventis.
Amisulpride is a selective dopamine antagonist. It has a high affinity for D2 (Ki 2.8 nM) and D3 (Ki 3.2 nM) dopaminergic receptors. Its dosage ranges from 200 to 1200 mg/day. Lower doses (less than 50 mg) preferentially block d2 autoreceptors that control the synthesis and release of dopamine. This results in an increase in dopaminergic transmission. This dopamine increase is hypothesized to cause a reduction in both depressive and negative symptoms. Higher doses of the drug block the postsynaptic dopamine receptors resulting in an improvement in psychoses.
Amisulpride is not approved by the Food and Drug Administration for use in the United States. Amisulpride (in 50mg doses) is marketed as a treatment for dysthymia in Italy (as Deniban) In one study, anxiety measured by HAM-A total mean score decreased significantly more with amisulpride 50mg/day (63%) than with fluoxetine 20mg/day (54%; P = 0.021).
# Side effects
Prolactin induction, nausea, weight gain, although much less than similar drugs in its class, and less commonly QT interval prolongation (which can lead to serious heart arrhythmias). Overdoses of amisulpride have been linked with torsades de pointes. | Amisulpride
Amisulpride (brand-name Solian) is an antipsychotic drug sold by Sanofi-Aventis.
Amisulpride is a selective dopamine antagonist. It has a high affinity for D2 (Ki 2.8 nM) and D3 (Ki 3.2 nM) dopaminergic receptors. Its dosage ranges from 200 to 1200 mg/day. Lower doses (less than 50 mg) preferentially block d2 autoreceptors that control the synthesis and release of dopamine. This results in an increase in dopaminergic transmission. This dopamine increase is hypothesized to cause a reduction in both depressive and negative symptoms. Higher doses of the drug block the postsynaptic dopamine receptors resulting in an improvement in psychoses.
Amisulpride is not approved by the Food and Drug Administration for use in the United States. Amisulpride (in 50mg doses) is marketed as a treatment for dysthymia in Italy (as Deniban) In one study, anxiety measured by HAM-A total mean score decreased significantly more with amisulpride 50mg/day (63%) than with fluoxetine 20mg/day (54%; P = 0.021).[3]
# Side effects
Prolactin induction, nausea, weight gain, although much less than similar drugs in its class, and less commonly QT interval prolongation (which can lead to serious heart arrhythmias). Overdoses of amisulpride have been linked with torsades de pointes.[4] | https://www.wikidoc.org/index.php/Amisulpride | |
75a9dff4734d28cc43f99498f08fa65ed3068be4 | wikidoc | Hippocampus | Hippocampus
The hippocampus is a part of the brain located in the medial temporal lobe (humans and other mammals have two hippocampi, one in each side of the brain). It forms a part of the limbic system and plays a part in memory and spatial navigation. The name derives from its curved shape in coronal sections of the brain, which resembles a seahorse (Greek: hippos = horse, kampi = curve).
In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among the first symptoms. Damage to the hippocampus can also result from oxygen starvation (anoxia) and encephalitis.
# Role in general memory
Psychologists and neuroscientists dispute the precise role of the hippocampus, but, in general, agree that it has an essential role in the formation of new memories about experienced events (episodic or autobiographical memory). Some researchers prefer to consider the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory (memories that can be explicitly verbalized — these would include, for example, memory for facts in addition to episodic memory).
Some evidence supports the idea that, although these forms of memory often last a lifetime, the hippocampus ceases to play a crucial role in the retention of the memory after a period of consolidation. Damage to the hippocampus usually results in profound difficulties in forming new memories (anterograde amnesia), and normally also affects access to memories prior to the damage (retrograde amnesia). Although the retrograde effect normally extends some years prior to the brain damage, in some cases older memories remain - this sparing of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain. However, experimentation has difficulties in testing the sparing of older memories; and, in some cases of retrograde amnesia, the sparing appears to affect memories formed decades before the damage to the hippocampus occurred, so its role in maintaining these older memories remains controversial.
Damage to the hippocampus does not affect some aspects of memory, such as the ability to learn new skills (playing a musical instrument, for example), suggesting that such abilities depend on a different type of memory (procedural memory) and different brain regions. And there is evidence to suggest that patient HM (who had his medial temporal lobes removed bilaterally as a treatment for epilepsy) can form new semantic memories.
# Role in spatial memory and navigation
Some evidence implicates the hippocampus in storing and processing spatial information. Studies in rats have shown that neurons in the hippocampus have spatial firing fields. These cells are called place cells. Some cells fire when the animal finds itself in a particular location, regardless of direction of travel, while most are at least partially sensitive to head direction and direction of travel. In rats, some cells, termed context-dependent cells, may alter their firing depending on the animal's past (retrospective) or expected future (prospective). Different cells fire at different locations, so that, by looking at the firing of the cells alone, it becomes possible to tell where the animal is. Place cells have now been seen in humans involved in finding their way around in a virtual reality town. The findings resulted from research with individuals that had electrodes implanted in their brains as a diagnostic part of surgical treatment for serious epilepsy.
The discovery of place cells led to the idea that the hippocampus might act as a cognitive map — a neural representation of the layout of the environment. Recent evidence has cast doubt on this perspective, indicating that the hippocampus might be crucial for more fundamental processes within navigation. Regardless, studies with animals have shown that an intact hippocampus is required for simple spatial memory tasks (for instance, finding the way back to a hidden goal).
Without a fully-functional hippocampus, humans may not successfully remember where they have been and how to get where they are going. Researchers believe that the hippocampus plays a particularly important role in finding shortcuts and new routes between familiar places. Some people exhibit more skill at this sort of navigation than do others, and brain imaging shows that these individuals have more active hippocampi when navigating.
London's taxi drivers must learn a large number of places — and know the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs). A study at University College London by Maguire, et al (2000) showed that part of the hippocampus is larger in taxi drivers than in the general public, and that more experienced drivers have bigger hippocampi. Whether having a bigger hippocampus helps an individual to become a cab driver or finding shortcuts for a living makes an individual's hippocampus grow is yet to be elucidated. However, in that study Maguire, et al examined the correlation between size of the grey matter and length of time that had been spent as a taxi driver, and found that the longer an individual had spent as a taxi driver, the larger the volume of the right hippocampus. This finding suggested to the authors that the hippocampus increases in size with use over time.
A study on rats at Indiana University suggested that the sexual dimorphism in the hippocampus morphology is tied to a sexual dimorphism in repeated maze performance. Males seem to be better at contexualizing their whereabouts because they have more hippocampus to work with.
# History
The anatomist Giulio Cesare Aranzi (circa 1564) first used the term hippocampus to describe the cerebral organ because of its visual resemblance to a seahorse. This organ was initially connected with the sense of smell, rather than with its known function in memory acquisition. The Russian Vladimir Bekhterev noted the role of the hippocampus in memory around 1900, based on observations of a patient with profound memory disturbances. However, for many years, the conventional view of the hippocampus was that, like the rest of the limbic system, it was responsible for emotion.
The importance of the hippocampus in memory was brought to the attention of researchers by patient HM. HM suffered from a number of anterograde and temporally-graded retrograde memory impairments (such impairments are the subject of the movie Memento) following the bilateral removal of various medial-temporal lobe structures (including bilateral ablation of his hippocampi) to relieve frequent epileptic seizures. Of particular importance is that HM was still able to learn procedural tasks (which are associated with the Striatum) and had an above-average IQ. HM demonstrated a striking single-dissociation between intelligence and declarative memory. The relative size of the hippocampal formation in relation with the total volume of the brain is often conserved in most of the mammalian species. Nevertheless, it has been found that these areas are relatively hypotrophic in cetaceans.
# Anatomy
Although there is a lack of consensus relating to terms describing the hippocampus and the adjacent cerebral cortex, the term hippocampal formation generally applies to the dentate gyrus, the Cornu Ammonis fields CA1-CA3 (and CA4, frequently called the hilus and considered part of the dentate gyrus), and the subiculum. The CA1, CA2 and CA3 fields make up the hippocampus proper.
Information flow through the hippocampus proceeds from the dentate gyrus to CA3 to CA1 to the subiculum, with additional input information at each stage and outputs at each of the two final stages. CA2 represents only a very small portion of the hippocampus and its presence is often ignored in accounts of hippocampal function, though it is notable that this small region seems unusually resistant to conditions that usually cause large amounts of cellular damage, such as epilepsy.
The perforant path, which brings information primarily from entorhinal cortex (but also perirhinal cortex, among others), is generally considered the main source of input to the hippocampus. Layer II of entorhinal cortex (EC) brings input to the dentate gyrus and field CA3, while EC layer III brings input to field CA1 and the subiculum. The main output pathways of the hippocampus are the cingulum bundle and the fimbria/fornix, which arise from field CA1 and the subiculum.
Perforant path input from EC layer II enters the dentate gyrus and is relayed to region CA3 (and to mossy cells, located in the hilus of the dentate gyrus, which then send information to distant portions of the dentate gyrus where the cycle is repeated). Region CA3 combines this input with signals from EC layer II and sends extensive connections within the region and also sends connections to region CA1 through a set of fibers called the Schaffer collaterals. Region CA1 receives input from the CA3 subfield, EC layer III and the nucleus reuniens of the thalamus (which project only to the terminal apical dendritic tufts in the stratum lacunosum-moleculare). In turn, CA1 projects to the subiculum as well as sending information along the aforementioned output paths of the hippocampus. The subiculum is the final stage in the pathway, combining information from the CA1 projection and EC layer III to also send information along the output pathways of the hippocampus.
The hippocampus also receives a number of subcortical inputs. In Macaca fascicularis, these inputs include the amygdala (specifically the anterior amygdaloid area, the basolateral nucleus, and the periamygdaloid cortex), the medial septum and the diagonal band of Broca, the claustrum, the substantia innominata and the basal nucleus of Meynert, the thalamus (including the anterior nuclear complex, the laterodorsal nucleus, the paraventricular and parataenial nuclei, the nucleus reuniens, and the nucleus centralis medialis), the lateral preoptic and lateral hypothalamic areas, the supramammillary and retromammillary regions, the ventral tegmental area, the tegmental reticular fields, the raphe nuclei (the nucleus centralis superior and the dorsal raphe nucleus), the nucleus reticularis tegementi pontis, the central gray, the dorsal tegmental nucleus, and the locus coeruleus.
The hippocampus also receives direct monosynaptic projections from the cerebellar fastigial nucleus (Heath and Harper 1974).
It is widely accepted that each of these regions has a unique functional role in the information processing of the hippocampus, but to date the specific contribution of each region is poorly understood. | Hippocampus
Template:Infobox Brain
The hippocampus is a part of the brain located in the medial temporal lobe (humans and other mammals have two hippocampi, one in each side of the brain). It forms a part of the limbic system and plays a part in memory and spatial navigation. The name derives from its curved shape in coronal sections of the brain, which resembles a seahorse (Greek: hippos = horse, kampi = curve).
In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among the first symptoms. Damage to the hippocampus can also result from oxygen starvation (anoxia) and encephalitis.
# Role in general memory
Psychologists and neuroscientists dispute the precise role of the hippocampus, but, in general, agree that it has an essential role in the formation of new memories about experienced events (episodic or autobiographical memory). Some researchers prefer to consider the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory (memories that can be explicitly verbalized — these would include, for example, memory for facts in addition to episodic memory).
Some evidence supports the idea that, although these forms of memory often last a lifetime, the hippocampus ceases to play a crucial role in the retention of the memory after a period of consolidation. Damage to the hippocampus usually results in profound difficulties in forming new memories (anterograde amnesia), and normally also affects access to memories prior to the damage (retrograde amnesia). Although the retrograde effect normally extends some years prior to the brain damage, in some cases older memories remain - this sparing of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain. However, experimentation has difficulties in testing the sparing of older memories; and, in some cases of retrograde amnesia, the sparing appears to affect memories formed decades before the damage to the hippocampus occurred, so its role in maintaining these older memories remains controversial.
Damage to the hippocampus does not affect some aspects of memory, such as the ability to learn new skills (playing a musical instrument, for example), suggesting that such abilities depend on a different type of memory (procedural memory) and different brain regions. And there is evidence to suggest that patient HM (who had his medial temporal lobes removed bilaterally as a treatment for epilepsy[1]) can form new semantic memories.[2]
# Role in spatial memory and navigation
Some evidence implicates the hippocampus in storing and processing spatial information. Studies in rats have shown that neurons in the hippocampus have spatial firing fields. These cells are called place cells. Some cells fire when the animal finds itself in a particular location, regardless of direction of travel, while most are at least partially sensitive to head direction and direction of travel. In rats, some cells, termed context-dependent cells, may alter their firing depending on the animal's past (retrospective) or expected future (prospective). Different cells fire at different locations, so that, by looking at the firing of the cells alone, it becomes possible to tell where the animal is. Place cells have now been seen in humans involved in finding their way around in a virtual reality town. The findings resulted from research with individuals that had electrodes implanted in their brains as a diagnostic part of surgical treatment for serious epilepsy.[3]
The discovery of place cells led to the idea that the hippocampus might act as a cognitive map — a neural representation of the layout of the environment. Recent evidence has cast doubt on this perspective, indicating that the hippocampus might be crucial for more fundamental processes within navigation. Regardless, studies with animals have shown that an intact hippocampus is required for simple spatial memory tasks (for instance, finding the way back to a hidden goal).
Without a fully-functional hippocampus, humans may not successfully remember where they have been and how to get where they are going. Researchers believe that the hippocampus plays a particularly important role in finding shortcuts and new routes between familiar places. Some people exhibit more skill at this sort of navigation than do others, and brain imaging shows that these individuals have more active hippocampi when navigating.
London's taxi drivers must learn a large number of places — and know the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs). A study at University College London by Maguire, et al (2000) showed that part of the hippocampus is larger in taxi drivers than in the general public, and that more experienced drivers have bigger hippocampi.[4] Whether having a bigger hippocampus helps an individual to become a cab driver or finding shortcuts for a living makes an individual's hippocampus grow is yet to be elucidated. However, in that study Maguire, et al examined the correlation between size of the grey matter and length of time that had been spent as a taxi driver, and found that the longer an individual had spent as a taxi driver, the larger the volume of the right hippocampus.[4] This finding suggested to the authors that the hippocampus increases in size with use over time.[4]
A study on rats at Indiana University suggested that the sexual dimorphism in the hippocampus morphology is tied to a sexual dimorphism in repeated maze performance.[citation needed] Males seem to be better at contexualizing their whereabouts because they have more hippocampus to work with.
# History
The anatomist Giulio Cesare Aranzi (circa 1564) first used the term hippocampus to describe the cerebral organ because of its visual resemblance to a seahorse. This organ was initially connected with the sense of smell, rather than with its known function in memory acquisition. The Russian Vladimir Bekhterev noted the role of the hippocampus in memory around 1900, based on observations of a patient with profound memory disturbances. However, for many years, the conventional view of the hippocampus was that, like the rest of the limbic system, it was responsible for emotion.
The importance of the hippocampus in memory was brought to the attention of researchers by patient HM. HM suffered from a number of anterograde and temporally-graded retrograde memory impairments (such impairments are the subject of the movie Memento) following the bilateral removal of various medial-temporal lobe structures (including bilateral ablation of his hippocampi) to relieve frequent epileptic seizures. Of particular importance is that HM was still able to learn procedural tasks (which are associated with the Striatum) and had an above-average IQ. HM demonstrated a striking single-dissociation between intelligence and declarative memory. The relative size of the hippocampal formation in relation with the total volume of the brain is often conserved in most of the mammalian species. Nevertheless, it has been found that these areas are relatively hypotrophic in cetaceans.
# Anatomy
Although there is a lack of consensus relating to terms describing the hippocampus and the adjacent cerebral cortex, the term hippocampal formation generally applies to the dentate gyrus, the Cornu Ammonis fields CA1-CA3 (and CA4, frequently called the hilus and considered part of the dentate gyrus), and the subiculum. The CA1, CA2 and CA3 fields make up the hippocampus proper.
Information flow through the hippocampus proceeds from the dentate gyrus to CA3 to CA1 to the subiculum, with additional input information at each stage and outputs at each of the two final stages. CA2 represents only a very small portion of the hippocampus and its presence is often ignored in accounts of hippocampal function, though it is notable that this small region seems unusually resistant to conditions that usually cause large amounts of cellular damage, such as epilepsy.
The perforant path, which brings information primarily from entorhinal cortex (but also perirhinal cortex, among others), is generally considered the main source of input to the hippocampus. Layer II of entorhinal cortex (EC) brings input to the dentate gyrus and field CA3, while EC layer III brings input to field CA1 and the subiculum. The main output pathways of the hippocampus are the cingulum bundle and the fimbria/fornix, which arise from field CA1 and the subiculum.
Perforant path input from EC layer II enters the dentate gyrus and is relayed to region CA3 (and to mossy cells, located in the hilus of the dentate gyrus, which then send information to distant portions of the dentate gyrus where the cycle is repeated). Region CA3 combines this input with signals from EC layer II and sends extensive connections within the region and also sends connections to region CA1 through a set of fibers called the Schaffer collaterals. Region CA1 receives input from the CA3 subfield, EC layer III and the nucleus reuniens of the thalamus (which project only to the terminal apical dendritic tufts in the stratum lacunosum-moleculare). In turn, CA1 projects to the subiculum as well as sending information along the aforementioned output paths of the hippocampus. The subiculum is the final stage in the pathway, combining information from the CA1 projection and EC layer III to also send information along the output pathways of the hippocampus.
The hippocampus also receives a number of subcortical inputs. In Macaca fascicularis, these inputs include the amygdala (specifically the anterior amygdaloid area, the basolateral nucleus, and the periamygdaloid cortex), the medial septum and the diagonal band of Broca, the claustrum, the substantia innominata and the basal nucleus of Meynert, the thalamus (including the anterior nuclear complex, the laterodorsal nucleus, the paraventricular and parataenial nuclei, the nucleus reuniens, and the nucleus centralis medialis), the lateral preoptic and lateral hypothalamic areas, the supramammillary and retromammillary regions, the ventral tegmental area, the tegmental reticular fields, the raphe nuclei (the nucleus centralis superior and the dorsal raphe nucleus), the nucleus reticularis tegementi pontis, the central gray, the dorsal tegmental nucleus, and the locus coeruleus.
The hippocampus also receives direct monosynaptic projections from the cerebellar fastigial nucleus (Heath and Harper 1974).
It is widely accepted that each of these regions has a unique functional role in the information processing of the hippocampus, but to date the specific contribution of each region is poorly understood. | https://www.wikidoc.org/index.php/Ammon%27s_horn | |
45f629f83779df35db5ac2240b735570162d4593 | wikidoc | Amphetamine | Amphetamine
# Overview
Amphetamine is a potent central nervous system stimulant used in the treatment of attention deficit hyperactivity disorder and narcolepsy.
# Amphetamine
Amphetamine (Lua error: expandTemplate: template "Template:IPA audio link" does not exist.; contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.
The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as Adderall, dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.
Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk of amphetamine abuse, but only rarely arises from medical use. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious side effects.
Amphetamine is also the parent compound of its own structural class, the substituted amphetamines, which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body.
# Uses
## Medical
Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy, and is sometimes prescribed off-label for its past medical indications, such as depression, obesity, and nasal congestion. Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth. Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus.
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. Controlled trials spanning two years have demonstrated treatment effectiveness and safety. One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems; these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex. Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 70% of those who use these stimulants see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. The Cochrane Collaboration's review on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.
A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals. Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.
## Enhancing performance
Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals. Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. Stimulants such as amphetamine can improve performance on difficult and boring tasks, and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants. However, high amphetamine doses that are above the therapeutic range can interfere with working memory and cognitive control.
Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness; however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time. Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.
# Contraindications
According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA), amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety. It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (an eye condition), hyperthyroidism (excessive production of thyroid hormone), or hypertension (elevated blood pressure). People who have experienced allergic reactions to other stimulants in the past or are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine. These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine. Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus. Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it. Due to the potential for reversible growth impairments, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.
# Side effects
The side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects. Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use. Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.
## Physical
At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person. Cardiovascular side effects can include irregular heartbeat (usually an increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon (reduced blood flow to extremities). Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss. Other potential side effects include dry mouth, excessive grinding of the teeth, acne, profuse sweating, blurred vision, reduced seizure threshold, and tics (a type of movement disorder). Dangerous physical side effects are rare at typical pharmaceutical doses.
Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control. The effects of amphetamine on the gastrointestinal tract are unpredictable. If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.
USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.
## Psychological
Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability. Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness; these effects depend on the user's personality and current mental state. Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants can produce aggressive behavior or hostility.
# Overdose
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. The severity of overdose symptoms vary positively with dosage and inversely with drug tolerance to amphetamine. Tolerant individuals have been known to take as much as 5 grams of amphetamine, roughly 100 times the maximum daily therapeutic dose, in a day. Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma. Chronic overdose of amphetamine poses a high risk of developing an addiction, since high doses result in increased expression of the addiction gene ΔFosB. Consistent aerobic exercise appears to magnitude-dependently reduce this risk.
## Addiction
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical medical use at therapeutic doses. Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.
### Biomolecular mechanisms
Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB). ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the associated neural adaptations that occur; it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phenylcyclidine, and substituted amphetamines. ΔJunD is the transcription factor which directly opposes ΔFosB. Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since natural rewards induce expression of ΔFosB just like drugs of abuse do, chronic acquisition of these rewards can result in a similar pathological state of addiction. Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced sex addictions, a phenomenon known as dopamine dysregulation syndrome which has been observed in some patients taking dopaminergic medications.
The effects of amphetamine on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.
### Pharmacological treatments
A Cochrane Collaboration review on amphetamine and methamphetamine addiction and abuse indicates that the current evidence on effective treatments is extremely limited. The review indicated that fluoxetine and imipramine have some limited benefits in treating abuse and addiction, but concluded that there is currently no effective pharmacological treatment for amphetamine addiction or abuse. A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic dopamine pathway (a pathway in the brain that connects the ventral tegmental area to the nucleus accumbens). This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels. It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium, like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.
### Behavioral treatments
Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction. Additionally, research on the neurobiological effects of physical exercise suggests that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction. Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).
### Withdrawal
According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams. The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms. Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.
## Psychosis
Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia and delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
## Toxicity
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.
# Interactions
Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both. Inhibitors of the enzymes that metabolize amphetamine (i.e., CYP2D6 and flavin-containing monooxygenase 3) will prolong its elimination half-life. Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous. Amphetamine will modulate the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants. Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively. In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively. Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite. Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH.
# Pharmacology
## Pharmacodynamics
Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain, collectively known as the mesocorticolimbic projection. The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine due to its effects on monoamine transporters. The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.
Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines. Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons. As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.
In addition to the neuronal monoamine transporters, amphetamine also inhibits vesicular monoamine transporter 2 (VMAT2), SLC1A1, SLC22A3, and SLC22A5. SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter. Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression, a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro. The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR. Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.
The full profile of amphetamine's short-term drug effects is derived through increased cellular communication or neurotransmission of dopamine, serotonin, norepinephrine, epinephrine, histamine, CART peptides, acetylcholine, and glutamate, which it effects through interactions with CART, EAAT3, TAAR1, and VMAT2.
Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine. Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.
### Dopamine
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft. Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux). Amphetamine is also known to increase intracellular calcium, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux. Through direct activation of G protein-coupled inwardly-rectifying potassium channels and increased dopamine release, TAAR1 reduces the firing rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2. Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange. Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.
### Norepinephrine
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine. In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.
### Serotonin
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.
### Other neurotransmitters
Amphetamine has no direct effect on acetylcholine neurotransmission, but several studies have noted that acetylcholine release increases after its use. In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect. In humans, a similar phenomenon occurs via the ghrelin-mediated cholinergic–dopaminergic reward link in the ventral tegmental area. This heightened cholinergic activity leads to increased nicotinic receptor activation in the CNS, a factor which likely contributes to the nootropic effects of amphetamine.
Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine. This cotransmission effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission. Amphetamine also induces effluxion of histamine from synaptic vesicles in CNS mast cells and histaminergic neurons through VMAT2.
## Pharmacokinetics
The oral bioavailability of amphetamine varies with gastrointestinal pH; it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine. Amphetamine is a weak base with a pKa of 9–10; consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. Conversely, an acidic pH means the drug is predominantly in a water soluble cationic (salt) form, and less is absorbed. Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.
The half-life of amphetamine enantiomers differ and vary with urine pH. At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours. The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. Amphetamine is usually eliminated within two days of the last oral dose. Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.
The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract; following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis. The elimination half-life of lisdexamfetamine is generally less than one hour.
CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine, 4‑hydroxynorephedrine, and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known pathways and detectable metabolites in humans include the following:
## Related endogenous compounds
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula). In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well. In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1; unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.
# Physical and chemical properties
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula Template:Chemical formula. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images. This racemic mixture can be separated into its optical isomers: levoamphetamine and dextroamphetamine. Physically, at room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste. Frequently prepared solid salts of amphetamine include amphetamine aspartate, hydrochloride, phosphate, saccharate, and sulfate, the last of which is the most common amphetamine salt. Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives. In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.
## Derivatives
Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone". The class includes stimulants like methamphetamine, serotonergic empathogens like MDMA (ecstasy), and decongestants like ephedrine, among other subgroups. This class of chemicals is sometimes referred to collectively as the "amphetamine family."
## Synthesis
Since the first preparation was reported in 1887, numerous synthetic routes to amphetamine have been developed. Many of these syntheses are based on classic organic reactions. One such example is the Friedel–Crafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1). Another example employs the Ritter reaction (method 2). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate. A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 3).
A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional group. In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 4). Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 5).
The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 6). In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine. For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine. Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale. In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.
## Detection in body fluids
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics. Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs. Chromatographic methods specific for amphetamine are employed to prevent false positive results. Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products (e.g., Vicks VapoInhaler, which contains levomethamphetamine) or illicitly obtained substituted amphetamines. Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others. These compounds may produce positive results for amphetamine on drug tests. Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for two to four days.
For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry. Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine. GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine. Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.
# History, society, and culture
Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine; its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties. Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant. During World War II, amphetamines and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects. As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine. For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act. In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors, musicians, mathematicians, and athletes.
Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries. Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013. During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states; the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period. Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.
## Legal status
As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties. Consequently, it is heavily regulated in most countries. Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use. In other nations, such as Canada (schedule I drug), the United States (schedule II drug), Thailand (category 1 narcotic), and United Kingdom (class B drug), amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.
## Pharmaceutical products
The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall. Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively. Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine. The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine. Levoamphetamine was previously available as Cydril. All current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base. Some of the current brands and their generic equivalents are listed below.
# Notes
- ↑ Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name ), β-phenylisopropylamine, desoxynorephedrine, and speed.
- ↑ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.
- ↑ Jump up to: 3.0 3.1 "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate") is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
- ↑ Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for the class.
- ↑ Again, due to confusion that may arise from use of the plural form, this article will only use "phenethylamine" and "phenethylamines" to refer to the compound itself and reserve the term "substituted phenethylamines" for the class.
- ↑ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.
- ↑ The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
- ↑ In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted. The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.
- ↑ Transcription factors are proteins that increase or decrease the expression of specific genes.
- ↑ During short-term treatment, fluoxetine may decrease drug craving.
- ↑ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.
- ↑ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior; other forms of magnesium were not mentioned.
- ↑ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.
- ↑ Ion channel G proteins & linked receptors (Text color) Transcription factors
# Reference notes
- ↑ Jump up to: 7.0 7.1 | Amphetamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amphetamine is a potent central nervous system stimulant used in the treatment of attention deficit hyperactivity disorder and narcolepsy.
# Amphetamine
Amphetamine[note 1] (Lua error: expandTemplate: template "Template:IPA audio link" does not exist.; contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 2] Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.[sources 1]
The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[sources 2]
Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk of amphetamine abuse, but only rarely arises from medical use. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious side effects.[sources 3]
Amphetamine is also the parent compound of its own structural class, the substituted amphetamines,[note 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine[note 5] and N-methylphenethylamine, both of which are produced within the human body.[sources 4]
# Uses
## Medical
Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy, and is sometimes prescribed off-label for its past medical indications, such as depression, obesity, and nasal congestion.[11][27] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[38][39] but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.[40][41][42] Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus.[40][41][42]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[43][44] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[44][45] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.[45]
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[46] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[46] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[24][46][47] Approximately 70% of those who use these stimulants see improvements in ADHD symptoms.[48][49] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[43][48] The Cochrane Collaboration's review[note 6] on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[51]
A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[52] Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.[53][54][55]
## Enhancing performance
Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals.[24][56] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[24][57][58] Stimulants such as amphetamine can improve performance on difficult and boring tasks,[24][57] and are used by some students as a study and test-taking aid.[59] Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants.[60] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and cognitive control.[24][57]
Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[23][35] however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.[61][62] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[23][63][64] Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[63][64][65] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[23][63][64] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[22][31][63]
# Contraindications
According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 7] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety.[66][67] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (an eye condition), hyperthyroidism (excessive production of thyroid hormone), or hypertension (elevated blood pressure).[66][67] People who have experienced allergic reactions to other stimulants in the past or are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine.[66][67] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[66][67] Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus.[67] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[66][67] Due to the potential for reversible growth impairments,[note 8] the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[66]
# Side effects
The side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.[22][31][35] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[29][31] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[35]
## Physical
At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[31] Cardiovascular side effects can include irregular heartbeat (usually an increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon (reduced blood flow to extremities).[31][35][68] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[31] Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.[31] Other potential side effects include dry mouth, excessive grinding of the teeth, acne, profuse sweating, blurred vision, reduced seizure threshold, and tics (a type of movement disorder).[31][35][68] Dangerous physical side effects are rare at typical pharmaceutical doses.[35]
Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[35] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[35] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[35] The effects of amphetamine on the gastrointestinal tract are unpredictable.[35] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[35] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[35] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.[35]
USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 5]
## Psychological
Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[31][35] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 6] these effects depend on the user's personality and current mental state.[35] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[22][31][32] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[22][31][33] According to the USFDA, "there is no systematic evidence" that stimulants can produce aggressive behavior or hostility.[31]
# Overdose
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[67][74] The severity of overdose symptoms vary positively with dosage and inversely with drug tolerance to amphetamine.[35][67] Tolerant individuals have been known to take as much as 5 grams of amphetamine, roughly 100 times the maximum daily therapeutic dose, in a day.[67] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[22][35] Chronic overdose of amphetamine poses a high risk of developing an addiction, since high doses result in increased expression of the addiction gene ΔFosB.[75] Consistent aerobic exercise appears to magnitude-dependently reduce this risk.[76]
Template:Amphetamine overdose
## Addiction
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical medical use at therapeutic doses.[22][34][35] Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[82][83]
### Biomolecular mechanisms
Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[84][85][86] The most important transcription factors[note 9] that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[85] ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the associated neural adaptations that occur;[85] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phenylcyclidine, and substituted amphetamines.[85][88][89] ΔJunD is the transcription factor which directly opposes ΔFosB.[85] Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[85] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[85][88][90] Since natural rewards induce expression of ΔFosB just like drugs of abuse do, chronic acquisition of these rewards can result in a similar pathological state of addiction.[88][85] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced sex addictions, a phenomenon known as dopamine dysregulation syndrome which has been observed in some patients taking dopaminergic medications.[88][90][91]
The effects of amphetamine on gene regulation are both dose- and route-dependent.[86] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[86] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[86]
### Pharmacological treatments
A Cochrane Collaboration review on amphetamine and methamphetamine addiction and abuse indicates that the current evidence on effective treatments is extremely limited.[92] The review indicated that fluoxetine[note 10] and imipramine[note 11] have some limited benefits in treating abuse and addiction, but concluded that there is currently no effective pharmacological treatment for amphetamine addiction or abuse.[92] A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic dopamine pathway (a pathway in the brain that connects the ventral tegmental area to the nucleus accumbens).[93] This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels.[93] It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[93] Supplemental magnesium,[note 12] like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.[92][93]
### Behavioral treatments
Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction.[94] Additionally, research on the neurobiological effects of physical exercise suggests that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.[76][88] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[76] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).[88]
### Withdrawal
According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[95] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[95] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[95] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[95] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[96][97][98]
## Psychosis
Template:Main section
Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia and delusions).[32] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[32][99] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[32] Psychosis very rarely arises from therapeutic use.[33][66]
## Toxicity
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[100] There is no evidence that amphetamine is directly neurotoxic in humans.[101][102] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[38][103][104]
# Interactions
Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[1][105] Inhibitors of the enzymes that metabolize amphetamine (i.e., CYP2D6 and flavin-containing monooxygenase 3) will prolong its elimination half-life.[5][105] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[105] Amphetamine will modulate the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants.[105] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[105] In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.[105] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[105] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH.[105]
# Pharmacology
## Pharmacodynamics
Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain, collectively known as the mesocorticolimbic projection.[30][47] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine due to its effects on monoamine transporters.[30][47][106] The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[24]
Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[30][112] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[30][113] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[30] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[30] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[30] As of 2010,[update] co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[30]
In addition to the neuronal monoamine transporters, amphetamine also inhibits vesicular monoamine transporter 2 (VMAT2), SLC1A1, SLC22A3, and SLC22A5.[sources 7] SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter.[sources 7] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[118] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[119][120][121] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[121][122] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[14][123]
The full profile of amphetamine's short-term drug effects is derived through increased cellular communication or neurotransmission of dopamine,[30] serotonin,[30] norepinephrine,[30] epinephrine,[106] histamine,[106] CART peptides,[118] acetylcholine,[124][125] and glutamate,[126][127] which it effects through interactions with CART, EAAT3, TAAR1, and VMAT2.[sources 8]
Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[128] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[35][128]
### Dopamine
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[30] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[30] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[30] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[30] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[30][129] Amphetamine is also known to increase intracellular calcium, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[112][110][111] Through direct activation of G protein-coupled inwardly-rectifying potassium channels and increased dopamine release, TAAR1 reduces the firing rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.[130][108][109]
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[106] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.[106] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.[30][106]
### Norepinephrine
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[37][47] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[30][106][129] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[30][106]
### Serotonin
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[30][47] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[30][106]
### Other neurotransmitters
Amphetamine has no direct effect on acetylcholine neurotransmission, but several studies have noted that acetylcholine release increases after its use.[124][125] In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.[124] In humans, a similar phenomenon occurs via the ghrelin-mediated cholinergic–dopaminergic reward link in the ventral tegmental area.[125] This heightened cholinergic activity leads to increased nicotinic receptor activation in the CNS, a factor which likely contributes to the nootropic effects of amphetamine.[131]
Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine.[126][127] This cotransmission effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission.[126][127] Amphetamine also induces effluxion of histamine from synaptic vesicles in CNS mast cells and histaminergic neurons through VMAT2.[106]
## Pharmacokinetics
The oral bioavailability of amphetamine varies with gastrointestinal pH;[105] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[9] Amphetamine is a weak base with a pKa of 9–10;[1] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[1][105] Conversely, an acidic pH means the drug is predominantly in a water soluble cationic (salt) form, and less is absorbed.[1] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[10]
The half-life of amphetamine enantiomers differ and vary with urine pH.[1] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[1] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[132][133] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[1] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[1] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[1] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[1] Amphetamine is usually eliminated within two days of the last oral dose.[132] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.[134]
The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[135] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[135] The elimination half-life of lisdexamfetamine is generally less than one hour.[135]
CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 9] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[1][132][136] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[137] 4‑hydroxynorephedrine,[138] and norephedrine.[139] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[1][132] The known pathways and detectable metabolites in humans include the following:[1][5][136]
Template:Amphetamine Pharmacokinetics
## Related endogenous compounds
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[30][37] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[30][37][140] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[37][140] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[37][140] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[30][140] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[37][140]
# Physical and chemical properties
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula Template:Chemical formula. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images.[15] This racemic mixture can be separated into its optical isomers:[note 13] levoamphetamine and dextroamphetamine.[15] Physically, at room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[141] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[22] hydrochloride,[142] phosphate,[143] saccharate,[22] and sulfate,[22] the last of which is the most common amphetamine salt.[36] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[15] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[144]
## Derivatives
Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".[145][146] The class includes stimulants like methamphetamine, serotonergic empathogens like MDMA (ecstasy), and decongestants like ephedrine, among other subgroups.[145][146] This class of chemicals is sometimes referred to collectively as the "amphetamine family."[147]
## Synthesis
Template:Details3
Since the first preparation was reported in 1887,[148] numerous synthetic routes to amphetamine have been developed.[149][150] Many of these syntheses are based on classic organic reactions. One such example is the Friedel–Crafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1).[151] Another example employs the Ritter reaction (method 2). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate.[152][153] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 3).[154]
A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional group.[149] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 4).[155][156] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 5).[156]
The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 6).[36][156] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[156][157]
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[150] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[158] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[159] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[159]
## Detection in body fluids
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 10] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[163] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[164] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products (e.g., Vicks VapoInhaler, which contains levomethamphetamine) or illicitly obtained substituted amphetamines.[164][165][166] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[27][167][168] These compounds may produce positive results for amphetamine on drug tests.[167][168] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for two to four days.[163]
For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry.[165] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[164] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[164] Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.[164]
# History, society, and culture
Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[148][170][171] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[171] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant.[28] During World War II, amphetamines and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[148][172][173] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[148] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[174] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[175] musicians,[176] mathematicians,[177] and athletes.[23]
Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[169] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[178] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[178] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[178] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[169]
## Legal status
As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties.[21] Consequently, it is heavily regulated in most countries.[179][180] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[181][182] In other nations, such as Canada (schedule I drug),[183] the United States (schedule II drug),[22] Thailand (category 1 narcotic),[184] and United Kingdom (class B drug),[185] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[26][169]
## Pharmaceutical products
The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall.[note 3][15][27] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[29][186] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[186] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[15][27] Levoamphetamine was previously available as Cydril.[27] All current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[27][29][36] Some of the current brands and their generic equivalents are listed below.
# Notes
- ↑ Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.[14][15][16]
- ↑ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[17]Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[14]
- ↑ Jump up to: 3.0 3.1 "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[29]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
- ↑ Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for the class.
- ↑ Again, due to confusion that may arise from use of the plural form, this article will only use "phenethylamine" and "phenethylamines" to refer to the compound itself and reserve the term "substituted phenethylamines" for the class.
- ↑ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[50]
- ↑ The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
- ↑ In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.[44][45][68] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.[68]
- ↑ Transcription factors are proteins that increase or decrease the expression of specific genes.[87]
- ↑ During short-term treatment, fluoxetine may decrease drug craving.[92]
- ↑ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.[92]
- ↑ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[93] other forms of magnesium were not mentioned.
- ↑ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[17]
- ↑ Ion channel G proteins & linked receptors (Text color) Transcription factors
# Reference notes
- ↑ [18][19][20][21][22][23][24][25][26][27][28]
- ↑ [11][23][24][25][27][28][30][31]
- ↑ [22][24][32][33][34][35]
- ↑ [36][37]
- ↑ [69][70][71][72]
- ↑ [25][31][35][73]
- ↑ Jump up to: 7.0 7.1 [106][110][114][115][116][117]
- ↑ [30][106][114][118]
- ↑ [1][2][3][4][5][6][7][8]
- ↑ [23][160][161][162] | https://www.wikidoc.org/index.php/Amphetamine | |
05f3c57325cb1e03b0afa4d15ee3d987db4f033c | wikidoc | Amphiphysin | Amphiphysin
Amphiphysin is a protein that in humans is encoded by the AMPH gene.
# Function
This gene encodes a protein associated with the cytoplasmic surface of synaptic vesicles. A subset of patients with stiff person syndrome who were also affected by breast cancer are positive for autoantibodies against this protein. Alternate splicing of this gene results in two transcript variants encoding different isoforms. Additional splice variants have been described, but their full length sequences have not been determined.
Amphiphysin is a brain-enriched protein with an N-terminal lipid interaction, dimerisation and membrane bending BAR domain, a middle clathrin and adaptor binding domain and a C-terminal SH3 domain. In the brain, its primary function is thought to be the recruitment of dynamin to sites of clathrin-mediated endocytosis. There are 2 mammalian amphiphysins with similar overall structure. A ubiquitous splice form of amphiphysin 2 that does not contain clathrin or adaptor interactions is highly expressed in muscle tissue and is involved in the formation and stabilization of the T-tubule network. In other tissues amphiphysin is likely involved in other membrane bending and curvature stabilization events.
# Interactions
Amphiphysin has been shown to interact with DNM1, Phospholipase D1, CDK5R1, PLD2, CABIN1 and SH3GL2. | Amphiphysin
Amphiphysin is a protein that in humans is encoded by the AMPH gene.[1][2]
# Function
This gene encodes a protein associated with the cytoplasmic surface of synaptic vesicles. A subset of patients with stiff person syndrome who were also affected by breast cancer are positive for autoantibodies against this protein. Alternate splicing of this gene results in two transcript variants encoding different isoforms. Additional splice variants have been described, but their full length sequences have not been determined.[2]
Amphiphysin is a brain-enriched protein with an N-terminal lipid interaction, dimerisation and membrane bending BAR domain, a middle clathrin and adaptor binding domain and a C-terminal SH3 domain. In the brain, its primary function is thought to be the recruitment of dynamin to sites of clathrin-mediated endocytosis. There are 2 mammalian amphiphysins with similar overall structure. A ubiquitous splice form of amphiphysin 2 that does not contain clathrin or adaptor interactions is highly expressed in muscle tissue and is involved in the formation and stabilization of the T-tubule network. In other tissues amphiphysin is likely involved in other membrane bending and curvature stabilization events.
# Interactions
Amphiphysin has been shown to interact with DNM1,[3][4][5][6][7] Phospholipase D1,[8] CDK5R1,[9] PLD2,[8] CABIN1[10] and SH3GL2.[3][11] | https://www.wikidoc.org/index.php/Amphiphysin | |
5905de7ed610347a0a3459c219b3e7e6dc71da2c | wikidoc | Amsler grid | Amsler grid
The Amsler grid, used since 1945, is a grid of horizontal and vertical lines used to monitor a person's central visual field. It is a diagnostic tool that aids in the detection of visual disturbances caused by changes in the retina, particularly the macula (e.g. macular degeneration, Epiretinal membrane), as well as the optic nerve and the visual pathway to the brain.
In the test, the person looks with each eye separately at the little dot in the center of the grid. Patients may notice that they don't see the lines as straight, or lines are missing.
Amsler grids can be obtained from an ophthalmologist or optometrist and may be used to test one's vision at home.
The original Amsler grid was black and white. A color version with a blue and yellow grid is more sensitive and can be used to test for a wide variety of visual pathway abnormalities, including those associated with the retina, the optic nerve, and the pituitary gland. | Amsler grid
The Amsler grid, used since 1945, is a grid of horizontal and vertical lines used to monitor a person's central visual field. It is a diagnostic tool that aids in the detection of visual disturbances caused by changes in the retina, particularly the macula (e.g. macular degeneration, Epiretinal membrane), as well as the optic nerve and the visual pathway to the brain.
In the test, the person looks with each eye separately at the little dot in the center of the grid. Patients may notice that they don't see the lines as straight, or lines are missing.
Amsler grids can be obtained from an ophthalmologist or optometrist and may be used to test one's vision at home.
The original Amsler grid was black and white. A color version with a blue and yellow grid is more sensitive and can be used to test for a wide variety of visual pathway abnormalities, including those associated with the retina, the optic nerve, and the pituitary gland. | https://www.wikidoc.org/index.php/Amsler_Grid | |
ff5249506c438b347be183fe2c4520ce30fb2635 | wikidoc | Amylopectin | Amylopectin
# Overview
Amylopectin (CAS# 9037-22-3) is a highly branched polymer of glucose found in plants. It is one of the two components of starch, the other being amylose. It is soluble in water.
Glucose units are linked in a linear way with α(1→4) bonds. Branching takes place with α(1→6) bonds occurring every 24 to 30 glucose units.
Its counterpart in animals is glycogen which has the same composition and structure, but with more extensive branching that occurs every 8 to 12 glucose units.
Plants store starch within specialized organelles called amyloplasts. When energy is needed for cell work, the plant hydrolyzes the starch releasing the glucose subunits. Humans and other animals that eat plant foods also have enzymes to hydrolyze starch.
Starch is made of about 70% amylopectin. Amylopectin is highly branched, being formed of 2,000 to 200,000 glucose units. Its inner chains are formed of 20-24 glucose subunits.
de:Amylopektin
eo:Amilopektino
id:Amilopektin
it:Amilopectina
he:עמילופקטין
nl:Amylopectine
no:Amylopektin
uk:Амілопектин | Amylopectin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Amylopectin (CAS# 9037-22-3) is a highly branched polymer of glucose found in plants. It is one of the two components of starch, the other being amylose. It is soluble in water.
Glucose units are linked in a linear way with α(1→4) bonds. Branching takes place with α(1→6) bonds occurring every 24 to 30 glucose units.
Its counterpart in animals is glycogen which has the same composition and structure, but with more extensive branching that occurs every 8 to 12 glucose units.
Plants store starch within specialized organelles called amyloplasts. When energy is needed for cell work, the plant hydrolyzes the starch releasing the glucose subunits. Humans and other animals that eat plant foods also have enzymes to hydrolyze starch.
Starch is made of about 70% amylopectin. Amylopectin is highly branched, being formed of 2,000 to 200,000 glucose units. Its inner chains are formed of 20-24 glucose subunits.
Template:Carbohydrates
de:Amylopektin
eo:Amilopektino
id:Amilopektin
it:Amilopectina
he:עמילופקטין
nl:Amylopectine
no:Amylopektin
uk:Амілопектин
Template:WS | https://www.wikidoc.org/index.php/Amylopectin | |
a81489e789f1f47ce8e5a8f187c2481b03d8162d | wikidoc | Anacetrapib | Anacetrapib
Anacetrapib (MK-0859, Merck) is cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. Cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein, is a plasma protein that amasses triglycerides (TG) from VLDL cholesterol or LDL cholesterol and actively exchanges them for cholesteryl esters from HDL cholesterol. CETP inhibition leads to increase in size of HDL cholesterol particle and apolipoprotein A-I concentration, which is a major HDL protein. Development of Torcetrapib, the first CETP inhibitor, was halted during a phase III randomized clinical trial due to a 25% increase in cardiovascular adverse events within the cohort that received the active treatment. The increase in adverse events was thought to be secondary to "off target" toxicity including elevated aldosterone levels and consequent electrolyte abnormalities and elevated blood pressure.
# Results of the Phase II DEFINE Study
Download the DEFINE slides here:
## Design of DEFINE
DEFINEwas a Phase II randomized, double-blind, placebo-controlled trial designed to assess the safety and lipid-lowering efficacy of anacetrapib. Patients in the study had known coronary heart disease or were at an elevated risk for the devlopment of coronary heart disease. These patients had a LDL cholesterol level <100 and 99.3% were on statin therapy. Patients (1,623) were randomized to treatment with either 100 mg of anacetrapib or placebo daily for 18 months in a 1:1 fashion. The primary end point was percent change in LDL cholesterol from baseline at 24 weeks and safety and tolerability at 76 weeks. Percent change in HDL cholesterol from base line was a secondary end point.
## Efficacy Results of DEFINE
The LDL cholesterol was reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) at 24 weeks in the anacetrapib group versus 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) among placebo treated patients (P<0.001). This represents a 39.8% reduction with anacetrapib realtive to placebo. Anacetrapib increased the HDL cholesterol level from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) versus placebo which increased HDL from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) (P<0.001). This represents a 138.1% increase in HDL associated with anacetrapib treatment versus placebo.
It should be noted that the trial was underpowered to detect a meaningful difference in clinical events. The composite of death from cardiovascular causes, hospitalization from unstable angina, myocardial infarction or stroke occurred in 2% (16) of patients treated with Anacetrapib and 2.6% (21) in placebo group. The decrease in total cardiovascular events and total revascularizations was very impressive (8 vs. 28, P = 0.001).
## Safety Results of DEFINE
Throughout the 76 weeks of therapy there were no changes in either systolic or diastolic blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. In this modest sized study there were no liver function test abnormalities and no excess of myalgias. It should be noted that a study of this size may not exclude a risk of low frequency events such as Hy's law.
## Limitations of DEFINE
Limitations of the study include the fact that this was a small population and the majority of patients were Caucasians. Further studies are also needed to further evaluate the effects of decreasing LDL cholesterol to extremely low levels. In the DEFINE study; Anacetrapib was discontinued in those patients with extremely low cholesterol levels. Larger studies are required to ensure the safety and tolerability of this drug. Given the promising results of this study, Merck has already launched the REVEAL HPS-3 TIMI-55 trial in collaboration with researchers at Harvard and Oxford. This study will include 30,000 patients with CHD who are already on statin therapy.
# REFERENCES
1. Barter PJ, Caulfield M, Eriksson M, et al. Effects of Torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
2. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505-15.
3. Cannon CP, Shah S, Dansky HM, et al. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med 2010; DOI: 10.1056/NEJMoa1009744.
4. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the Efficacy and tolerability of CETP Inhibition with Anacetrapib. Am Heart J 2009;158(4):513.e3-519.e3.
5. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-73.
6. Gotto AM. High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Am Heart J 2002;144:S33-42
7. www.wikipedia.com
- ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B (2007). "Effects of torcetrapib in patients at high risk for coronary events". The New England Journal of Medicine. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | Anacetrapib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Anacetrapib (MK-0859, Merck) is cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. Cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein, is a plasma protein that amasses triglycerides (TG) from VLDL cholesterol or LDL cholesterol and actively exchanges them for cholesteryl esters from HDL cholesterol. CETP inhibition leads to increase in size of HDL cholesterol particle and apolipoprotein A-I concentration, which is a major HDL protein. Development of Torcetrapib, the first CETP inhibitor, was halted during a phase III randomized clinical trial due to a 25% increase in cardiovascular adverse events within the cohort that received the active treatment. [1] The increase in adverse events was thought to be secondary to "off target" toxicity including elevated aldosterone levels and consequent electrolyte abnormalities and elevated blood pressure.
# Results of the Phase II DEFINE Study
Download the DEFINE slides here:
media:DEFINE.ppt
## Design of DEFINE
DEFINEwas a Phase II randomized, double-blind, placebo-controlled trial designed to assess the safety and lipid-lowering efficacy of anacetrapib. Patients in the study had known coronary heart disease or were at an elevated risk for the devlopment of coronary heart disease. These patients had a LDL cholesterol level <100 and 99.3% were on statin therapy. Patients (1,623) were randomized to treatment with either 100 mg of anacetrapib or placebo daily for 18 months in a 1:1 fashion. The primary end point was percent change in LDL cholesterol from baseline at 24 weeks and safety and tolerability at 76 weeks. Percent change in HDL cholesterol from base line was a secondary end point.
## Efficacy Results of DEFINE
The LDL cholesterol was reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) at 24 weeks in the anacetrapib group versus 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) among placebo treated patients (P<0.001). This represents a 39.8% reduction with anacetrapib realtive to placebo. Anacetrapib increased the HDL cholesterol level from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) versus placebo which increased HDL from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) (P<0.001). This represents a 138.1% increase in HDL associated with anacetrapib treatment versus placebo.
It should be noted that the trial was underpowered to detect a meaningful difference in clinical events. The composite of death from cardiovascular causes, hospitalization from unstable angina, myocardial infarction or stroke occurred in 2% (16) of patients treated with Anacetrapib and 2.6% (21) in placebo group. The decrease in total cardiovascular events and total revascularizations was very impressive (8 vs. 28, P = 0.001).
## Safety Results of DEFINE
Throughout the 76 weeks of therapy there were no changes in either systolic or diastolic blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. In this modest sized study there were no liver function test abnormalities and no excess of myalgias. It should be noted that a study of this size may not exclude a risk of low frequency events such as Hy's law.
## Limitations of DEFINE
Limitations of the study include the fact that this was a small population and the majority of patients were Caucasians. Further studies are also needed to further evaluate the effects of decreasing LDL cholesterol to extremely low levels. In the DEFINE study; Anacetrapib was discontinued in those patients with extremely low cholesterol levels. Larger studies are required to ensure the safety and tolerability of this drug. Given the promising results of this study, Merck has already launched the REVEAL HPS-3 TIMI-55 trial in collaboration with researchers at Harvard and Oxford. This study will include 30,000 patients with CHD who are already on statin therapy.
# REFERENCES
1. Barter PJ, Caulfield M, Eriksson M, et al. Effects of Torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
2. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505-15.
3. Cannon CP, Shah S, Dansky HM, et al. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med 2010; DOI: 10.1056/NEJMoa1009744.
4. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the Efficacy and tolerability of CETP Inhibition with Anacetrapib. Am Heart J 2009;158(4):513.e3-519.e3.
5. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-73.
6. Gotto AM. High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Am Heart J 2002;144:S33-42
7. www.wikipedia.com
- ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B (2007). "Effects of torcetrapib in patients at high risk for coronary events". The New England Journal of Medicine. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Anacetrapib | |
a0f7ae6e99ea571bcf6ed56706c645150719d223 | wikidoc | Anal glands | Anal glands
The anal glands or anal sacs are small, paired sacs located on either side of the anus between the external and internal sphincter muscles. Sebaceous glands within the lining secrete a foul smelling liquid that is used for identification of members within a species. These sacs are found in all carnivora except bears and sea otters.
# Dogs
In dogs, these glands are occasionally referred to as "scent glands", because they enable the animals to mark their territory and identify other dogs. The glands can spontaneously empty, especially under times of stress, and create a very sudden unpleasant change in the odor of the dog. The anal glands normally empty when the dog defecates. Failure to empty results in discomfort from the full anal gland pushing on the anus. The glands can be emptied by the dog's keeper, or more typically by a groomer or veterinarian, by squeezing the gland so the contents are released through the small openings on either side of the anus. Discomfort is evidenced by the dog scooting its posterior on the ground, licking or biting at the anus, sitting uncomfortably, difficulty sitting or standing, or chasing its tail.
Discomfort may also be evident with impaction or infection of the anal glands. Anal gland impaction results from blockage of the duct leading from the gland to the opening. The gland is usually nonpainful and swollen. Anal gland infection results in pain, swelling, and sometimes abscessation and fever. Treatment is by expression of the gland, lancing of an abscess, and oral antibiotics and antibiotic infusion into the gland in the case of infection. The most common bacterial isolates from anal gland infection are E. coli, Enterococcus faecalis, Clostridium perfringens, and Proteus species.
Anal glands may be removed surgically in a procedure known as anal sacculectomy. This is usually done in the case of recurrent infection or because of the presence of an anal sac adenocarcinoma, a malignant tumor. Potential complications include fecal incontinence (especially when both glands are removed), tenesmus from stricture or scar formation, and persistent draining fistulae.
Anal gland fluid is normally yellow to tan in color and watery in consistency. Impacted anal gland material is usually brown or gray and thick. The presence of blood or pus indicates infection.
# Opossums
Opossums use their anal glands when they "play possum". As the opossum mimics death, the glands secrete a foul-smelling liquid, suggesting the opossum is rotting. Note that opossums are not members of the carnivora, and that their anal sacs differ from those of dogs and their relatives.
# Skunks
Skunks use their anal glands to spray a foul-smelling and sticky fluid as a defense against predators.
# Weasels
Research by the Institute for Pheromone Research and the Department of Chemistry, Indiana University suggests that weasels may well use their anal glands in gender recognition. | Anal glands
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The anal glands or anal sacs are small, paired sacs located on either side of the anus between the external and internal sphincter muscles. Sebaceous glands within the lining secrete a foul smelling liquid that is used for identification of members within a species. These sacs are found in all carnivora except bears[1] and sea otters.[2]
# Dogs
In dogs, these glands are occasionally referred to as "scent glands", because they enable the animals to mark their territory and identify other dogs. The glands can spontaneously empty, especially under times of stress, and create a very sudden unpleasant change in the odor of the dog. The anal glands normally empty when the dog defecates. Failure to empty results in discomfort from the full anal gland pushing on the anus. The glands can be emptied by the dog's keeper, or more typically by a groomer or veterinarian, by squeezing the gland so the contents are released through the small openings on either side of the anus. Discomfort is evidenced by the dog scooting its posterior on the ground, licking or biting at the anus, sitting uncomfortably, difficulty sitting or standing, or chasing its tail.
Discomfort may also be evident with impaction or infection of the anal glands. Anal gland impaction results from blockage of the duct leading from the gland to the opening. The gland is usually nonpainful and swollen. Anal gland infection results in pain, swelling, and sometimes abscessation and fever. Treatment is by expression of the gland, lancing of an abscess, and oral antibiotics and antibiotic infusion into the gland in the case of infection. The most common bacterial isolates from anal gland infection are E. coli, Enterococcus faecalis, Clostridium perfringens, and Proteus species.[3]
Anal glands may be removed surgically in a procedure known as anal sacculectomy. This is usually done in the case of recurrent infection or because of the presence of an anal sac adenocarcinoma, a malignant tumor. Potential complications include fecal incontinence (especially when both glands are removed), tenesmus from stricture or scar formation, and persistent draining fistulae.[4]
Anal gland fluid is normally yellow to tan in color and watery in consistency. Impacted anal gland material is usually brown or gray and thick. The presence of blood or pus indicates infection.
# Opossums
Opossums use their anal glands when they "play possum". As the opossum mimics death, the glands secrete a foul-smelling liquid, suggesting the opossum is rotting. Note that opossums are not members of the carnivora, and that their anal sacs differ from those of dogs and their relatives.
# Skunks
Skunks use their anal glands to spray a foul-smelling and sticky fluid as a defense against predators.
# Weasels
Research by the Institute for Pheromone Research and the Department of Chemistry, Indiana University suggests that weasels may well use their anal glands in gender recognition.[5] | https://www.wikidoc.org/index.php/Anal_glands | |
20a0c96a0238ca94eb2a7fa313af260ad9f080bb | wikidoc | Anastomosis | Anastomosis
# Overview
Anastomosis (plural anastomoses) refers to a form of network in which streams both branch out and reconnect. The term is used in medicine, biology, and geology.
# Medicine
Anastomosis is the surgical connection of two structures. It commonly refers to connections between blood vessels or connections between other tubular structures such as loops of intestine. In circulatory anastomosis, many arteries naturally anastomose with each other. For example: the inferior epigastric artery and superior epigastric artery. In surgery, surgical anastomosis occurs when a segment of intestine is resected and the two remaining ends are sewn or stapled together (anastomosed). The procedure is referred to as intestinal anastomosis.
Pathological anastomosis results from trauma or disease and may involve veins, arteries, or intestines. These are usually referred to as fistulas. In the cases of veins or arteries, traumatic fistulas usually occur between artery and vein. Traumatic intestinal fistulas usually occur between two loops of intestine (enetero-enteric fistula) or intestine and skin (enterocutaneous fistula). Portacaval anastomosis, by contrast, is an anastomosis between a vein of the portal circulation and a vein of the systemic circulation, which allows blood to bypass the liver in patients with portal hypertension, often resulting in hemorrhoids, esophageal varices, or caput medusae.
# Biology
In evolution, anastomosis is a recombination of evolutionary lineage. Conventional accounts of evolutionary lineage present themselves as the simple branching out of species into novel forms. Under anastomosis, species might recombine after initial branching out, such as in the case of recent research which shows that humans and chimpanzees may have interbred after an initial branching out. A second case in which the idea of anastomosis finds application is in the theory of Symbiogenesis, in which new forms of life (species) are seen to emerge from the formation of novel symbiotic relationships. | Anastomosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Anastomosis (plural anastomoses) refers to a form of network in which streams both branch out and reconnect. The term is used in medicine, biology, and geology.
# Medicine
Anastomosis is the surgical connection of two structures.[1] It commonly refers to connections between blood vessels or connections between other tubular structures such as loops of intestine. In circulatory anastomosis, many arteries naturally anastomose with each other. For example: the inferior epigastric artery and superior epigastric artery. In surgery, surgical anastomosis occurs when a segment of intestine is resected and the two remaining ends are sewn or stapled together (anastomosed). The procedure is referred to as intestinal anastomosis.
Pathological anastomosis results from trauma or disease and may involve veins, arteries, or intestines. These are usually referred to as fistulas. In the cases of veins or arteries, traumatic fistulas usually occur between artery and vein. Traumatic intestinal fistulas usually occur between two loops of intestine (enetero-enteric fistula) or intestine and skin (enterocutaneous fistula). Portacaval anastomosis, by contrast, is an anastomosis between a vein of the portal circulation and a vein of the systemic circulation, which allows blood to bypass the liver in patients with portal hypertension, often resulting in hemorrhoids, esophageal varices, or caput medusae.
# Biology
In evolution, anastomosis is a recombination of evolutionary lineage. Conventional accounts of evolutionary lineage present themselves as the simple branching out of species into novel forms. Under anastomosis, species might recombine after initial branching out, such as in the case of recent research which shows that humans and chimpanzees may have interbred after an initial branching out.[2] A second case in which the idea of anastomosis finds application is in the theory of Symbiogenesis, in which new forms of life (species) are seen to emerge from the formation of novel symbiotic relationships. | https://www.wikidoc.org/index.php/Anastamosis | |
2affff5aac799cddd948cada6c5db298c0966934 | wikidoc | Anastrozole | Anastrozole
# Disclaimer
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# Overview
Anastrozole is an aromatase inhibitor that is FDA approved for the treatment of adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer, advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Common adverse reactions include hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema and lymphedema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Anastrozole tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
- Anastrozole tablets are indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer.
- Anastrozole tablets are indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole tablets.
- Recommended Dose
- The dose of anastrozole tablet is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole tablets should be continued until tumor progression. Anastrozole tablets can be taken with or without food.
- For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, anastrozole was administered for five years.
- No dosage adjustment is necessary for patients with renal impairment or for elderly patients.
- Patients with Hepatic Impairment
- No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole has not been studied in patients with severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anastrozole in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Anastrozole 1 milligram (mg) orally daily.
- Dosing Information
- Anastrozole significantly reduced the risk of breast cancer by 53% compared with placebo (2% vs 4%) in a randomized trial of postmenopausal high-risk women.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Anastrozole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anastrozole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anastrozole in pediatric patients.
# Contraindications
- Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using anastrozole. If anastrozole is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus or potential risk for loss of the pregnancy.
- Anastrozole is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria.
# Warnings
### Precautions
- Ischemic Cardiovascular Events
- In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole in the ATAC trial (17% of patients on anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole therapy in patients with pre-existing ischemic heart disease.
- Bone Effects
- Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with anastrozole.
- Cholesterol
- During the ATAC trial, more patients receiving anastrozole were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).
# Adverse Reactions
## Clinical Trials Experience
- Serious adverse reactions with anastrozole occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling.
- Common adverse reactions (occurring with an incidence of ≥10%) in women taking anastrozole included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, pain, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema.
- In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the anastrozole group.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adjuvant Therapy
- Adverse reaction data for adjuvant therapy are based on the ATAC trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively.
Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.
Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2).
- Ischemic Cardiovascular Events
- Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the anastrozole arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the anastrozole arm and 34/3094 (1.1%) patients in the tamoxifen arm.
- In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on anastrozole and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving anastrozole and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving anastrozole and 8/249 (3.2%) patients receiving tamoxifen.
- Bone Mineral Density Findings
- Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.
- Because anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density.
- A post-marketing trial assessed the combined effects of anastrozole and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates.
- Bisphosphonate treatment preserved bone density in most patients at risk of fracture.
- Postmenopausal women with early breast cancer scheduled to be treated with anastrozole should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.
- Cholesterol
- During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).
- A post-marketing trial also evaluated any potential effects of anastrozole on lipid profile. In the primary analysis population for lipids (anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months.
- In secondary population for lipids (anastrozole+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.
- In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline.
- In this trial, treatment for 12 months with anastrozole alone had a neutral effect on lipid profile. Combination treatment with anastrozole and risedronate also had a neutral effect on lipid profile.
- The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with anastrozole should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.
- Other Adverse Reactions
- Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) compared with patients receiving tamoxifen .
- Patients receiving anastrozole had a higher incidence of carpal tunnel syndrome compared with patients receiving tamoxifen .
- Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the anastrozole -treated patients 317 (10%) versus 167 (5%), respectively.
- Patients receiving anastrozole had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.
- 10-year median follow-up Safety Results from the ATAC Trial
- Results are consistent with the previous analyses.
- Serious adverse reactions were similar between anastrozole (50%) and tamoxifen (51%).
- Cardiovascular events were consistent with the known safety profiles of anastrozole and tamoxifen.
- The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the anastrozole group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period.
- The cumulative incidence of new primary cancers was similar in the anastrozole group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the anastrozole group (0.2%).
- The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the anastrozole treatment group.
- First-Line Therapy
- Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.
- Less frequent adverse experiences reported in patients receiving anastrozole 1 mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.
- Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.
- Second-Line Therapy
- Anastrozole was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction.
- The principal adverse reaction more common with anastrozole than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:
- Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.
- Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection
- Cardiovascular: Hypertension; thrombophlebitis
- Hepatic: Gamma GT increased; SGOT increased; SGPT increased
- Hematologic: Anemia; leukopenia
- Metabolic and Nutritional: Alkaline phosphatase increased; weight loss
- Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole. Increases in LDL cholesterol have been shown to contribute to these changes.
- Musculoskeletal: Myalgia; arthralgia; pathological fracture
- Nervous: Somnolence; confusion; insomnia; anxiety; nervousness
- Respiratory: Sinusitis; bronchitis; rhinitis
- Skin and Appendages: Hair thinning (alopecia); pruritus
- Urogenital: Urinary tract infection; breast pain
- The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below.
## Postmarketing Experience
- These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of anastrozole:
- Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis
- Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome.
- Cases of allergic reactions including angioedema, urticaria and anaphylaxis.
- Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone)
# Drug Interactions
- Tamoxifen
- Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.
- Estrogen
- Estrogen-containing therapies should not be used with anastrozole as they may diminish its pharmacological action.
- Warfarin
- In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC), and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.
- Cytochrome P450
- Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole 1 mg will affect other drugs as a result of inhibition of cytochrome P450.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. In animal studies, anastrozole caused pregnancy failure, increased pregnancy loss, and signs of delayed fetal development. There are no studies of anastrozole use in pregnant women. If anastrozole is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.
- In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m2 basis. In both species, anastrozole crossed the placenta, and there was increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses). In rats, these effects were dose related, and placental weights were significantly increased. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC0-24hr 9 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anastrozole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Anastrozole during labor and delivery.
### Nursing Mothers
- It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of anastrozole in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.
Gynecomastia Study
- A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either anastrozole 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥50% reduction in gynecomastia (primary efficacy analysis). Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at Month 6 of treatment were reduced by 15.4% in the anastrozole group and 4.5% in the placebo group.
- Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the anastrozole-treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% anastrozole and 2.7% placebo) and headache (7% anastrozole and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with anastrozole discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm3 in the anastrozole-treated patients and + 5.2 ± 8.0 cm3 in the placebo group.
- McCune-Albright Syndrome Study
- A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of anastrozole. The trial duration was 12 months. Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age. Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81. Compared to pre-treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age). There were no clinically significant changes in Tanner staging,mean ovarian volume, mean uterine volume and mean predicted adult height. A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients.
- Five patients (18%) experienced adverse reactions that were considered possibly related to anastrozole. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis.
- Pharmacokinetics in Pediatric Patients
- Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and V/F of 98.4 L (50.7 to 330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune- Albright Syndrome.
### Geriatic Use
- In studies 0030 and 0027, about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005, 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients.
- In the ATAC study, 45% of patients were 65 years of age or older. The efficacy of anastrozole compared to tamoxifen in patients who were 65 years or older (N=1413 for anastrozole and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 ) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for anastrozole and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 ).
- The pharmacokinetics of anastrozole is not affected by age.
### Gender
There is no FDA guidance on the use of Anastrozole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Anastrozole with respect to specific racial populations.
### Renal Impairment
- Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary.
### Hepatic Impairment
- The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. Anastrozole has not been studied in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Anastrozole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Anastrozole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Anastrozole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Anastrozole in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Clinical trials have been conducted with anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established.
### Management
- There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Anastrozole in the drug label.
# Pharmacology
## Mechanism of Action
- The growth of many cancers of the breast is stimulated or maintained by estrogens.
- In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
- Anastrozole is a selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
## Structure
- Anastrozole tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5 and its structural formula is:
- Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
- Each tablet contains as inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.
## Pharmacodynamics
- Effect on Estradiol
- Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of anastrozole in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, anastrozole 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with anastrozole 1 mg.
- The effect of anastrozole in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, anastrozole would not be expected to lower estradiol levels in premenopausal women.
- Effect on Corticosteroids
- In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole.
- Other Endocrine Effects
- In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of anastrozole. Anastrozole does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.
## Pharmacokinetics
- Absorption
- Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of anastrozole absorption. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of anastrozole were similar in patients and healthy volunteers.
- Distribution
- Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of anastrozole. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anastrozole is 40% bound to plasma proteins in the therapeutic range.
- Metabolism
- Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole (triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide conjugate of anastrozole itself) have been identified in human plasma and urine. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity.
- Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.
- Excretion
- Eighty-five percent of radiolabeled anastrozole was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of anastrozole is 50 hours.
- Effect of Gender and Age
- Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range 80 years.
- Effect of Race
- Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.
- Effect of Renal Impairment
- Anastrozole pharmacokinetics have been investigated in subjects with renal impairment. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment.
- Effect of Hepatic Impairment
- Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis.
## Nonclinical Toxicology
- A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.
- Anastrozole has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).
- Oral administration of anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m2 basis and 9 times higher than the AUC0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.
- Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.
- Reproductive Toxicology
- Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 1 and 1.9 times the recommended human dose, respectively, on a mg/m2 basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m2 basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses); effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.
- Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m2 basis).
# Clinical Studies
- A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.
- The primary endpoint of the trial was disease-free survival (ie, time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.
- Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7).
- Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent- to-treat population was statistically significantly improved in the anastrozole arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the anastrozole arm compared to the tamoxifen arm.
- Figure 1- Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC trial (Intent-to-Treat)
- Figure 2- Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial
- The survival data with 68 months follow-up is presented in Table 9.
- In the group of patients who had previous adjuvant chemotherapy (N=698 for anastrozole and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the anastrozole arm compared to the tamoxifen arm.
- The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.
- A summary of the study efficacy results is provided in Table 9.
- 10-year median follow-up Efficacy Results from the ATAC Trial
- In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years). Patients received study treatment for a median of 60 months (5 years) (see Table 10).
- Figure 3 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat)(a)
- Figure 4 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial(b)
- Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of anastrozole compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of anastrozole once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumor progression, objective tumor response rate, and safety.
- Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.
- For the primary endpoints, trial 0030 showed that anastrozole had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for anastrozole and tamoxifen. Trial 0027 showed that anastrozole and tamoxifen had similar objective tumor response rates and time to tumor progression (see Table 12 and Figures 5 and 6)
- Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
- Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.
- Anastrozole was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of anastrozole. or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to anastrozole. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were cal culated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.
- Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.
- Efficacy results from the two studies were similar as presented in Table 13. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.
- When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to anastrozole 1 mg and megestrol acetate. There is, in this data, no indication that anastrozole 10 mg is superior to anastrozole 1 mg.
# How Supplied
- Anastrozole tablets, 1 mg are white to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side and are supplied as follows:
- Bottles of 30 tablets (NDC 16729-035-10)
- Bottles of 90 tablets (NDC 16729-035-15)
- Bottles of 500 tablets (NDC 16729-035-16)
- Bottles of 1000 tablets (NDC 16729-035-17)
- Storage
- Store at controlled room temperature, 20 to 25°C (68 to 77°F).
## Storage
There is limited information regarding Anastrozole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Pregnancy
- Patients should be advised that anastrozole may cause fetal harm. They should also be advised that anastrozole is not for use in premenopausal women; therefore, if they become pregnant, they should stop taking anastrozole tablets and immediately contact their doctor.
- Allergic (Hypersensitivity) Reactions
- Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to seek medical attention immediately.
- Ischemic Cardiovascular Events
- Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with anastrozole use compared to tamoxifen use. If patients have new or worsening chest pain or shortness of breath they should seek medical attention immediately.
- Bone Effects
- Patients should be informed that anastrozole lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.
- Cholesterol
- Patients should be informed that an increased level of cholesterol might be seen while receiving anastrozole.
- Tamoxifen
- Patients should be advised not to take anastrozole with tamoxifen.
- Missed Doses
- Inform patients that if they miss a dose, take it as soon as they remember. If it is almost time for their next dose, skip the missed dose and take the next regularly scheduled dose. Patients should not take two doses at the same time.
# Precautions with Alcohol
- Alcohol-Anastrozole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Anastrozole®
# Look-Alike Drug Names
There is limited information regarding Anastrozole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Anastrozole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]; Sree Teja Yelamanchili, MBBS [3]
# Disclaimer
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# Overview
Anastrozole is an aromatase inhibitor that is FDA approved for the treatment of adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer, advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Common adverse reactions include hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema and lymphedema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Anastrozole tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
- Anastrozole tablets are indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer.
- Anastrozole tablets are indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole tablets.
- Recommended Dose
- The dose of anastrozole tablet is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole tablets should be continued until tumor progression. Anastrozole tablets can be taken with or without food.
- For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, anastrozole was administered for five years.
- No dosage adjustment is necessary for patients with renal impairment or for elderly patients.
- Patients with Hepatic Impairment
- No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole has not been studied in patients with severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anastrozole in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Anastrozole 1 milligram (mg) orally daily.[1]
- Dosing Information
- Anastrozole significantly reduced the risk of breast cancer by 53% compared with placebo (2% vs 4%) in a randomized trial of postmenopausal high-risk women.[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Anastrozole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Anastrozole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Anastrozole in pediatric patients.
# Contraindications
- Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using anastrozole. If anastrozole is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus or potential risk for loss of the pregnancy.
- Anastrozole is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria.
# Warnings
### Precautions
- Ischemic Cardiovascular Events
- In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole in the ATAC trial (17% of patients on anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole therapy in patients with pre-existing ischemic heart disease.
- Bone Effects
- Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with anastrozole.
- Cholesterol
- During the ATAC trial, more patients receiving anastrozole were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).
# Adverse Reactions
## Clinical Trials Experience
- Serious adverse reactions with anastrozole occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling.
- Common adverse reactions (occurring with an incidence of ≥10%) in women taking anastrozole included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, pain, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema.
- In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the anastrozole group.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adjuvant Therapy
- Adverse reaction data for adjuvant therapy are based on the ATAC trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively.
Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.
Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2).
- Ischemic Cardiovascular Events
- Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the anastrozole arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the anastrozole arm and 34/3094 (1.1%) patients in the tamoxifen arm.
- In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on anastrozole and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving anastrozole and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving anastrozole and 8/249 (3.2%) patients receiving tamoxifen.
- Bone Mineral Density Findings
- Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.
- Because anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density.
- A post-marketing trial assessed the combined effects of anastrozole and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates.
- Bisphosphonate treatment preserved bone density in most patients at risk of fracture.
- Postmenopausal women with early breast cancer scheduled to be treated with anastrozole should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.
- Cholesterol
- During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).
- A post-marketing trial also evaluated any potential effects of anastrozole on lipid profile. In the primary analysis population for lipids (anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months.
- In secondary population for lipids (anastrozole+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.
- In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline.
- In this trial, treatment for 12 months with anastrozole alone had a neutral effect on lipid profile. Combination treatment with anastrozole and risedronate also had a neutral effect on lipid profile.
- The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with anastrozole should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.
- Other Adverse Reactions
- Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)].
- Patients receiving anastrozole had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)].
- Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the anastrozole -treated patients 317 (10%) versus 167 (5%), respectively.
- Patients receiving anastrozole had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.
- 10-year median follow-up Safety Results from the ATAC Trial
- Results are consistent with the previous analyses.
- Serious adverse reactions were similar between anastrozole (50%) and tamoxifen (51%).
- Cardiovascular events were consistent with the known safety profiles of anastrozole and tamoxifen.
- The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the anastrozole group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period.
- The cumulative incidence of new primary cancers was similar in the anastrozole group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the anastrozole group (0.2%).
- The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the anastrozole treatment group.
- First-Line Therapy
- Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.
- Less frequent adverse experiences reported in patients receiving anastrozole 1 mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.
- Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.
- Second-Line Therapy
- Anastrozole was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction.
- The principal adverse reaction more common with anastrozole than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:
- Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.
- Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection
- Cardiovascular: Hypertension; thrombophlebitis
- Hepatic: Gamma GT increased; SGOT increased; SGPT increased
- Hematologic: Anemia; leukopenia
- Metabolic and Nutritional: Alkaline phosphatase increased; weight loss
- Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole. Increases in LDL cholesterol have been shown to contribute to these changes.
- Musculoskeletal: Myalgia; arthralgia; pathological fracture
- Nervous: Somnolence; confusion; insomnia; anxiety; nervousness
- Respiratory: Sinusitis; bronchitis; rhinitis
- Skin and Appendages: Hair thinning (alopecia); pruritus
- Urogenital: Urinary tract infection; breast pain
- The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below.
## Postmarketing Experience
- These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of anastrozole:
- Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis
- Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome.
- Cases of allergic reactions including angioedema, urticaria and anaphylaxis.
- Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone)
# Drug Interactions
- Tamoxifen
- Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.
- Estrogen
- Estrogen-containing therapies should not be used with anastrozole as they may diminish its pharmacological action.
- Warfarin
- In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC), and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.
- Cytochrome P450
- Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole 1 mg will affect other drugs as a result of inhibition of cytochrome P450.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. In animal studies, anastrozole caused pregnancy failure, increased pregnancy loss, and signs of delayed fetal development. There are no studies of anastrozole use in pregnant women. If anastrozole is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.
- In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m2 basis. In both species, anastrozole crossed the placenta, and there was increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses). In rats, these effects were dose related, and placental weights were significantly increased. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC0-24hr 9 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anastrozole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Anastrozole during labor and delivery.
### Nursing Mothers
- It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of anastrozole in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.
Gynecomastia Study
- A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either anastrozole 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥50% reduction in gynecomastia (primary efficacy analysis). Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at Month 6 of treatment were reduced by 15.4% in the anastrozole group and 4.5% in the placebo group.
- Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the anastrozole-treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% anastrozole and 2.7% placebo) and headache (7% anastrozole and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with anastrozole discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm3 in the anastrozole-treated patients and + 5.2 ± 8.0 cm3 in the placebo group.
- McCune-Albright Syndrome Study
- A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of anastrozole. The trial duration was 12 months. Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age. Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81. Compared to pre-treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age). There were no clinically significant changes in Tanner staging,mean ovarian volume, mean uterine volume and mean predicted adult height. A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients.
- Five patients (18%) experienced adverse reactions that were considered possibly related to anastrozole. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis.
- Pharmacokinetics in Pediatric Patients
- Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and V/F of 98.4 L (50.7 to 330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune- Albright Syndrome.
### Geriatic Use
- In studies 0030 and 0027, about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005, 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients.
- In the ATAC study, 45% of patients were 65 years of age or older. The efficacy of anastrozole compared to tamoxifen in patients who were 65 years or older (N=1413 for anastrozole and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for anastrozole and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]).
- The pharmacokinetics of anastrozole is not affected by age.
### Gender
There is no FDA guidance on the use of Anastrozole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Anastrozole with respect to specific racial populations.
### Renal Impairment
- Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary.
### Hepatic Impairment
- The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. Anastrozole has not been studied in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Anastrozole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Anastrozole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Anastrozole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Anastrozole in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Clinical trials have been conducted with anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established.
### Management
- There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Anastrozole in the drug label.
# Pharmacology
## Mechanism of Action
- The growth of many cancers of the breast is stimulated or maintained by estrogens.
- In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
- Anastrozole is a selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
## Structure
- Anastrozole tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5 and its structural formula is:
- Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
- Each tablet contains as inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.
## Pharmacodynamics
- Effect on Estradiol
- Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of anastrozole in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, anastrozole 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with anastrozole 1 mg.
- The effect of anastrozole in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, anastrozole would not be expected to lower estradiol levels in premenopausal women.
- Effect on Corticosteroids
- In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole.
- Other Endocrine Effects
- In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of anastrozole. Anastrozole does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.
## Pharmacokinetics
- Absorption
- Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of anastrozole absorption. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of anastrozole were similar in patients and healthy volunteers.
- Distribution
- Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of anastrozole. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anastrozole is 40% bound to plasma proteins in the therapeutic range.
- Metabolism
- Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole (triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide conjugate of anastrozole itself) have been identified in human plasma and urine. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity.
- Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.
- Excretion
- Eighty-five percent of radiolabeled anastrozole was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of anastrozole is 50 hours.
- Effect of Gender and Age
- Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years.
- Effect of Race
- Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.
- Effect of Renal Impairment
- Anastrozole pharmacokinetics have been investigated in subjects with renal impairment. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment.
- Effect of Hepatic Impairment
- Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis.
## Nonclinical Toxicology
- A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.
- Anastrozole has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).
- Oral administration of anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m2 basis and 9 times higher than the AUC0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.
- Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.
- Reproductive Toxicology
- Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 1 and 1.9 times the recommended human dose, respectively, on a mg/m2 basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m2 basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses); effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.
- Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m2 basis).
# Clinical Studies
- A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.
- The primary endpoint of the trial was disease-free survival (ie, time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.
- Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7).
- Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent- to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the anastrozole arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the anastrozole arm compared to the tamoxifen arm.
- Figure 1- Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC trial (Intent-to-Treat)
- Figure 2- Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial
- The survival data with 68 months follow-up is presented in Table 9.
- In the group of patients who had previous adjuvant chemotherapy (N=698 for anastrozole and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the anastrozole arm compared to the tamoxifen arm.
- The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.
- A summary of the study efficacy results is provided in Table 9.
- 10-year median follow-up Efficacy Results from the ATAC Trial
- In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years). Patients received study treatment for a median of 60 months (5 years) (see Table 10).
- Figure 3 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat)(a)
- Figure 4 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole or Tamoxifen Monotherapy in the ATAC Trial(b)
- Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of anastrozole compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of anastrozole once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumor progression, objective tumor response rate, and safety.
- Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.
- For the primary endpoints, trial 0030 showed that anastrozole had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for anastrozole and tamoxifen. Trial 0027 showed that anastrozole and tamoxifen had similar objective tumor response rates and time to tumor progression (see Table 12 and Figures 5 and 6)
- Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.
- Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.
- Anastrozole was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of anastrozole. or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to anastrozole. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were cal culated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.
- Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.
- Efficacy results from the two studies were similar as presented in Table 13. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.
- When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to anastrozole 1 mg and megestrol acetate. There is, in this data, no indication that anastrozole 10 mg is superior to anastrozole 1 mg.
# How Supplied
- Anastrozole tablets, 1 mg are white to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side and are supplied as follows:
- Bottles of 30 tablets (NDC 16729-035-10)
- Bottles of 90 tablets (NDC 16729-035-15)
- Bottles of 500 tablets (NDC 16729-035-16)
- Bottles of 1000 tablets (NDC 16729-035-17)
- Storage
- Store at controlled room temperature, 20 to 25°C (68 to 77°F).
## Storage
There is limited information regarding Anastrozole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Pregnancy
- Patients should be advised that anastrozole may cause fetal harm. They should also be advised that anastrozole is not for use in premenopausal women; therefore, if they become pregnant, they should stop taking anastrozole tablets and immediately contact their doctor.
- Allergic (Hypersensitivity) Reactions
- Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to seek medical attention immediately.
- Ischemic Cardiovascular Events
- Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with anastrozole use compared to tamoxifen use. If patients have new or worsening chest pain or shortness of breath they should seek medical attention immediately.
- Bone Effects
- Patients should be informed that anastrozole lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.
- Cholesterol
- Patients should be informed that an increased level of cholesterol might be seen while receiving anastrozole.
- Tamoxifen
- Patients should be advised not to take anastrozole with tamoxifen.
- Missed Doses
- Inform patients that if they miss a dose, take it as soon as they remember. If it is almost time for their next dose, skip the missed dose and take the next regularly scheduled dose. Patients should not take two doses at the same time.
# Precautions with Alcohol
- Alcohol-Anastrozole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Anastrozole®[5]
# Look-Alike Drug Names
There is limited information regarding Anastrozole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Anastrozole | |
4c44507282a7f93cf6ff4826da824010f7fa0fb1 | wikidoc | Oxandrolone | Oxandrolone
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# Black Box Warning
# Overview
Oxandrolone is an anabolic steroid that is FDA approved for the {{{indicationType}}} of weight loss following extensive surgery, chronic infections, or severe trauma, and in some patients who without definite pathophysiologic reasons fail to gain or to maintain normal weight, to offset the protein catabolism associated with prolonged administration of corticosteroids, and for the relief of the bone pain frequently accompanying osteoporosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, increased risk of atherosclerosis, cholestatic hepatitis, jaundice, testicular atropy, erectile dysfunction, and priapism.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Oxandrolone is indicated as adjunctive therapy to promote weight gain after weight loss following extensive surgery, chronic infections, or severe trauma, and in some patients who without definite pathophysiologic reasons fail to gain or to maintain normal weight, to offset the protein catabolism associated with prolonged administration of corticosteroids, and for the relief of the bone pain frequently accompanying osteoporosis.
- Therapy with anabolic steroids is adjunctive to and not a replacement for conventional therapy. The duration of therapy with oxandrolone will depend on the response of the patient and the possible appearance of adverse reactions. Therapy should be intermittent.
- The response of individuals to anabolic steroids varies. The daily adult dosage is 2.5 mg to 20 mg given in 2 to 4 divided doses. The desired response may be achieved with as little as 2.5 mg or as much as 20 mg daily. A course of therapy of 2 to 4 weeks is usually adequate. This may be repeated intermittently as indicated.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxandrolone in adult patients.
### Non–Guideline-Supported Use
- Oxandrolone (80 milligrams daily).
- Oxandrolone 20 mg/day in 2 divided doses.
- Oxandrolone 20 milligrams.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The total daily dosage of oxandrolone is ≤0.1 mg per kilogram body weight or ≤0.045 mg per pound of body weight. This may be repeated intermittently as indicated.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxandrolone in pediatric patients.
### Non–Guideline-Supported Use
- Oxandrolone 0.1 mg/kg orally twice daily.
- Oral oxandrolone in usual dosages of 0.125 mg/kg/day for 1 to 2 years.
# Contraindications
- Known or suspected prostate cancer or the male breast.
- Breast cancer in females with hypercalcemia (androgenic anabolic steroids may stimulate osteolytic bone resorption).
- Pregnancy, because of possible masculinization of the fetus. Oxandrolone has been shown to cause embryotoxicity, fetotoxicity, infertility, and masculinization of female animal offspring when given in doses 9 times the human dose.
- Nephrosis, the nephrotic phase of nephritis.
- Hypercalcemia.
# Warnings
- Cholestatic hepatitis and jaundice may occur with 17-alpha-alkylated androgens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, oxandrolone should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued.
- In patients with breast cancer, anabolic steroid therapy may cause hypercalcemia by stimulating osteolysis. Oxandrolone therapy should be discontinued if hypercalcemia occurs.
- Edema with or without congestive heart failure may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. Concomitant administration of adrenal cortical steroid or ACTH may increase the edema.
- In children, androgen therapy may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect results in compromised adult height. The younger the child, the greater the risk of compromising final mature height. The effect on bone maturation should be monitored by assessing bone age of the left wrist and hand every 6 months.
- Geriatric patients treated with androgenic anabolic steroids may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma.
- Anabolic steroids have not been shown to enhance athletic ability.
### Precautions
- Concurrent dosing of oxandrolone with warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). When oxandrolone is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain the desirable INR level and diminish the risk of potentially serious bleeding.
- General
- Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Some virilizing changes in women are irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens. Menstrual irregularities may also occur.
- Anabolic steroids may cause suppression of clotting factors II, V, VII, and X, and an increase in prothrombin time.
# Adverse Reactions
## Clinical Trials Experience
- Patients with moderate to severe COPD or COPD patients who are unresponsive to bronchodilators should be monitored closely for COPD exacerbation and fluid retention.
- The following adverse reactions have been associated with use of anabolic steroids: Hepatic: Cholestatic jaundice with, rarely, hepatic necrosis and death. Hepatocellular neoplasms and peliosis hepatis with long-term therapy. Reversible changes in liver function tests also occur including increased bromsulfophthalein (BSP) retention, changes in alkaline phosphatase and increases in serum bilirubin, aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT)
- In males:
- Prepubertal: Phallic enlargement and increased frequency or persistence of erections.
- Postpubertal: Inhibition of testicular function, testicular atrophy and oligospermia, impotence, chronic priapism, epididymitis, and bladder irritability.
- In females:
- Clitoromegaly, menstrual irregularities.
Habituation, excitation, insomnia, depression, and changes in libido.
Bleeding in patients on concomitant oral anticoagulant therapy.
Gynecomastia.
Deepening of the voice in females.
Hirsutism and male pattern baldness in females.
Acne (especially in females and prepubertal males).
Premature closure of epiphyses in children.
Edema, retention of serum electrolytes (sodium chloride, potassium, phosphate, calcium).
Decreased glucose tolerance, increased creatinine excretion, increased serum levels of creatinine phosphokinase (CPK). Masculinization of the fetus. Inhibition of gonadotropin secretion.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Oxandrolone in the drug label.
# Drug Interactions
- Anticoagulants
- Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped.
- Warfarin
- A multidose study of oxandrolone, given as 5 or 10 mg bid in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL; similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding.
- Oral hypoglycemic agents
- Oxandrolone may inhibit the metabolism of oral hypoglycemic agents.
- Adrenal steroids or ACTH
- In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxandrolone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oxandrolone during labor and delivery.
### Nursing Mothers
- It is not known whether anabolic steroids are excreted in human milk. Because of the potential of serious adverse reactions in nursing infants from oxandrolone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Anabolic agents may accelerate epiphyseal maturation more rapidly than linear growth in children and the effect may continue for 6 months after the drug has been stopped. Therefore, therapy should be monitored by x-ray studies at 6-month intervals in order to avoid the risk of compromising adult height. Androgenic anabolic steroid therapy should be used very cautiously in children and only by specialists who are aware of the effects on bone maturation.
### Geriatic Use
There is no FDA guidance on the use of Oxandrolone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Oxandrolone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oxandrolone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Oxandrolone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Oxandrolone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxandrolone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxandrolone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Oxandrolone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Oxandrolone in the drug label.
# Overdosage
## Acute Overdose
- No symptoms or signs associated with overdosage have been reported. It is possible that sodium and water retention may occur.
- The oral LD50 of oxandrolone in mice and dogs is greater than 5,000 mg/kg. No specific antidote is known, but gastric lavage may be used.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Oxandrolone in the drug label.
# Pharmacology
## Mechanism of Action
- Anabolic steroids are synthetic derivatives of testosterone. Certain clinical effects and adverse reactions demonstrate the androgenic properties of this class of drugs. Complete dissociation of anabolic and androgenic effects has not been achieved. The actions of anabolic steroids are therefore similar to those of male sex hormones with the possibility of causing serious disturbances of growth and sexual development if given to young children. Anabolic steroids suppress the gonadotropic functions of the pituitary and may exert a direct effect upon the testes.
- During exogenous administration of anabolic androgens, endogenous testosterone release is inhibited through inhibition of pituitary luteinizing hormone (LH). At large doses, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH)
## Structure
- Oxandrolone oral tablets contain 2.5 mg or 10 mg of the anabolic steroid oxandrolone. Oxandrolone is 17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one with the following structural formula:
- Inactive ingredients include cornstarch, lactose, magnesium stearate, and hydroxypropyl methylcellulose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Oxandrolone in the drug label.
## Pharmacokinetics
- In a single dose pharmacokinetic study of oxandrolone in elderly subjects, the mean elimination half-life was 13.3 hours. In a previous single dose pharmacokinetic study in younger volunteers, the mean elimination half-life was 10.4 hours. No significant differences between younger and elderly volunteers were found for time to peak, peak plasma concentration or AUC after a single dose of oxandrolone. The correlation between plasma level and therapeutic effect has not been defined.
## Nonclinical Toxicology
- Oxandrolone has not been tested in laboratory animals for carcinogenic or mutagenic effects. In 2-year chronic oral rat studies, a dose-related reduction of spermatogenesis and decreased organ weights (testes, prostate, seminal vesicles, ovaries, uterus, adrenals, and pituitary) were shown.
# Clinical Studies
There is limited information regarding Clinical Studies of Oxandrolone in the drug label.
# How Supplied
- Oxandrolone 2.5 mg tablets are oval, white, and scored with OX on one side and “11” on each side of the scoreline on the other side; bottles of 100 (NDC 0591-3544-01).
- Oxandrolone 10 mg tablets are capsule shaped, white, with OX on one side and “10” on the other side; bottles of 60 (NDC 0591-3545-60).
## Storage
There is limited information regarding Oxandrolone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The physician should instruct patients to report immediately any use of warfarin and any bleeding.
- The physician should instruct patients to report any of the following side effects of androgens:
- Males: Too frequent or persistent erections of the penis, appearance or aggravation of acne.
- Females: Hoarseness, acne, changes in menstrual periods, or more facial hair.
- All patients: Nausea, vomiting, changes in skin color, or ankle swelling.
# Precautions with Alcohol
- Alcohol-Oxandrolone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- OXANDROLONE®
# Look-Alike Drug Names
There is limited information regarding Oxandrolone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oxandrolone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Oxandrolone is an anabolic steroid that is FDA approved for the {{{indicationType}}} of weight loss following extensive surgery, chronic infections, or severe trauma, and in some patients who without definite pathophysiologic reasons fail to gain or to maintain normal weight, to offset the protein catabolism associated with prolonged administration of corticosteroids, and for the relief of the bone pain frequently accompanying osteoporosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, increased risk of atherosclerosis, cholestatic hepatitis, jaundice, testicular atropy, erectile dysfunction, and priapism.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Oxandrolone is indicated as adjunctive therapy to promote weight gain after weight loss following extensive surgery, chronic infections, or severe trauma, and in some patients who without definite pathophysiologic reasons fail to gain or to maintain normal weight, to offset the protein catabolism associated with prolonged administration of corticosteroids, and for the relief of the bone pain frequently accompanying osteoporosis.
- Therapy with anabolic steroids is adjunctive to and not a replacement for conventional therapy. The duration of therapy with oxandrolone will depend on the response of the patient and the possible appearance of adverse reactions. Therapy should be intermittent.
- The response of individuals to anabolic steroids varies. The daily adult dosage is 2.5 mg to 20 mg given in 2 to 4 divided doses. The desired response may be achieved with as little as 2.5 mg or as much as 20 mg daily. A course of therapy of 2 to 4 weeks is usually adequate. This may be repeated intermittently as indicated.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxandrolone in adult patients.
### Non–Guideline-Supported Use
- Oxandrolone (80 milligrams daily).[1]
- Oxandrolone 20 mg/day in 2 divided doses.[2]
- Oxandrolone 20 milligrams.[3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The total daily dosage of oxandrolone is ≤0.1 mg per kilogram body weight or ≤0.045 mg per pound of body weight. This may be repeated intermittently as indicated.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxandrolone in pediatric patients.
### Non–Guideline-Supported Use
- Oxandrolone 0.1 mg/kg orally twice daily.[4]
- Oral oxandrolone in usual dosages of 0.125 mg/kg/day for 1 to 2 years.[5]
# Contraindications
- Known or suspected prostate cancer or the male breast.
- Breast cancer in females with hypercalcemia (androgenic anabolic steroids may stimulate osteolytic bone resorption).
- Pregnancy, because of possible masculinization of the fetus. Oxandrolone has been shown to cause embryotoxicity, fetotoxicity, infertility, and masculinization of female animal offspring when given in doses 9 times the human dose.
- Nephrosis, the nephrotic phase of nephritis.
- Hypercalcemia.
# Warnings
- Cholestatic hepatitis and jaundice may occur with 17-alpha-alkylated androgens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, oxandrolone should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued.
- In patients with breast cancer, anabolic steroid therapy may cause hypercalcemia by stimulating osteolysis. Oxandrolone therapy should be discontinued if hypercalcemia occurs.
- Edema with or without congestive heart failure may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. Concomitant administration of adrenal cortical steroid or ACTH may increase the edema.
- In children, androgen therapy may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect results in compromised adult height. The younger the child, the greater the risk of compromising final mature height. The effect on bone maturation should be monitored by assessing bone age of the left wrist and hand every 6 months.
- Geriatric patients treated with androgenic anabolic steroids may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma.
- Anabolic steroids have not been shown to enhance athletic ability.
### Precautions
- Concurrent dosing of oxandrolone with warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). When oxandrolone is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain the desirable INR level and diminish the risk of potentially serious bleeding.
- General
- Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Some virilizing changes in women are irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens. Menstrual irregularities may also occur.
- Anabolic steroids may cause suppression of clotting factors II, V, VII, and X, and an increase in prothrombin time.
# Adverse Reactions
## Clinical Trials Experience
- Patients with moderate to severe COPD or COPD patients who are unresponsive to bronchodilators should be monitored closely for COPD exacerbation and fluid retention.
- The following adverse reactions have been associated with use of anabolic steroids: Hepatic: Cholestatic jaundice with, rarely, hepatic necrosis and death. Hepatocellular neoplasms and peliosis hepatis with long-term therapy. Reversible changes in liver function tests also occur including increased bromsulfophthalein (BSP) retention, changes in alkaline phosphatase and increases in serum bilirubin, aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT)
- In males:
- Prepubertal: Phallic enlargement and increased frequency or persistence of erections.
- Postpubertal: Inhibition of testicular function, testicular atrophy and oligospermia, impotence, chronic priapism, epididymitis, and bladder irritability.
- In females:
- Clitoromegaly, menstrual irregularities.
Habituation, excitation, insomnia, depression, and changes in libido.
Bleeding in patients on concomitant oral anticoagulant therapy.
Gynecomastia.
Deepening of the voice in females.
Hirsutism and male pattern baldness in females.
Acne (especially in females and prepubertal males).
Premature closure of epiphyses in children.
Edema, retention of serum electrolytes (sodium chloride, potassium, phosphate, calcium).
Decreased glucose tolerance, increased creatinine excretion, increased serum levels of creatinine phosphokinase (CPK). Masculinization of the fetus. Inhibition of gonadotropin secretion.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Oxandrolone in the drug label.
# Drug Interactions
- Anticoagulants
- Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped.
- Warfarin
- A multidose study of oxandrolone, given as 5 or 10 mg bid in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL; similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding.
- Oral hypoglycemic agents
- Oxandrolone may inhibit the metabolism of oral hypoglycemic agents.
- Adrenal steroids or ACTH
- In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxandrolone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oxandrolone during labor and delivery.
### Nursing Mothers
- It is not known whether anabolic steroids are excreted in human milk. Because of the potential of serious adverse reactions in nursing infants from oxandrolone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Anabolic agents may accelerate epiphyseal maturation more rapidly than linear growth in children and the effect may continue for 6 months after the drug has been stopped. Therefore, therapy should be monitored by x-ray studies at 6-month intervals in order to avoid the risk of compromising adult height. Androgenic anabolic steroid therapy should be used very cautiously in children and only by specialists who are aware of the effects on bone maturation.
### Geriatic Use
There is no FDA guidance on the use of Oxandrolone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Oxandrolone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oxandrolone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Oxandrolone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Oxandrolone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxandrolone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxandrolone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Oxandrolone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Oxandrolone in the drug label.
# Overdosage
## Acute Overdose
- No symptoms or signs associated with overdosage have been reported. It is possible that sodium and water retention may occur.
- The oral LD50 of oxandrolone in mice and dogs is greater than 5,000 mg/kg. No specific antidote is known, but gastric lavage may be used.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Oxandrolone in the drug label.
# Pharmacology
## Mechanism of Action
- Anabolic steroids are synthetic derivatives of testosterone. Certain clinical effects and adverse reactions demonstrate the androgenic properties of this class of drugs. Complete dissociation of anabolic and androgenic effects has not been achieved. The actions of anabolic steroids are therefore similar to those of male sex hormones with the possibility of causing serious disturbances of growth and sexual development if given to young children. Anabolic steroids suppress the gonadotropic functions of the pituitary and may exert a direct effect upon the testes.
- During exogenous administration of anabolic androgens, endogenous testosterone release is inhibited through inhibition of pituitary luteinizing hormone (LH). At large doses, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH)
## Structure
- Oxandrolone oral tablets contain 2.5 mg or 10 mg of the anabolic steroid oxandrolone. Oxandrolone is 17β-hydroxy-17α-methyl-2-oxa-5α-androstan-3-one with the following structural formula:
- Inactive ingredients include cornstarch, lactose, magnesium stearate, and hydroxypropyl methylcellulose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Oxandrolone in the drug label.
## Pharmacokinetics
- In a single dose pharmacokinetic study of oxandrolone in elderly subjects, the mean elimination half-life was 13.3 hours. In a previous single dose pharmacokinetic study in younger volunteers, the mean elimination half-life was 10.4 hours. No significant differences between younger and elderly volunteers were found for time to peak, peak plasma concentration or AUC after a single dose of oxandrolone. The correlation between plasma level and therapeutic effect has not been defined.
## Nonclinical Toxicology
- Oxandrolone has not been tested in laboratory animals for carcinogenic or mutagenic effects. In 2-year chronic oral rat studies, a dose-related reduction of spermatogenesis and decreased organ weights (testes, prostate, seminal vesicles, ovaries, uterus, adrenals, and pituitary) were shown.
# Clinical Studies
There is limited information regarding Clinical Studies of Oxandrolone in the drug label.
# How Supplied
- Oxandrolone 2.5 mg tablets are oval, white, and scored with OX on one side and “11” on each side of the scoreline on the other side; bottles of 100 (NDC 0591-3544-01).
- Oxandrolone 10 mg tablets are capsule shaped, white, with OX on one side and “10” on the other side; bottles of 60 (NDC 0591-3545-60).
## Storage
There is limited information regarding Oxandrolone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The physician should instruct patients to report immediately any use of warfarin and any bleeding.
- The physician should instruct patients to report any of the following side effects of androgens:
- Males: Too frequent or persistent erections of the penis, appearance or aggravation of acne.
- Females: Hoarseness, acne, changes in menstrual periods, or more facial hair.
- All patients: Nausea, vomiting, changes in skin color, or ankle swelling.
# Precautions with Alcohol
- Alcohol-Oxandrolone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- OXANDROLONE®[6]
# Look-Alike Drug Names
There is limited information regarding Oxandrolone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Anavar | |
4f9563485854d5ce5b36b8e6e146208ddb98b74d | wikidoc | Anchor cell | Anchor cell
The anchor cell is a type of cell responsible for patterning during development in multicellular organisms. The anchor produces a signal which nearby equipotent precursor cells receive. A precursor cells may produce one or more secondary signals, which are received by other precursors. The combination of these signals--and variations in concentration--is used by these cells to determine their ultimate fate.
# Models
- In Graded Signaling, a concentration gradient of some molecule--proportional to the distance from the anchor cell--acts to signal the precursor cell. Different concentrations produce different fates.
- In Sequential Signaling, the anchor cell initiates a signaling cascade which begins in nearby precursors and spreads to those further away.
- In Combined Signaling, the graded and sequential models are merged. Either concentration or a signaling cascade may specify precursor cell fate. | Anchor cell
The anchor cell is a type of cell responsible for patterning during development in multicellular organisms. The anchor produces a signal which nearby equipotent precursor cells receive. A precursor cells may produce one or more secondary signals, which are received by other precursors. The combination of these signals--and variations in concentration--is used by these cells to determine their ultimate fate.
# Models
- In Graded Signaling, a concentration gradient of some molecule--proportional to the distance from the anchor cell--acts to signal the precursor cell. Different concentrations produce different fates.
- In Sequential Signaling, the anchor cell initiates a signaling cascade which begins in nearby precursors and spreads to those further away.
- In Combined Signaling, the graded and sequential models are merged. Either concentration or a signaling cascade may specify precursor cell fate.[1] | https://www.wikidoc.org/index.php/Anchor_cell | |
0de5d36db1e218b675b68295080b654b9d629048 | wikidoc | Anellovirus | Anellovirus
Not much is known about the family of Anelloviri, having been recently discovered. It has been classified as a vertebrate virus and consisting of a non-enveloped capsid, which is round with isometric, icosahedral symmetry.
The genome is not segmented and contains a single molecule of circular, negative-sense, single-stranded DNA. The complete genome is 3000-4000 nucleotides long. .
# Literature
- ↑ ICTVdB Management (2006). 00.107.0.01. Anellovirus. In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA | Anellovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Not much is known about the family of Anelloviri, having been recently discovered. It has been classified as a vertebrate virus and consisting of a non-enveloped capsid, which is round with isometric, icosahedral symmetry.
The genome is not segmented and contains a single molecule of circular, negative-sense, single-stranded DNA. The complete genome is 3000-4000 nucleotides long. [1].
# Literature
- ↑ ICTVdB Management (2006). 00.107.0.01. Anellovirus. In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA
Template:Virus-stub
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Anellovirus | |
7a533d7e75954369ea44b3e63715cd52d3701910 | wikidoc | Anencephaly | Anencephaly
# Overview
Anencephaly is a cephalic disorder in which there is the partial or total absence of the brain. It is an open neural tube defect occurs when the rostral (head) end of the neural tube fails to close resulting in the absence of a major portion of the brain, skull and spinal cord. Children with this disorder are born without a forebrain, the largest part of the brain consisting mainly of the cerebral hemispheres which is responsible for higher cognitive functions and cerebellum which control balance and movement. However, hindbrain is developed. The remaining brain tissue is often exposed - not covered by bone or skin.
# Historical Perspective
- Anencephaly was first recognized in the 16th century. In 1989, Aubrey Milunsky and his colleagues observed a reduction in the cases of neural tube defects in the mothers who took folic acid supplements during pregnancy.
- In 1992, Thresa was born with anencephaly. Her parents knew their daughter is going to die. So, they requested if her organs could be used for transplantation. This initiated a debate on anencephalic infant organ donation.
# Classification
# Pathophysiology
- By the 3rd week of gestation, the embryo has 3 layers, from outer to inner these layers are ectoderm, mesoderm and endoderm. Notochord in the mesoderm sends signal molecule called Sonic Hedgehog protein to the overlying ectoderm forming it a neuroectoderm.
- The neural plate folds and closes to form a tube-like structure called neural tube and neural crest cells. The neural tube then goes on to form structures of the adult brain.
- A neural tube defect occurs if the the opening of the neural tube, called neuropore, fails to close in the 4th week of gestation. Neural tube has two neuropores, rostral and caudial. Anencephaly results from failure of the rostral neuropore to close anteriorly around day 25.
- The craniofacial abnormalities in anencephaly are caused by abnormal induction by the neural crest cells.
# Clinical Features
- Infants born with anencephaly have the following clinical features:
Facial features: Cleft lip, cleft palate.
CNS: Absence of bony covering over the back of the head, spina bifida, blindness, deafness.
GIT: Absence or underdeveloped organs, gastroschisis, omphalocele.
Genito-urinary system: Hypospadias, penile hypoplasia, renal agenesis.
Skeletal system: Clubbed foot, clubbed hands.
Lungs: Diapharagmatic hernia.
- Facial features: Cleft lip, cleft palate.
- CNS: Absence of bony covering over the back of the head, spina bifida, blindness, deafness.
- GIT: Absence or underdeveloped organs, gastroschisis, omphalocele.
- Genito-urinary system: Hypospadias, penile hypoplasia, renal agenesis.
- Skeletal system: Clubbed foot, clubbed hands.
- Lungs: Diapharagmatic hernia.
# Differentiating Anencephalopathy from other Disorders
At times, anencephaly could be misdiagnosed with other similar diagnosis such as;
- exencephaly
- microcephaly
# Epidemiology and Demographics
## Incidence
In the United States, approximately 1,000 to 2,000 babies are born with anencephaly each year. In 2001, the National Center for Health Statistics reported 9.4 cases among 100,000 live births. Anually, more than 300,000 babies are born with neural tube defects throughout the world.
## Demographics
In United States, the highest prevalence has been seen among the Hispanic . Female babies, whites and children born to mothers who are at extreme of ages are more likely to be affected by the disorder. Worldwide, Ireland and British Islands has higher prevalence as compared to Asia and Africa which has a lower prevalence rate.
## Recurrence rate
Like any other neural tube defect, the recurrence rate of anencephaly is 2-4 percent if one sibling is affected and 10 percent if two siblings are affected. This familial tendency is due to genetics, environmental factors, or both.
# Risk Factors
## Folate deficiency
- Studies show that most of the neural tube defects are caused by folic acid deficiency.
- This inadequate folate could be due to less oral intake, decreased intestinal absorption, or due to abnormal folate metabolism due to gene mutation. Some drugs antagonize the effect of folic acid resulting in folic acid deficiency and hence NTD. Most important ones are anti-epileptic drugs such as valproic acid and carbamazepine. Also, methotrexate, which is an antineoplastic drug also used for the treatment of ectopic pregnancy, has been linked with increased risk of NTD.
## Genetics
Neural tube defects do not follow direct patterns of heredity, though there is some indirect evidence of inheritance. Recent animal models indicate a possible association with deficiencies of the transcription factor TEAD2.
The motivation behind studying genetic patterns is the following:
- NTDs are consistently prevalent among monozygotic twins as compared to dizygotic twins.
- There is a high recurrence rate within families. Statistics show the recurrence risk of 1/20 if one previous pregnancy is affected and 1/10 if two pregnancies are affected in a family.
- There is higher female preponderence as compared to the males.
## Syndromes
- Anencephaly is associated with:
Trisomy 13 or Trisomy 18
Meckel-Gruber syndrome
Roberts syndrome
Jarcho-Levin syndrome
HARD (hydrocephalus, agyria and retinal dysplasia)
OEIS complex (omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects)
Limb-body wall complex (LBWC)
- Trisomy 13 or Trisomy 18
- Meckel-Gruber syndrome
- Roberts syndrome
- Jarcho-Levin syndrome
- HARD (hydrocephalus, agyria and retinal dysplasia)
- OEIS complex (omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects)
- Limb-body wall complex (LBWC)
## Fever/hyperthermia
- If a pregnant mother’s core body temperature elevates from baseline it could lead to congenital anomalies such neural tube defects, including anencephaly.
- The risk is more profound if this happens during the first trimester as this is the time during which organogenesis takes place. The National Birth Defects Prevention Study (NBDPS) infers that the risk of birth defects due to maternal infection-related fever can be reduced by the usage of acetaminophen.
## Amniotic bands
- If a pregnant mother develops amniotic bands, it could affect the normal development and growth of the central nervous system. It could result in neural tube defects including anencephaly.
## Pregestational diabetes
- If a woman has uncontrolled diabetes mellitus before conception, it could result in neural tube defects including anencephaly.
- Therefore, close monitoring of periconceptional glycemic level is essential to prevent neural tube defects and other congenital anomalies.
## Maternal Obesity
- Obesity doubles the risk of neural tube defects. Also, it provides a limitation to fetal imaging.
- Folic acid supplementation does not decrease this risk of NTD, therefore it is mandatory to control weight before conceiving.
## Toxins
- Anencephaly and other physical and mental deformities have also been blamed on high exposure to such toxins as lead, chromium, mercury, and nickel.
# Natural History, Complications, Prognosis
- Prognosis of children born with anencephaly is extremely poor as there is no cure or standard treatment available so far. Most anencephalic babies do not survive birth, accounting for 55% of non-aborted cases. If the infant is not stillborn, then he or she will usually die within a few hours or days after birth from cardiorespiratory arrest.
- Anencephalic infants are not aggressively resuscitated as there is very little chance of the infant to achieve a full level of consciousness. Instead, clinicians prefer to provide them with adequate hydration, nutrition and comfort. Artificial ventilation, surgery (to fix any co-existing congenital defects), and medications are not considered an option as they have no role in any improvement. Due to this poor prognosis, couple are discussed about the option of the terminating the pregnancy soon after the prenatal diagnosis is established.
# Diagnosis
## Diagnostic Criteria
- The diagnosis of Anencephaly is made either during a prenatal scan or after the birth.
- In prenatal ultrasound, features like absent calvarium and characteristic frog-like appearance or Micky mouse appearance of the fetus are diagnostic.
- After the birth, clinical features like lack of bony covering over the back of the head and less number of bones around the front and sides of the head are diagnostic.
## Symptoms
- Majority of the infants are stillborn or die soon after birth.
- Symptoms of anencephaly may include the following:
- Decrease or loss of consciousness.
- Blindness
- Deafness
- Inability to feel pain.
## Physical Examination
- Physical examination may be remarkable for:
- Flattened head
- Absence of the cranial vault
- Positive grasp reflex in both the hands and feet
- Moro reflex could be present or absent depending on the severity of the defect.
- A heart murmur could be present due to associated congenital heart disease.
- cleft lip and/or cleft palate could be present.
- Clubbed foot could be present.
- Gastroschisis, omphalocele, hypospadias could be present in some anencephalic infants.
## Laboratory Findings
### Alpha-Fetoprotein
- Alpha-fetoprotein (AFP) levels can be measured in maternal serum (MSAFP), amniotic fluid, and fetal plasma.
- Normally, the level rises in early pregnancy, peaks between 10 and 13th week, and then the level declines becoming extremely low near the term.
- For the purpose of prenatal screening, alpha-fetoprotein levels are checked and are found to elevated. This test is non-specific for NTD, as AFP can also be elevated due to other maternal and fetal factors. Therefore, results should always be combined with ultrasound findings and the levels of Acetylcholinesterase (AChE).
## Acetylcholinesterase
AChE is an enzyme contained in blood cells, muscle, and nerve tissue. Its levels can be checked from the amniotic fluid via amniocentesis. An elevation of both AFP and AChE values is highly suggestive and accurate for fetal NTD.
## Triple screen
Triple screen is a prenatal screening test which includes 3 biomarkers; AFP, hCG and estradiol. It helps to detect certain congenital anomalies, including neural tube defect. The following table shows the triple screening of neural tube defect and how it is differentiated from other anomalies.
## Imaging Findings
### Ultrasound
Ultrasound provides a definitive diagnosis of anencephaly before birth. It can often be diagnosed through a transvaginal ultrasound performed at 12th week postmenstrual.
The ultrasound findings include:
- Absent calvarium.
- No parenchymal tissue above the orbits.
- Reduced crown rump length (CRL)
- A characteristic frog-like appearance or Micky mouse appearance of the fetus due to absent brain and cranial bone and, protruding orbits.
- A large amount of amniotic fluid called polyhydromnios is also seen.
# Management
## Medical Therapy
- There is no known medical therapy available for anencephaly.
## Surgery
- At this point in time, there are no surgical options available."Anencephaly: Causes, Symptoms, Diagnosis and Treatment for Newborns | St. Louis Childrens Hospital"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
## Prevention
- Recent studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily, especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%.
- It is not advisable to wait until pregnancy has begun, since by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid (4 mg/day) for women who have had a previous pregnancy with a neural tube defect. | Anencephaly
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayesha Javid, MBBS[2]
For patient information click here
# Overview
Anencephaly is a cephalic disorder in which there is the partial or total absence of the brain. It is an open neural tube defect occurs when the rostral (head) end of the neural tube fails to close resulting in the absence of a major portion of the brain, skull and spinal cord. Children with this disorder are born without a forebrain, the largest part of the brain consisting mainly of the cerebral hemispheres which is responsible for higher cognitive functions and cerebellum which control balance and movement. However, hindbrain is developed. The remaining brain tissue is often exposed - not covered by bone or skin.
# Historical Perspective
- Anencephaly was first recognized in the 16th century. In 1989, Aubrey Milunsky and his colleagues observed a reduction in the cases of neural tube defects in the mothers who took folic acid supplements during pregnancy.[1]
- In 1992, Thresa was born with anencephaly. Her parents knew their daughter is going to die. So, they requested if her organs could be used for transplantation. This initiated a debate on anencephalic infant organ donation.[2]
# Classification
# Pathophysiology
- By the 3rd week of gestation, the embryo has 3 layers, from outer to inner these layers are ectoderm, mesoderm and endoderm. Notochord in the mesoderm sends signal molecule called Sonic Hedgehog protein to the overlying ectoderm forming it a neuroectoderm.[5]
- The neural plate folds and closes to form a tube-like structure called neural tube and neural crest cells. The neural tube then goes on to form structures of the adult brain.[6]
- A neural tube defect occurs if the the opening of the neural tube, called neuropore, fails to close in the 4th week of gestation. Neural tube has two neuropores, rostral and caudial. Anencephaly results from failure of the rostral neuropore to close anteriorly around day 25.[4]
- The craniofacial abnormalities in anencephaly are caused by abnormal induction by the neural crest cells.[7]
# Clinical Features
- Infants born with anencephaly have the following clinical features:[8]
Facial features: Cleft lip, cleft palate.
CNS: Absence of bony covering over the back of the head, spina bifida, blindness, deafness.
GIT: Absence or underdeveloped organs, gastroschisis, omphalocele.
Genito-urinary system: Hypospadias, penile hypoplasia, renal agenesis.
Skeletal system: Clubbed foot, clubbed hands.
Lungs: Diapharagmatic hernia.
- Facial features: Cleft lip, cleft palate.
- CNS: Absence of bony covering over the back of the head, spina bifida, blindness, deafness.
- GIT: Absence or underdeveloped organs, gastroschisis, omphalocele.
- Genito-urinary system: Hypospadias, penile hypoplasia, renal agenesis.
- Skeletal system: Clubbed foot, clubbed hands.
- Lungs: Diapharagmatic hernia.
# Differentiating Anencephalopathy from other Disorders
At times, anencephaly could be misdiagnosed with other similar diagnosis such as;
- exencephaly
- microcephaly[9]
# Epidemiology and Demographics
## Incidence
In the United States, approximately 1,000 to 2,000 babies are born with anencephaly each year. In 2001, the National Center for Health Statistics reported 9.4 cases among 100,000 live births.[10] Anually, more than 300,000 babies are born with neural tube defects throughout the world.[11]
## Demographics
In United States, the highest prevalence has been seen among the Hispanic [12]. Female babies, whites and children born to mothers who are at extreme of ages are more likely to be affected by the disorder. Worldwide, Ireland and British Islands has higher prevalence as compared to Asia and Africa which has a lower prevalence rate.[13]
## Recurrence rate
Like any other neural tube defect, the recurrence rate of anencephaly is 2-4 percent if one sibling is affected and 10 percent if two siblings are affected.[14][15] This familial tendency is due to genetics, environmental factors, or both.[16]
# Risk Factors
## Folate deficiency
- Studies show that most of the neural tube defects are caused by folic acid deficiency[17].
- This inadequate folate could be due to less oral intake, decreased intestinal absorption, or due to abnormal folate metabolism due to gene mutation. Some drugs antagonize the effect of folic acid resulting in folic acid deficiency and hence NTD. Most important ones are anti-epileptic drugs such as valproic acid and carbamazepine. Also, methotrexate, which is an antineoplastic drug also used for the treatment of ectopic pregnancy, has been linked with increased risk of NTD.[18]
## Genetics
Neural tube defects do not follow direct patterns of heredity, though there is some indirect evidence of inheritance.[19] Recent animal models indicate a possible association with deficiencies of the transcription factor TEAD2.[20]
The motivation behind studying genetic patterns is the following:
- NTDs are consistently prevalent among monozygotic twins as compared to dizygotic twins.[21]
- There is a high recurrence rate within families. Statistics show the recurrence risk of 1/20 if one previous pregnancy is affected and 1/10 if two pregnancies are affected in a family.[22]
- There is higher female preponderence as compared to the males. [23]
## Syndromes
- Anencephaly is associated with:[24]
Trisomy 13 or Trisomy 18
Meckel-Gruber syndrome
Roberts syndrome
Jarcho-Levin syndrome
HARD (hydrocephalus, agyria and retinal dysplasia)
OEIS complex (omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects)
Limb-body wall complex (LBWC)
- Trisomy 13 or Trisomy 18
- Meckel-Gruber syndrome
- Roberts syndrome
- Jarcho-Levin syndrome
- HARD (hydrocephalus, agyria and retinal dysplasia)
- OEIS complex (omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects)
- Limb-body wall complex (LBWC)
## Fever/hyperthermia
- If a pregnant mother’s core body temperature elevates from baseline it could lead to congenital anomalies such neural tube defects, including anencephaly.[25][26]
- The risk is more profound if this happens during the first trimester as this is the time during which organogenesis takes place. The National Birth Defects Prevention Study (NBDPS) infers that the risk of birth defects due to maternal infection-related fever can be reduced by the usage of acetaminophen.[27]
## Amniotic bands
- If a pregnant mother develops amniotic bands, it could affect the normal development and growth of the central nervous system. It could result in neural tube defects including anencephaly.[28]
## Pregestational diabetes
- If a woman has uncontrolled diabetes mellitus before conception, it could result in neural tube defects including anencephaly.[23]
- Therefore, close monitoring of periconceptional glycemic level is essential to prevent neural tube defects and other congenital anomalies.
## Maternal Obesity
- Obesity doubles the risk of neural tube defects. Also, it provides a limitation to fetal imaging.[29]
- Folic acid supplementation does not decrease this risk of NTD, therefore it is mandatory to control weight before conceiving.[30]
## Toxins
- Anencephaly and other physical and mental deformities have also been blamed on high exposure to such toxins as lead, chromium, mercury, and nickel. [31]
# Natural History, Complications, Prognosis
- Prognosis of children born with anencephaly is extremely poor as there is no cure or standard treatment available so far. Most anencephalic babies do not survive birth, accounting for 55% of non-aborted cases. If the infant is not stillborn, then he or she will usually die within a few hours or days after birth from cardiorespiratory arrest.[32]
- Anencephalic infants are not aggressively resuscitated as there is very little chance of the infant to achieve a full level of consciousness. Instead, clinicians prefer to provide them with adequate hydration, nutrition and comfort.[33] Artificial ventilation, surgery (to fix any co-existing congenital defects), and medications are not considered an option as they have no role in any improvement.[34] Due to this poor prognosis, couple are discussed about the option of the terminating the pregnancy soon after the prenatal diagnosis is established.[35]
# Diagnosis
## Diagnostic Criteria
- The diagnosis of Anencephaly is made either during a prenatal scan or after the birth.
- In prenatal ultrasound, features like absent calvarium and characteristic frog-like appearance or Micky mouse appearance of the fetus are diagnostic.[36]
- After the birth, clinical features like lack of bony covering over the back of the head and less number of bones around the front and sides of the head are diagnostic.[37]
## Symptoms
- Majority of the infants are stillborn or die soon after birth.[38][39]
- Symptoms of anencephaly may include the following:
- Decrease or loss of consciousness.
- Blindness
- Deafness
- Inability to feel pain.[40] [41]
## Physical Examination
- Physical examination may be remarkable for:
- Flattened head
- Absence of the cranial vault[42]
- Positive grasp reflex in both the hands and feet
- Moro reflex could be present or absent depending on the severity of the defect.[43]
- A heart murmur could be present due to associated congenital heart disease.
- cleft lip and/or cleft palate could be present.
- Clubbed foot could be present.
- Gastroschisis, omphalocele, hypospadias could be present in some anencephalic infants.[8]
## Laboratory Findings
### Alpha-Fetoprotein
- Alpha-fetoprotein (AFP) levels can be measured in maternal serum (MSAFP), amniotic fluid, and fetal plasma.[44]
- Normally, the level rises in early pregnancy, peaks between 10 and 13th week, and then the level declines becoming extremely low near the term.[45]
- For the purpose of prenatal screening, alpha-fetoprotein levels are checked and are found to elevated. This test is non-specific for NTD, as AFP can also be elevated due to other maternal and fetal factors. Therefore, results should always be combined with ultrasound findings and the levels of Acetylcholinesterase (AChE).
## Acetylcholinesterase
AChE is an enzyme contained in blood cells, muscle, and nerve tissue. Its levels can be checked from the amniotic fluid via amniocentesis. An elevation of both AFP and AChE values is highly suggestive and accurate for fetal NTD.
## Triple screen
Triple screen is a prenatal screening test which includes 3 biomarkers; AFP, hCG and estradiol. It helps to detect certain congenital anomalies, including neural tube defect. The following table shows the triple screening of neural tube defect and how it is differentiated from other anomalies.[46]
## Imaging Findings
### Ultrasound
Ultrasound provides a definitive diagnosis of anencephaly before birth. It can often be diagnosed through a transvaginal ultrasound performed at 12th week postmenstrual.[47]
The ultrasound findings include:
- Absent calvarium.
- No parenchymal tissue above the orbits.
- Reduced crown rump length (CRL)
- A characteristic frog-like appearance or Micky mouse appearance of the fetus due to absent brain and cranial bone and, protruding orbits.
- A large amount of amniotic fluid called polyhydromnios is also seen.[48]
.
# Management
## Medical Therapy
- There is no known medical therapy available for anencephaly.
## Surgery
- At this point in time, there are no surgical options available."Anencephaly: Causes, Symptoms, Diagnosis and Treatment for Newborns | St. Louis Childrens Hospital"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
## Prevention
- Recent studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily, especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%.[49]
- It is not advisable to wait until pregnancy has begun, since by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid (4 mg/day) for women who have had a previous pregnancy with a neural tube defect.[50] | https://www.wikidoc.org/index.php/Anencephalic | |
bdb4b77c13fdb239c334004447b23711dfc45834 | wikidoc | Angor animi | Angor animi
Synonyms and keywords: Angina animi; Gairdner's disease; angina pectoris sine dolore
# Overview
Angor animi (also referred to as angina animi, Gairdner's disease and also angina pectoris sine dolore), in medicine, is a symptom defined as a patient's perception that they are in fact dying. Most cases of angor animi are found in patients suffering from acute coronary syndrome such as unstable angina or acute myocardial infarction. It is, however, occasionally found in patients suffering from other conditions.
Angor animi is differentiated from a fear or desire for death, since angor animi refers to a patient's actual and genuine belief that they are in the present act of dying. The phrase is derived from the two Latin terms which it is composed of, namely angor and animi.
Angor (different but related to the word anger), in modern English, refers to a great anxiety often accompanied by a painful constriction and palpitations at the upper abdomen and lower thorax (chest). Animi means an animating spirit, intention or temper. | Angor animi
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Angina animi; Gairdner's disease; angina pectoris sine dolore
# Overview
Angor animi (also referred to as angina animi, Gairdner's disease and also angina pectoris sine dolore), in medicine, is a symptom defined as a patient's perception that they are in fact dying. Most cases of angor animi are found in patients suffering from acute coronary syndrome such as unstable angina or acute myocardial infarction. It is, however, occasionally found in patients suffering from other conditions.
Angor animi is differentiated from a fear or desire for death, since angor animi refers to a patient's actual and genuine belief that they are in the present act of dying. The phrase is derived from the two Latin terms which it is composed of, namely angor and animi.
Angor (different but related to the word anger), in modern English, refers to a great anxiety often accompanied by a painful constriction and palpitations at the upper abdomen and lower thorax (chest). Animi means an animating spirit, intention or temper. | https://www.wikidoc.org/index.php/Angina_animi | |
de8e7a62fe86f3e65594da142cefed29c18e180d | wikidoc | Bivalirudin | Bivalirudin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Bivalirudin is a direct thrombin inhibitor that is FDA approved for the prophylaxis of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and patients with unstable angina or risk of heparin induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention (PCI).. Common adverse reactions include bleeding, headache, thrombocytopenia and fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose: 0.75 mg/kg IV bolus
- Maintenance dose: 1.75 mg/kg/hr IV infusion for the duration of the procedure
- May be continued 4 hours post-procedure
- Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.
- Dosing Information
- Initial dose: 0.75 mg/kg IV bolus
- Maintenance dose: 1.75 mg/kg/hr IV infusion for the duration of the procedure
- May be continued 4 hours post-procedure
- Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bivalirudin in adult patients.
### Non–Guideline-Supported Use
### Adjunct to Thrombolytic Therapy in Acute Myocardial Infarction,
- Dosing Information
- Initial dose: 0.25 mg/kg IV bolus'
- Followed by an infusion of 0.5 mg/kg/hr for 12 hr and then 0.25 mg/kg/hr for 36 h
- Streptokinase was given after initial bolus, as 1.5 million units infused over 30 to 60 minutes.
### Prophylaxis in Deep venous thrombosis
- Dosing Information
- 1 mg/kg SQ q8h
### Prophylaxis in Heart Surgery in Patients with Heparin-induced Thrombocytopenia with Thrombosis
- CHOOSE-ON Trial
- 1 mg/kg IV bolus
- Followed by 2.5 mg/kg/hour infusion continued until 15 minutes before the end of cardiopulmonary bypass.
- Additionally, bivalirudin 50 mg was added to the cardiopulmonary bypass priming solution.
- CHOOSE-OFF Trial
- 0.75 mg/kg IV bolus
- Followed by continuous infusion of 1.75 mg/kg/hour.
### Thromboprophylaxis in Peripheral Arterial Bypass
- Dosing Information
- 0.75 mg/kg IV bolus
- Followed by 1.75 mg/kg/hour infusion for the duration of the procedure
### Thromboprophylaxis in Unstable angina
- Dosing Information
- 0.1 mg/kg IV bolus
- Followed by 0.25 mg/kg/hr
- Titrated to an activated partial thromboplastin time (aPTT) of 55 to 85 seconds to be maintained for a minimum of 72 hr.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Bivalirudin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bivalirudin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bivalirudin in pediatric patients.
# Contraindications
- Active major bleeding
- Hypersensitivity (e.g., anaphylaxis) to bivalirudin or its components.
# Warnings
- Although most bleeding associated with the use of bivalirudin in PCI/PTCA occurs at the site of arterial puncture, hemorrhage can occur at any site.
- An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin administration.
- Bivalirudin should be used with caution in patients with disease states associated with an increased risk of bleeding.
- An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of bivalirudin in gamma brachytherapy.
- If a decision is made to use bivalirudin during brachytherapy procedures, maintain meticulous catheter technique, with frequent aspiration and flushing, paying special attention to minimizing conditions of stasis within the catheter or vessels.
# Adverse Reactions
## Clinical Trials Experience
### Bleeding
In 6010 patients undergoing PCI treated in the REPLACE-2 trial, bivalirudin patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2.
In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing bivalirudin to heparin, bivalirudin patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 3. The incidence of major bleeding was lower in the bivalirudin group than in the heparin group.
In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia.
### Other Adverse Reactions
Adverse reactions, other than bleeding, observed in clinical trials were similar between the bivalirudin treated patients and the control groups.
Adverse reactions (related adverse events ) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5.
Serious, non-bleeding adverse events were experienced in 2% of 2161 bivalirudin-treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between bivalirudin- and heparin-treated patients.
- Fever
- Infection
- Sepsis
- Hypotension
- Syncope
- Vascular anomaly
- Ventricular fibrillation
- Cerebral ischemia
- Confusion
- Facial paralysis
- Lung edema
- Kidney failure
- Oliguria
### Immunogenicity/Re-Exposure
In in vitro studies, bivalirudin exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS. Among 494 subjects who received Angiomax in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.
## Postmarketing Experience
Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during postapproval use of bivalirudin: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.
# Drug Interactions
- In clinical trials in patients undergoing PCI/PTCA, co-administration of bivalirudin with heparin, warfarin, thrombolytics, or GPIs was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications.
- There is no experience with co-administration of bivalirudin and plasma expanders such as dextran.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no evidence of impaired fertility or harm to the fetus attributable to bivalirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Bivalirudin is intended for use with aspirin. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, bivalirudin and aspirin should be used together during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bivalirudin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bivalirudin during labor and delivery.
### Nursing Mothers
It is not known whether bivalirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when bivalirudin is administered to a nursing woman.
### Pediatric Use
The safety and effectiveness of bivalirudin in pediatric patients have not been established.
### Geriatic Use
In studies of patients undergoing PCI, 44% were ≥65 years of age and 12% of patients were ≥75 years old. Elderly patients experienced more bleeding events than younger patients. Patients treated with bivalirudin experienced fewer bleeding events in each age stratum, compared to heparin.
### Gender
There is no FDA guidance on the use of Bivalirudin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bivalirudin with respect to specific racial populations.
### Renal Impairment
The disposition of bivalirudin was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of bivalirudin was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. The infusion dose of bivalirudin may need to be reduced, and anticoagulant status monitored in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Bivalirudin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bivalirudin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bivalirudin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Bivalirudin is intended for intravenous bolus injection and continuous infusion after reconstitution and dilution. To each 250 mg vial, add 5 mL of sterile water for injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 50 mL of 5% dextrose in water or 0.9% sodium chloride for injection to yield a final concentration of 5 mg/mL (e.g., 1 vial in 50 mL; 2 vials in 100 mL; 5 vials in 250 mL). The dose to be administered is adjusted according to the patient's weight.
If the low-rate infusion is used after the initial infusion, a lower concentration bag should be prepared. In order to prepare this bag, reconstitute the 250 mg vial with 5 mL of sterile water for injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 5% dextrose in water or 0.9% sodium chloride for Injection to yield a final concentration of 0.5 mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 1.
Bivalirudin should be administered via an intravenous line. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of bivalirudin containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution.
### Monitoring
### Renal Impairment
No reduction in the bolus dose is needed for any degree of renal impairment. The infusion dose of bivalirudin may need to be reduced, and anticoagulant status monitored in patients with renal impairment. Patients with moderate renal impairment (30-59 mL/min) should receive an infusion of 1.75 mg/kg/h. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1 mg/kg/h should be considered. If a patient is on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/h
# IV Compatibility
The following drugs should not be administered in the same intravenous line with bivalirudin , since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with bivalirudin: alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl. Dobutamine was compatible at concentrations up to 4 mg/mL but incompatible at a concentration of 12.5 mg/mL.
# Overdosage
- Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of bivalirudin have been reported in clinical trials and in postmarketing reports.
- A number of the reported overdoses were due to failure to adjust the infusion dose of bivalirudin in persons with renal dysfunction including persons on hemodialysis.
- Bleeding, as well as deaths due to hemorrhage, have been observed in some reports of overdose.
- In cases of suspected overdosage, discontinue bivalirudin immediately and monitor the patient closely for signs of bleeding. There is no antidote to bivalirudin. Bivalirudin is hemodialyzable.
# Pharmacology
## Mechanism of Action
Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.
In in vitro studies, bivalirudin inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown.
## Structure
Bivalirudin is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name is D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-L-leucine trifluoroacetate (salt) hydrate (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide).
## Pharmacodynamics
In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine PTCA), bivalirudin exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of bivalirudin produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration.
In 291 patients with ≥70% vessel occlusion undergoing routine PTCA , a positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300 sec or 350 sec. At an bivalirudin dose of 1 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.
## Pharmacokinetics
Bivalirudin exhibits linear pharmacokinetics following IV administration to patients undergoing PTCA. In these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 mcg/mL is achieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells. bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of 25 min.
The disposition of bivalirudin was studied in PTCA patients with mild, moderate, and severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with normal renal function and with mild renal impairment (60-89 mL/min). Clearance was reduced in patients with moderate and severe renal impairment and in dialysis-dependent patients.
Bivalirudin is hemodialyzable, with approximately 25% cleared by hemodialysis.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of bivalirudin up to 150 mg/kg/day, about 1.6 times the dose on a body surface area basis (mg/m2) of a 50 kg person given the maximum recommended dose of 15 mg/kg/day.
# Clinical Studies
### PCI/PTCA
Bivalirudin has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6062 of the patients in these trials - mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty, atherectomy or other procedures were performed in the remaining patients.
### REPLACE-2 Trial
This was a randomized, double-blind, multicenter study reporting 6002 (intent-to-treat) patients undergoing PCI. Patients were randomized to treatment with bivalirudin with the "provisional" use of platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a "provisional" basis to patients who were randomized to bivalirudin in the following circumstances:
- decreased TIMI flow (0 to 2) or slow reflow;
- dissection with decreased flow;
- new or suspected thrombus;
- persistent residual stenosis;
- distal embolization;
- unplanned stent;
- suboptimal stenting;
- side branch closure;
- abrupt closure; clinical instability; and
- prolonged ischemia.
During the study, one or more of these circumstances occurred in 12.7% of patients in the bivalirudin with provisional GPI arm. GPIs were administered to 7.2% of patients in the bivalirudin with provisional GPI arm (62.2% of eligible patients).
Patients ranged in age from 25-95 years (median, 63); weight ranged from 35-199 kg (median 85.5); 74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.
Bivalirudin was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 0.3 mg/kg was given. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 20 units/kg was given. GPIs (either abciximab or eptifibatide) were given according to manufacturers' instructions. Both randomized groups could be given "provisional" treatments during the PCI at investigator discretion, but under double-blind conditions. "Provisional" treatment with GPI was requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2% patients randomized to bivalirudin with provisional GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).
The percent of patients reaching protocol-specified levels of anticoagulation was greater in the bivalirudin with provisional GPI group than in the heparin plus GPI group. For patients randomized to bivalirudin with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (bivalirudin group) and 276 sec (heparin plus GPI group).
For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%)(95% confidence interval 6.7%-8.6%) in the bivalirudin with "provisional" GPI arm when compared to the heparin plus GPI arm (7.1%)(95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the bivalirudin with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 7.
At 12 months' follow-up, mortality was 1.9% among patients randomized to bivalirudin with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.
### Bivalirudin Angioplasty Trial (BAT)
bivalirudin was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with bivalirudin or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to bivalirudin were started on an intravenous infusion of bivalirudin (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to bivalirudin (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The bivalirudin dose was not titrated to ACT. Median ACT values were: ACT in sec (5th percentile-95th percentile): 345 sec (240-595 sec) at 5 min and 346 sec (range 269-583 sec) at 45 min after initiation of dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under double-blinded conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blind bolus of heparin (60 IU/kg) was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. All ACTs were determined with the Hemochron® device. The protocol allowed use of open-label heparin at the discretion of the investigator after discontinuation of blinded study medication, whether or not an endpoint event (procedural failure) had occurred. The use of open-label heparin was similar between bivalirudin and heparin treatment groups (about 20% in both groups).
The studies were designed to demonstrate the safety and efficacy of bivalirudin in patients undergoing PTCA as a treatment for unstable angina as compared with a control group of similar patients receiving heparin during and up to 24 hours after initiation of PTCA. The primary protocol endpoint was a composite endpoint called procedural failure, which included both clinical and angiographic elements measured during hospitalization. The clinical elements were: the occurrence of death, MI, or urgent revascularization, adjudicated under double-blind conditions. The angiographic elements were: impending or abrupt vessel closure. The protocol-specified safety endpoint was major hemorrhage.
The median duration of hospitalization was 4 days for both the bivalirudin and the heparin treatment groups. The rates of procedural failure were similar in the bivalirudin and heparin treatment groups. Study outcomes are shown in Table 8.
### AT-BAT Trial
This was a single-group open-label study which enrolled 51 patients with heparin-induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Evidence for the diagnosis of HIT/HITTS was based on a clinical history of a decrease of platelets in patients after heparin administration . Patients ranged in age from 48-89 years (median 70); weight ranged from 42-123 kg (median 76); 50% were male and 50% were female. Bivalirudin was administered as either 1 mg/kg bolus followed by 2.5 mg/kg/h (high dose in 28 patients) or 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion (lower dose in 25 patients) for up to 4 hours. Ninety-eight percent of patients received aspirin, 86% received clopidogrel and 19% received GPIs.
The median ACT values at the time of device activation were 379 sec (high dose) and 317 sec (lower dose). Following the procedure, 48 of the 51 patients (94%) had TIMI grade 3 flow and stenosis <50%. One patient died during a bradycardic episode 46 hours after successful PCI, another patient required surgical revascularization, and one patient experienced no flow requiring a temporary intra-aortic balloon.
Two of the fifty-one patients with the diagnosis of HIT/HITTS developed thrombocytopenia after receiving bivalirudin and GPIs.
# How Supplied
Bivalirudin is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of bivalirudin.
- NDC 65293-001-01
## Storage
Store bivalirudin dosage units at 20-25°C (68-77°F). Excursions to 15-30°C permitted.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.
- Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter medications or herbal products, prior to bivalirudin use.
- Examples of other medications that should not be taken with bivalirudin are warfarin and heparin.
# Precautions with Alcohol
Alcohol-Bivalirudin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Angiomax
# Look-Alike Drug Names
There is limited information regarding Bivalirudin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Bivalirudin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
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# Overview
Bivalirudin is a direct thrombin inhibitor that is FDA approved for the prophylaxis of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and patients with unstable angina or risk of heparin induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention (PCI).. Common adverse reactions include bleeding, headache, thrombocytopenia and fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose: 0.75 mg/kg IV bolus
- Maintenance dose: 1.75 mg/kg/hr IV infusion for the duration of the procedure
- May be continued 4 hours post-procedure
- Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.
- Dosing Information
- Initial dose: 0.75 mg/kg IV bolus
- Maintenance dose: 1.75 mg/kg/hr IV infusion for the duration of the procedure
- May be continued 4 hours post-procedure
- Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bivalirudin in adult patients.
### Non–Guideline-Supported Use
### Adjunct to Thrombolytic Therapy in Acute Myocardial Infarction,
- Dosing Information[1]
- Initial dose: 0.25 mg/kg IV bolus'
- Followed by an infusion of 0.5 mg/kg/hr for 12 hr and then 0.25 mg/kg/hr for 36 h
- Streptokinase was given after initial bolus, as 1.5 million units infused over 30 to 60 minutes.
### Prophylaxis in Deep venous thrombosis
- Dosing Information
- 1 mg/kg SQ q8h[2]
### Prophylaxis in Heart Surgery in Patients with Heparin-induced Thrombocytopenia with Thrombosis
- CHOOSE-ON Trial[3]
- 1 mg/kg IV bolus
- Followed by 2.5 mg/kg/hour infusion continued until 15 minutes before the end of cardiopulmonary bypass.
- Additionally, bivalirudin 50 mg was added to the cardiopulmonary bypass priming solution.
- CHOOSE-OFF Trial[4]
- 0.75 mg/kg IV bolus
- Followed by continuous infusion of 1.75 mg/kg/hour.
### Thromboprophylaxis in Peripheral Arterial Bypass
- Dosing Information[5]
- 0.75 mg/kg IV bolus
- Followed by 1.75 mg/kg/hour infusion for the duration of the procedure
### Thromboprophylaxis in Unstable angina
- Dosing Information[6]
- 0.1 mg/kg IV bolus
- Followed by 0.25 mg/kg/hr
- Titrated to an activated partial thromboplastin time (aPTT) of 55 to 85 seconds to be maintained for a minimum of 72 hr.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Bivalirudin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Bivalirudin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bivalirudin in pediatric patients.
# Contraindications
- Active major bleeding
- Hypersensitivity (e.g., anaphylaxis) to bivalirudin or its components.
# Warnings
- Although most bleeding associated with the use of bivalirudin in PCI/PTCA occurs at the site of arterial puncture, hemorrhage can occur at any site.
- An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin administration.
- Bivalirudin should be used with caution in patients with disease states associated with an increased risk of bleeding.
- An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of bivalirudin in gamma brachytherapy.
- If a decision is made to use bivalirudin during brachytherapy procedures, maintain meticulous catheter technique, with frequent aspiration and flushing, paying special attention to minimizing conditions of stasis within the catheter or vessels.
# Adverse Reactions
## Clinical Trials Experience
### Bleeding
In 6010 patients undergoing PCI treated in the REPLACE-2 trial, bivalirudin patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2.
In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing bivalirudin to heparin, bivalirudin patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 3. The incidence of major bleeding was lower in the bivalirudin group than in the heparin group.
In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia.
### Other Adverse Reactions
Adverse reactions, other than bleeding, observed in clinical trials were similar between the bivalirudin treated patients and the control groups.
Adverse reactions (related adverse events ) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5.
Serious, non-bleeding adverse events were experienced in 2% of 2161 bivalirudin-treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between bivalirudin- and heparin-treated patients.
- Fever
- Infection
- Sepsis
- Hypotension
- Syncope
- Vascular anomaly
- Ventricular fibrillation
- Cerebral ischemia
- Confusion
- Facial paralysis
- Lung edema
- Kidney failure
- Oliguria
### Immunogenicity/Re-Exposure
In in vitro studies, bivalirudin exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS. Among 494 subjects who received Angiomax in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.
## Postmarketing Experience
Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during postapproval use of bivalirudin: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.
# Drug Interactions
- In clinical trials in patients undergoing PCI/PTCA, co-administration of bivalirudin with heparin, warfarin, thrombolytics, or GPIs was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications.
- There is no experience with co-administration of bivalirudin and plasma expanders such as dextran.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no evidence of impaired fertility or harm to the fetus attributable to bivalirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Bivalirudin is intended for use with aspirin. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, bivalirudin and aspirin should be used together during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bivalirudin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Bivalirudin during labor and delivery.
### Nursing Mothers
It is not known whether bivalirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when bivalirudin is administered to a nursing woman.
### Pediatric Use
The safety and effectiveness of bivalirudin in pediatric patients have not been established.
### Geriatic Use
In studies of patients undergoing PCI, 44% were ≥65 years of age and 12% of patients were ≥75 years old. Elderly patients experienced more bleeding events than younger patients. Patients treated with bivalirudin experienced fewer bleeding events in each age stratum, compared to heparin.
### Gender
There is no FDA guidance on the use of Bivalirudin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Bivalirudin with respect to specific racial populations.
### Renal Impairment
The disposition of bivalirudin was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of bivalirudin was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. The infusion dose of bivalirudin may need to be reduced, and anticoagulant status monitored in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Bivalirudin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bivalirudin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Bivalirudin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Bivalirudin is intended for intravenous bolus injection and continuous infusion after reconstitution and dilution. To each 250 mg vial, add 5 mL of sterile water for injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 50 mL of 5% dextrose in water or 0.9% sodium chloride for injection to yield a final concentration of 5 mg/mL (e.g., 1 vial in 50 mL; 2 vials in 100 mL; 5 vials in 250 mL). The dose to be administered is adjusted according to the patient's weight.
If the low-rate infusion is used after the initial infusion, a lower concentration bag should be prepared. In order to prepare this bag, reconstitute the 250 mg vial with 5 mL of sterile water for injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 5% dextrose in water or 0.9% sodium chloride for Injection to yield a final concentration of 0.5 mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 1.
Bivalirudin should be administered via an intravenous line. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of bivalirudin containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution.
### Monitoring
### Renal Impairment
No reduction in the bolus dose is needed for any degree of renal impairment. The infusion dose of bivalirudin may need to be reduced, and anticoagulant status monitored in patients with renal impairment. Patients with moderate renal impairment (30-59 mL/min) should receive an infusion of 1.75 mg/kg/h. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1 mg/kg/h should be considered. If a patient is on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/h
# IV Compatibility
The following drugs should not be administered in the same intravenous line with bivalirudin , since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with bivalirudin: alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl. Dobutamine was compatible at concentrations up to 4 mg/mL but incompatible at a concentration of 12.5 mg/mL.
# Overdosage
- Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of bivalirudin have been reported in clinical trials and in postmarketing reports.
- A number of the reported overdoses were due to failure to adjust the infusion dose of bivalirudin in persons with renal dysfunction including persons on hemodialysis.
- Bleeding, as well as deaths due to hemorrhage, have been observed in some reports of overdose.
- In cases of suspected overdosage, discontinue bivalirudin immediately and monitor the patient closely for signs of bleeding. There is no antidote to bivalirudin. Bivalirudin is hemodialyzable.
# Pharmacology
## Mechanism of Action
Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.
In in vitro studies, bivalirudin inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown.
## Structure
Bivalirudin is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name is D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-L-leucine trifluoroacetate (salt) hydrate (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide).
## Pharmacodynamics
In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine PTCA), bivalirudin exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of bivalirudin produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration.
In 291 patients with ≥70% vessel occlusion undergoing routine PTCA , a positive correlation was observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300 sec or 350 sec. At an bivalirudin dose of 1 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.
## Pharmacokinetics
Bivalirudin exhibits linear pharmacokinetics following IV administration to patients undergoing PTCA. In these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 mcg/mL is achieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells. bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of 25 min.
The disposition of bivalirudin was studied in PTCA patients with mild, moderate, and severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with normal renal function and with mild renal impairment (60-89 mL/min). Clearance was reduced in patients with moderate and severe renal impairment and in dialysis-dependent patients.
Bivalirudin is hemodialyzable, with approximately 25% cleared by hemodialysis.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of bivalirudin up to 150 mg/kg/day, about 1.6 times the dose on a body surface area basis (mg/m2) of a 50 kg person given the maximum recommended dose of 15 mg/kg/day.
# Clinical Studies
### PCI/PTCA
Bivalirudin has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6062 of the patients in these trials - mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty, atherectomy or other procedures were performed in the remaining patients.
### REPLACE-2 Trial
This was a randomized, double-blind, multicenter study reporting 6002 (intent-to-treat) patients undergoing PCI. Patients were randomized to treatment with bivalirudin with the "provisional" use of platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a "provisional" basis to patients who were randomized to bivalirudin in the following circumstances:
- decreased TIMI flow (0 to 2) or slow reflow;
- dissection with decreased flow;
- new or suspected thrombus;
- persistent residual stenosis;
- distal embolization;
- unplanned stent;
- suboptimal stenting;
- side branch closure;
- abrupt closure; clinical instability; and
- prolonged ischemia.
During the study, one or more of these circumstances occurred in 12.7% of patients in the bivalirudin with provisional GPI arm. GPIs were administered to 7.2% of patients in the bivalirudin with provisional GPI arm (62.2% of eligible patients).
Patients ranged in age from 25-95 years (median, 63); weight ranged from 35-199 kg (median 85.5); 74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.
Bivalirudin was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 0.3 mg/kg was given. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 20 units/kg was given. GPIs (either abciximab or eptifibatide) were given according to manufacturers' instructions. Both randomized groups could be given "provisional" treatments during the PCI at investigator discretion, but under double-blind conditions. "Provisional" treatment with GPI was requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2% patients randomized to bivalirudin with provisional GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).
The percent of patients reaching protocol-specified levels of anticoagulation was greater in the bivalirudin with provisional GPI group than in the heparin plus GPI group. For patients randomized to bivalirudin with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (bivalirudin group) and 276 sec (heparin plus GPI group).
For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%)(95% confidence interval 6.7%-8.6%) in the bivalirudin with "provisional" GPI arm when compared to the heparin plus GPI arm (7.1%)(95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the bivalirudin with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 7.
At 12 months' follow-up, mortality was 1.9% among patients randomized to bivalirudin with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.
### Bivalirudin Angioplasty Trial (BAT)
bivalirudin was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with bivalirudin or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to bivalirudin were started on an intravenous infusion of bivalirudin (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to bivalirudin (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The bivalirudin dose was not titrated to ACT. Median ACT values were: ACT in sec (5th percentile-95th percentile): 345 sec (240-595 sec) at 5 min and 346 sec (range 269-583 sec) at 45 min after initiation of dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under double-blinded conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blind bolus of heparin (60 IU/kg) was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. All ACTs were determined with the Hemochron® device. The protocol allowed use of open-label heparin at the discretion of the investigator after discontinuation of blinded study medication, whether or not an endpoint event (procedural failure) had occurred. The use of open-label heparin was similar between bivalirudin and heparin treatment groups (about 20% in both groups).
The studies were designed to demonstrate the safety and efficacy of bivalirudin in patients undergoing PTCA as a treatment for unstable angina as compared with a control group of similar patients receiving heparin during and up to 24 hours after initiation of PTCA. The primary protocol endpoint was a composite endpoint called procedural failure, which included both clinical and angiographic elements measured during hospitalization. The clinical elements were: the occurrence of death, MI, or urgent revascularization, adjudicated under double-blind conditions. The angiographic elements were: impending or abrupt vessel closure. The protocol-specified safety endpoint was major hemorrhage.
The median duration of hospitalization was 4 days for both the bivalirudin and the heparin treatment groups. The rates of procedural failure were similar in the bivalirudin and heparin treatment groups. Study outcomes are shown in Table 8.
### AT-BAT Trial
This was a single-group open-label study which enrolled 51 patients with heparin-induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Evidence for the diagnosis of HIT/HITTS was based on a clinical history of a decrease of platelets in patients after heparin administration [new diagnosis or history of clinically suspected or objectively documented HIT/HITTS defined as either: 1) HIT: positive heparin-induced platelet aggregation (HIPA) or other functional assay where the platelet count has decreased to <100,000/mL (minimum 30% from prior to heparin), or has decreased to <150,000/mL (minimum 40% from prior to heparin), or has decreased as above within hours of receiving heparin in a patient with a recent, previous exposure to heparin; 2) HITTS: thrombocytopenia as above plus arterial or venous thrombosis diagnosed by physician examination/laboratory and/or appropriate imaging studies]. Patients ranged in age from 48-89 years (median 70); weight ranged from 42-123 kg (median 76); 50% were male and 50% were female. Bivalirudin was administered as either 1 mg/kg bolus followed by 2.5 mg/kg/h (high dose in 28 patients) or 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion (lower dose in 25 patients) for up to 4 hours. Ninety-eight percent of patients received aspirin, 86% received clopidogrel and 19% received GPIs.
The median ACT values at the time of device activation were 379 sec (high dose) and 317 sec (lower dose). Following the procedure, 48 of the 51 patients (94%) had TIMI grade 3 flow and stenosis <50%. One patient died during a bradycardic episode 46 hours after successful PCI, another patient required surgical revascularization, and one patient experienced no flow requiring a temporary intra-aortic balloon.
Two of the fifty-one patients with the diagnosis of HIT/HITTS developed thrombocytopenia after receiving bivalirudin and GPIs.
# How Supplied
Bivalirudin is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of bivalirudin.
- NDC 65293-001-01
## Storage
Store bivalirudin dosage units at 20-25°C (68-77°F). Excursions to 15-30°C permitted.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.
- Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter medications or herbal products, prior to bivalirudin use.
- Examples of other medications that should not be taken with bivalirudin are warfarin and heparin.
# Precautions with Alcohol
Alcohol-Bivalirudin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Angiomax
# Look-Alike Drug Names
There is limited information regarding Bivalirudin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Angiomax | |
9347577433fbc4c628d5dc658e964b7ed45c22f0 | wikidoc | Angioplasty | Angioplasty
# Overview
Angioplasty is the mechanical widening of a narrowed or totally obstructed blood vessel. These obstructions are often caused by atherosclerosis. The term angioplasty is a portmanteau of the words "angio" (from the Latin/Greek word meaning "vessel") and "plasticos" (Greek: fit for moulding). Angioplasty has come to include all manner of vascular interventions typically performed in a minimally invasive or percutaneous method.
# Coronary Angioplasty
The distal left main coronary artery (LMCA) is in the left upper quadrant of the image. Its main branches (also visible) are the left circumflex artery (LCX), which courses top-to-bottom initially and then toward the centre-bottom, and the left anterior descending (LAD) artery, which courses from left-to-right on the image and then courses down the middle of the image to project underneath of the distal LCX. The LAD, as is usual, has two large diagonal branches, which arise at the centre- top of the image and course toward the centre- right of the image.
Percutaneous coronary intervention (PCI), commonly known as coronary angioplasty is a therapeutic procedure to treat the stenotic (narrowed) coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques that form due to atherosclerosis. PCI is usually performed by an interventional cardiologist.
# Peripheral Angioplasty
Peripheral angioplasty refers to the use of mechanical widening in opening blood vessels other than the coronary arteries. It is often called percutaneous transluminal angioplasty or PTA for short. PTA is most commonly done to treat narrowings in the leg arteries, especially the common iliac, external iliac, superficial femoral and popliteal arteries. PTA can also be done to treat narrowings in veins.
# Renal Artery Angioplasty
Atherosclerotic obstruction of the renal artery can be treated with angioplasty of the renal artery (percutaneous transluminal renal angioplasty, PTRA). Renal artery stenosis can lead to hypertension and loss of renal function.
# Carotid Angioplasty
Generally, carotid artery stenosis is treated with angioplasty and stenting for high-risk patients in many hospitals. It has changed since the FDA has approved the first carotid stent system (Cordis) in July 2004 and the second (Guidant) in August 2004. The system comprises a stent along with an embolic capture device designed to reduce or trap emboli and clot debris. Angioplasty and stenting is increasingly being used to also treat carotid stenosis, with success rates similar to carotid endarterectomy surgery. Simple angioplasty without stenting is falling out of favor in this vascular bed. SAPPHIRE, a large trial comparing carotid endarterectomy and carotid stenting with the Cordis stent found stenting non-inferior to carotid endarterectomy.
# 2011 ACCF/AHA Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)
## Laser Angioplasty (DO NOT EDIT)
## Cutting Balloon Angioplasty (DO NOT EDIT)
# Related Chapters
- Percutaneous coronary intervention
- Angiogram
- Charles Dotter
- Vascular surgery | Angioplasty
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Angioplasty is the mechanical widening of a narrowed or totally obstructed blood vessel. These obstructions are often caused by atherosclerosis. The term angioplasty is a portmanteau of the words "angio" (from the Latin/Greek word meaning "vessel") and "plasticos" (Greek: fit for moulding). Angioplasty has come to include all manner of vascular interventions typically performed in a minimally invasive or percutaneous method.
# Coronary Angioplasty
The distal left main coronary artery (LMCA) is in the left upper quadrant of the image. Its main branches (also visible) are the left circumflex artery (LCX), which courses top-to-bottom initially and then toward the centre-bottom, and the left anterior descending (LAD) artery, which courses from left-to-right on the image and then courses down the middle of the image to project underneath of the distal LCX. The LAD, as is usual, has two large diagonal branches, which arise at the centre- top of the image and course toward the centre- right of the image.
Percutaneous coronary intervention (PCI), commonly known as coronary angioplasty is a therapeutic procedure to treat the stenotic (narrowed) coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques that form due to atherosclerosis. PCI is usually performed by an interventional cardiologist.
# Peripheral Angioplasty
Peripheral angioplasty refers to the use of mechanical widening in opening blood vessels other than the coronary arteries. It is often called percutaneous transluminal angioplasty or PTA for short. PTA is most commonly done to treat narrowings in the leg arteries, especially the common iliac, external iliac, superficial femoral and popliteal arteries. PTA can also be done to treat narrowings in veins.
# Renal Artery Angioplasty
Atherosclerotic obstruction of the renal artery can be treated with angioplasty of the renal artery (percutaneous transluminal renal angioplasty, PTRA). Renal artery stenosis can lead to hypertension and loss of renal function.
# Carotid Angioplasty
Generally, carotid artery stenosis is treated with angioplasty and stenting for high-risk patients in many hospitals. It has changed since the FDA has approved the first carotid stent system (Cordis) in July 2004 and the second (Guidant) in August 2004. The system comprises a stent along with an embolic capture device designed to reduce or trap emboli and clot debris. Angioplasty and stenting is increasingly being used to also treat carotid stenosis, with success rates similar to carotid endarterectomy surgery. Simple angioplasty without stenting is falling out of favor in this vascular bed. SAPPHIRE, a large trial comparing carotid endarterectomy and carotid stenting with the Cordis stent found stenting non-inferior to carotid endarterectomy.[1]
# 2011 ACCF/AHA Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)[2]
## Laser Angioplasty (DO NOT EDIT)[2]
## Cutting Balloon Angioplasty (DO NOT EDIT)[2]
# Related Chapters
- Percutaneous coronary intervention
- Angiogram
- Charles Dotter
- Vascular surgery
# External Links
- National Heart Lung and Blood Institute, Diseases and Conditions Index | https://www.wikidoc.org/index.php/Angioplasty | |
83339fc3f29a92c4cedc6907ccfbaa2b9f42acc1 | wikidoc | Angiostatin | Angiostatin
Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor (i.e., it blocks the growth of new blood vessels), and it is currently undergoing clinical trials for its use in anticancer therapy.
# Structure
Angiostatin is a 38 kDa fragment of a larger protein, plasmin (itself a fragment of plasminogen) enclosing three to five contiguous Kringle modules. Each module contains two small beta sheets and three disulfide bonds.
# Generation
Angiostatin is produced, for example, by autoproteolytic cleavage of plasminogen, involving extracellular disulfide bond reduction by phosphoglycerate kinase. Furthermore angiostatin can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.
# Biological activity
Angiostatin is known to bind a lot of proteins, especially to angiomotin and endothelial cell surface ATP synthase but also integrins, annexin II, C-met receptor, NG2-proteoglycans, tissue-type plasminogen activator, chondroitin sulfate proteoglycans, and CD26. Also smaller fragments of angiostatin has been shown to bind several other proteins. There is still considerable uncertainty on its mechanism of action, but it seems to involve for example inhibition of endothelial cell migration, proliferation and induction of apoptosis. It has been proposed that angiostatin activity is related, among other things, to the coupling of its mechanical and redox properties | Angiostatin
Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor (i.e., it blocks the growth of new blood vessels), and it is currently undergoing clinical trials for its use in anticancer therapy.[1]
# Structure
Angiostatin is a 38 kDa fragment of a larger protein, plasmin (itself a fragment of plasminogen) enclosing three to five contiguous Kringle modules. Each module contains two small beta sheets and three disulfide bonds. [2] [3]
# Generation
Angiostatin is produced, for example, by autoproteolytic cleavage of plasminogen, involving extracellular disulfide bond reduction by phosphoglycerate kinase. Furthermore angiostatin can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.
# Biological activity
Angiostatin is known to bind a lot of proteins, especially to angiomotin and endothelial cell surface ATP synthase but also integrins, annexin II, C-met receptor, NG2-proteoglycans, tissue-type plasminogen activator, chondroitin sulfate proteoglycans, and CD26. Also smaller fragments of angiostatin has been shown to bind several other proteins. There is still considerable uncertainty on its mechanism of action, but it seems to involve for example inhibition of endothelial cell migration,[4] proliferation and induction of apoptosis. It has been proposed that angiostatin activity is related, among other things, to the coupling of its mechanical and redox properties [5] | https://www.wikidoc.org/index.php/Angiostatin |
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