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e953e93ffd24df1c803fc332b7984ffdb7f20589 | wikidoc | Ipilimumab | Ipilimumab
# 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
Ipilimumab is an monoclonal antibody that is FDA approved for the treatment of unresectable or metastatic melanoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, colitis, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ipilimumab is indicated for the treatment of unresectable or metastatic melanoma.
- Dosage: 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of ipilimumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of ipilimumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ipilimumab 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 ipilimumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of ipilimumab in pediatric patients.
# Contraindications
None
# Warnings
Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation.
### Immune-mediated Enterocolitis
- In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) ipilimumab-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) ipilimumab-treated patients. Across all ipilimumab-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.
- The median time to onset was 7.4 weeks (range: 1.6–13.4) and 6.3 weeks (range: 0.3–18.9) after the initiation of ipilimumab for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.
- Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.
- Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.
- Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
- Permanently discontinue ipilimumab in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.
- Withhold ipilimumab dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent.
### Immune-mediated Hepatitis
- In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) ipilimumab-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of ipilimumab-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.
- Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of ipilimumab. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
- Permanently discontinue ipilimumab in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for ipilimumab, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold ipilimumab in patients with Grade 2 hepatotoxicity.
- In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
### Immune-mediated Dermatitis
- In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) ipilimumab-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.
- The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of ipilimumab.
- Seven (54%) ipilimumab-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.
- Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
- Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
- Permanently discontinue ipilimumab in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold ipilimumab dosing in patients with moderate to severe signs and symptoms.
- For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
### Immune-mediated Neuropathies
- In Study 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of ipilimumab, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
- Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue ipilimumab in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold ipilimumab dosing in patients with moderate neuropathy (not interfering with daily activities).
### Immune-mediated Endocrinopathies
- In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) ipilimumab-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of ipilimumab.
- Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).
- Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
- Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
- Withhold ipilimumab dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy.
### Other Immune-mediated Adverse Reactions, Including Ocular Manifestations
- The following clinically significant immune-mediated adverse reactions were seen in less than 1% of ipilimumab-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.
- Across the clinical development program for ipilimumab, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis.
- Permanently discontinue ipilimumab for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
- Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.
# Adverse Reactions
## Clinical Trials Experience
- Immune-mediated enterocolitis
- Immune-mediated hepatitis
- Immune-mediated dermatitis
- Immune-mediated neuropathies
- Immune-mediated endocrinopathies
- Other immune-mediated adverse reactions, including ocular manifestations
## Postmarketing Experience
There is limited information regarding Ipilimumab Postmarketing Experience in the drug label.
# Drug Interactions
No formal pharmacokinetic drug interaction studies have been conducted with ipilimumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of ipilimumab in pregnant women. Use ipilimumab during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, at exposure levels either 2.6 or 7.2 times higher by AUC than the exposures at the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab treated groups experienced higher incidences of severe toxicities including abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls.
Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ipilimumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ipilimumab during labor and delivery.
### Nursing Mothers
It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from ipilimumab, a decision should be made whether to discontinue nursing or to discontinue ipilimumab, taking into account the importance of ipilimumab to the mother.
### Pediatric Use
Safety and effectiveness of ipilimumab have not been established in pediatric patients.
### Geriatic Use
Of the 511 patients treated with ipilimumab at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
### Gender
There is no FDA guidance on the use of Ipilimumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ipilimumab with respect to specific racial populations.
### Renal Impairment
No dose adjustment is needed for patients with renal impairment.
### Hepatic Impairment
No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin >1.0 × to 1.5 × the upper limit of normal or AST >ULN). Ipilimumab has not been studied in patients with moderate (TB >1.5 × to 3.0 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment.
### Females of Reproductive Potential and Males
Fertility studies have not been performed with ipilimumab.
### Immunocompromised Patients
There is no FDA guidance one the use of Ipilimumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Ipilimumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ipilimumab and IV administrations.
# Overdosage
There is no information on overdosage with ipilimumab
# Pharmacology
## Mechanism of Action
CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
## Structure
Is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.
## Pharmacodynamics
There is limited information regarding pharmacodynamics of ipilimumab
## Pharmacokinetics
The pharmacokinetics of ipilimumab were studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. Peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve (AUC) of ipilimumab increased dose proportionally within the dose range examined. Upon repeated dosing every 3 weeks, the clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady-state was 19.4 mcg/mL following repeated doses of 3 mg/kg. The mean value (% coefficient of variation) generated through population pharmacokinetic analysis for the terminal half-life (t1/2) was 15.4 days (34%) and for CL was 16.8 mL/h (38%).
### Specific Populations
The effects of various covariates on the pharmacokinetics of ipilimumab were assessed in population pharmacokinetic analyses. The CL of ipilimumab increased with increasing body weight; however, no dose adjustment is recommended for body weight after administration on a mg/kg basis. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23–88 years), gender, performance status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-Caucasian ethnic groups.
### Renal Impairment
The effect of renal impairment on the CL of ipilimumab was evaluated in patients with mild (GFR <90 and ≥60 mL/min/1.73 m2; n=349), moderate (GFR <60 and ≥30 mL/min/1.73 m2; n=82), or severe (GFR <30 and ≥15 mL/min/1.73 m2; n=4) renal impairment compared to patients with normal renal function (GFR ≥90 mL/min/1.73 m2; n=350) in population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function.
### Hepatic Impairment
The effect of hepatic impairment on the CL of ipilimumab was evaluated in patients with mild hepatic impairment (TB 1.0 × to 1.5 × ULN or AST >ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=76) compared to patients with normal hepatic function (TB and AST ≤ULN; n=708) in the population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function. ipilimumab has not been studied in patients with moderate (TB >1.5 × to 3 × ULN and any AST) or severe hepatic impairment (TB >3 × ULN and any AST).
## Nonclinical Toxicology
### Carcinogenesis
The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies.
### Mutagenesis
The genotoxic potential of ipilimumab has not been evaluated.
### Animal Toxicology and/or Pharmacology
- In addition to the severe findings of abortion, stillbirths, and postnatal deaths observed in pregnant cynomolgus monkeys that received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the clinically recommended dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.
- Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3–4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
# Clinical Studies
The safety and efficacy of ipilimumab were investigated in a randomized (3:1:1), double-blind, double-dummy study (Study 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive ipilimumab at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive ipilimumab at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. ipilimumab/placebo was administered at 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses. Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses. Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.
The major efficacy outcome measure was overall survival (OS) in the ipilimumab+gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the ipilimumab+gp100 arm compared to the ipilimumab arm, OS in the ipilimumab arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the study arms, and duration of response.
Of the randomized patients, 61%, 59%, and 54% in the ipilimumab+gp100, ipilimumab, and gp100 arms, respectively, were men. Twenty-nine percent were ≥65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either ipilimumab-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months.
The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the ipilimumab+gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the ipilimumab arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of response was 11.5 months in the ipilimumab+gp100 arm and has not been reached in the ipilimumab or gp100 arm.
# How Supplied
50 mg vial (5 mg/mL), single-use vial
- NDC 0003-2327-11
200 mg vial (5 mg/mL), single-use vial
- NDC 0003-2328-22
## Storage
Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the potential risk of immune-mediated adverse reactions.
- Advise patients to read the ipilimumab Medication Guide before each ipilimumab infusion.
- Advise women that ipilimumab may cause fetal harm.
- Advise nursing mothers not to breastfeed while taking ipilimumab.
# Precautions with Alcohol
Alcohol-ipilimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Yervoy
# Look-Alike Drug Names
There is limited information regarding Ipilimumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ipilimumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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
Ipilimumab is an monoclonal antibody that is FDA approved for the treatment of unresectable or metastatic melanoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, colitis, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ipilimumab is indicated for the treatment of unresectable or metastatic melanoma.
- Dosage: 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of ipilimumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of ipilimumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ipilimumab 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 ipilimumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of ipilimumab in pediatric patients.
# Contraindications
None
# Warnings
Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation.
### Immune-mediated Enterocolitis
- In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) ipilimumab-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) ipilimumab-treated patients. Across all ipilimumab-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.
- The median time to onset was 7.4 weeks (range: 1.6–13.4) and 6.3 weeks (range: 0.3–18.9) after the initiation of ipilimumab for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.
- Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.
- Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.
- Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
- Permanently discontinue ipilimumab in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.
- Withhold ipilimumab dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent.
### Immune-mediated Hepatitis
- In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) ipilimumab-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of ipilimumab-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.
- Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of ipilimumab. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
- Permanently discontinue ipilimumab in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for ipilimumab, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold ipilimumab in patients with Grade 2 hepatotoxicity.
- In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
### Immune-mediated Dermatitis
- In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) ipilimumab-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.
- The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of ipilimumab.
- Seven (54%) ipilimumab-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.
- Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
- Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
- Permanently discontinue ipilimumab in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold ipilimumab dosing in patients with moderate to severe signs and symptoms.
- For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
### Immune-mediated Neuropathies
- In Study 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of ipilimumab, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
- Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue ipilimumab in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold ipilimumab dosing in patients with moderate neuropathy (not interfering with daily activities).
### Immune-mediated Endocrinopathies
- In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) ipilimumab-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of ipilimumab.
- Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).
- Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
- Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
- Withhold ipilimumab dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy.
### Other Immune-mediated Adverse Reactions, Including Ocular Manifestations
- The following clinically significant immune-mediated adverse reactions were seen in less than 1% of ipilimumab-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.
- Across the clinical development program for ipilimumab, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis.
- Permanently discontinue ipilimumab for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
- Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.
# Adverse Reactions
## Clinical Trials Experience
- Immune-mediated enterocolitis
- Immune-mediated hepatitis
- Immune-mediated dermatitis
- Immune-mediated neuropathies
- Immune-mediated endocrinopathies
- Other immune-mediated adverse reactions, including ocular manifestations
## Postmarketing Experience
There is limited information regarding Ipilimumab Postmarketing Experience in the drug label.
# Drug Interactions
No formal pharmacokinetic drug interaction studies have been conducted with ipilimumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of ipilimumab in pregnant women. Use ipilimumab during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, at exposure levels either 2.6 or 7.2 times higher by AUC than the exposures at the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab treated groups experienced higher incidences of severe toxicities including abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls.
Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ipilimumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ipilimumab during labor and delivery.
### Nursing Mothers
It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from ipilimumab, a decision should be made whether to discontinue nursing or to discontinue ipilimumab, taking into account the importance of ipilimumab to the mother.
### Pediatric Use
Safety and effectiveness of ipilimumab have not been established in pediatric patients.
### Geriatic Use
Of the 511 patients treated with ipilimumab at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
### Gender
There is no FDA guidance on the use of Ipilimumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ipilimumab with respect to specific racial populations.
### Renal Impairment
No dose adjustment is needed for patients with renal impairment.
### Hepatic Impairment
No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 × to 1.5 × the upper limit of normal [ULN] or AST >ULN). Ipilimumab has not been studied in patients with moderate (TB >1.5 × to 3.0 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment.
### Females of Reproductive Potential and Males
Fertility studies have not been performed with ipilimumab.
### Immunocompromised Patients
There is no FDA guidance one the use of Ipilimumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Ipilimumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ipilimumab and IV administrations.
# Overdosage
There is no information on overdosage with ipilimumab
# Pharmacology
## Mechanism of Action
CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
## Structure
Is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.
## Pharmacodynamics
There is limited information regarding pharmacodynamics of ipilimumab
## Pharmacokinetics
The pharmacokinetics of ipilimumab were studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. Peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve (AUC) of ipilimumab increased dose proportionally within the dose range examined. Upon repeated dosing every 3 weeks, the clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady-state was 19.4 mcg/mL following repeated doses of 3 mg/kg. The mean value (% coefficient of variation) generated through population pharmacokinetic analysis for the terminal half-life (t1/2) was 15.4 days (34%) and for CL was 16.8 mL/h (38%).
### Specific Populations
The effects of various covariates on the pharmacokinetics of ipilimumab were assessed in population pharmacokinetic analyses. The CL of ipilimumab increased with increasing body weight; however, no dose adjustment is recommended for body weight after administration on a mg/kg basis. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23–88 years), gender, performance status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-Caucasian ethnic groups.
### Renal Impairment
The effect of renal impairment on the CL of ipilimumab was evaluated in patients with mild (GFR <90 and ≥60 mL/min/1.73 m2; n=349), moderate (GFR <60 and ≥30 mL/min/1.73 m2; n=82), or severe (GFR <30 and ≥15 mL/min/1.73 m2; n=4) renal impairment compared to patients with normal renal function (GFR ≥90 mL/min/1.73 m2; n=350) in population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function.
### Hepatic Impairment
The effect of hepatic impairment on the CL of ipilimumab was evaluated in patients with mild hepatic impairment (TB 1.0 × to 1.5 × ULN or AST >ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=76) compared to patients with normal hepatic function (TB and AST ≤ULN; n=708) in the population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function. ipilimumab has not been studied in patients with moderate (TB >1.5 × to 3 × ULN and any AST) or severe hepatic impairment (TB >3 × ULN and any AST).
## Nonclinical Toxicology
### Carcinogenesis
The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies.
### Mutagenesis
The genotoxic potential of ipilimumab has not been evaluated.
### Animal Toxicology and/or Pharmacology
- In addition to the severe findings of abortion, stillbirths, and postnatal deaths observed in pregnant cynomolgus monkeys that received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the clinically recommended dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.
- Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3–4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
# Clinical Studies
The safety and efficacy of ipilimumab were investigated in a randomized (3:1:1), double-blind, double-dummy study (Study 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive ipilimumab at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive ipilimumab at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. ipilimumab/placebo was administered at 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses. Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses. Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.
The major efficacy outcome measure was overall survival (OS) in the ipilimumab+gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the ipilimumab+gp100 arm compared to the ipilimumab arm, OS in the ipilimumab arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the study arms, and duration of response.
Of the randomized patients, 61%, 59%, and 54% in the ipilimumab+gp100, ipilimumab, and gp100 arms, respectively, were men. Twenty-nine percent were ≥65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either ipilimumab-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months.
The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the ipilimumab+gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the ipilimumab arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of response was 11.5 months in the ipilimumab+gp100 arm and has not been reached in the ipilimumab or gp100 arm.
# How Supplied
50 mg vial (5 mg/mL), single-use vial
- NDC 0003-2327-11
200 mg vial (5 mg/mL), single-use vial
- NDC 0003-2328-22
## Storage
Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the potential risk of immune-mediated adverse reactions.
- Advise patients to read the ipilimumab Medication Guide before each ipilimumab infusion.
- Advise women that ipilimumab may cause fetal harm.
- Advise nursing mothers not to breastfeed while taking ipilimumab.
# Precautions with Alcohol
Alcohol-ipilimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Yervoy [1]
# Look-Alike Drug Names
There is limited information regarding Ipilimumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ipilimumab | |
761375e869e4d5f3d0a9e46459b8fd934c90b6a2 | wikidoc | Iron oxide | Iron oxide
# Overview
Altogether there are sixteen known iron oxides and oxyhydroxides.
# Oxides
- FeO, iron(II) oxide, (wüstite)
- Fe3O4, iron(II,III) oxide, (magnetite)
- Fe2O3, iron(III) oxide, (α-Fe2O3,hematite; γ-Fe2O3 maghemite)
# Hydroxides
- iron(II) hydroxide (Fe(OH)2)
- iron(III) hydroxide (Fe(OH)3), (bernalite)
# Oxide-hydroxides
- goethite (α-FeOOH),
- akaganéite (β-FeOOH),
- lepidocrocite (γ-FeOOH),
- feroxyhyte (δ-FeOOH),
- ferrihydrite (Fe5HO8·4H2O approx.)
- high-pressure FeOOH
- schwertmannite
- green rusts
# Uses
Some of these oxides are widely used in ceramic applications, particularly in glazing. Many metal oxides provide the colours in glazes after being fired at high temperatures.
Iron oxides yield pigments (see Iron oxide pigments). Natural iron oxides pigments are called ochers. Many classic paint colors, such as raw and burnt siennas and umbers, are iron-oxide pigments. These pigments have been used in art since the earliest art prehistoric art known, the cave paintings at Lascaux and nearby sites. Iron (III) oxide is typically used.
Iron pigments are also widely used in the cosmetic field. They are considered to be nontoxic, moisture resistant, and nonbleeding. Iron oxides graded safe for cosmetic use are produced synthetically in order to avoid the inclusion of ferrous or ferric oxides, and impurities normally found in naturally occurring iron oxides. Typically, the Iron(II) oxide pigment is black, while the Iron(III) oxide is red or rust-colored. (Iron compounds other than oxides can be other colors.)
Magnetite (under the name Black Oxide) is used for coating steel tools . This protects them from corrosion and gives a pleasing appearance.
# Properties
- Iron(II) oxide (FeO) or ferrous oxide is also known as wüstite in its mineral form. As a powder this black oxide can cause explosions as it readily ignites.
- Iron(III) oxide (Fe2O3) or ferric oxide is also known as hematite (alpha form) or maghemite (gamma form) in its mineral form. As an industrial chemical it is commonly called rouge. Purified, it is used as a coating in magnetic audio and computer media. In a dry or alkaline environment it can cause passivation and inhibits rust, yet it is also a major component of rust.
- Iron(II,III) oxide (Fe3O4) or ferrous ferric oxide is also known as magnetite or lodestone in its mineral form, a major iron ore. Magnetite forms readily when iron oxidizes underwater, and so is often found inside tanks or below the waterline of ships.
It is not difficult to extract iron from ore as compared to the similarly abundant elements aluminum and titanium. | Iron oxide
# Overview
Altogether there are sixteen known iron oxides and oxyhydroxides.[1]
# Oxides
- FeO, iron(II) oxide, (wüstite)
- Fe3O4, iron(II,III) oxide, (magnetite)
- Fe2O3, iron(III) oxide, (α-Fe2O3,hematite; γ-Fe2O3 maghemite)
# Hydroxides
- iron(II) hydroxide (Fe(OH)2)
- iron(III) hydroxide (Fe(OH)3), (bernalite)
# Oxide-hydroxides
- goethite (α-FeOOH),
- akaganéite (β-FeOOH),
- lepidocrocite (γ-FeOOH),
- feroxyhyte (δ-FeOOH),
- ferrihydrite (Fe5HO8·4H2O approx.)
- high-pressure FeOOH
- schwertmannite
- green rusts
# Uses
Some of these oxides are widely used in ceramic applications, particularly in glazing. Many metal oxides provide the colours in glazes after being fired at high temperatures.
Iron oxides yield pigments (see Iron oxide pigments). Natural iron oxides pigments are called ochers. Many classic paint colors, such as raw and burnt siennas and umbers, are iron-oxide pigments. These pigments have been used in art since the earliest art prehistoric art known, the cave paintings at Lascaux and nearby sites. Iron (III) oxide is typically used.
Iron pigments are also widely used in the cosmetic field. They are considered to be nontoxic, moisture resistant, and nonbleeding. Iron oxides graded safe for cosmetic use are produced synthetically in order to avoid the inclusion of ferrous or ferric oxides, and impurities normally found in naturally occurring iron oxides. Typically, the Iron(II) oxide pigment is black, while the Iron(III) oxide is red or rust-colored. (Iron compounds other than oxides can be other colors.)
Magnetite (under the name Black Oxide) is used for coating steel tools [2]. This protects them from corrosion and gives a pleasing appearance.
# Properties
- Iron(II) oxide (FeO) or ferrous oxide is also known as wüstite in its mineral form. As a powder this black oxide can cause explosions as it readily ignites.
- Iron(III) oxide (Fe2O3) or ferric oxide is also known as hematite (alpha form) or maghemite (gamma form) in its mineral form. As an industrial chemical it is commonly called rouge. Purified, it is used as a coating in magnetic audio and computer media. In a dry or alkaline environment it can cause passivation and inhibits rust, yet it is also a major component of rust.
- Iron(II,III) oxide (Fe3O4) or ferrous ferric oxide is also known as magnetite or lodestone in its mineral form, a major iron ore. Magnetite forms readily when iron oxidizes underwater, and so is often found inside tanks or below the waterline of ships.
It is not difficult to extract iron from ore as compared to the similarly abundant elements aluminum and titanium. | https://www.wikidoc.org/index.php/Iron_oxide | |
56c5ccf200b37347063034d5d3faa115dc012baf | wikidoc | Irritation | Irritation
# Overview
Irritation or exacerbation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant. Irritants are typically thought of as chemical agents (for example phenol and capsaicin) but mechanical, thermal (heat) and radiative stimuli (for example ultraviolet light or ionising radiations) can also cause irritation.
Irritation also has non-clinical usages referring to bothersome physical or psychological pain or discomfort.
# Irritation in organisms
In higher organisms, the allergic response may be cause of irritation. An allergen is defined distinctly from an irritant, however, as allergy requires a specific interaction with the immune system and is thus dependent on the (possibly unique) sensitivity of the organism involved while an irritant, classically, acts in a non-specific manner.
In humans, it is a mild form of suffering, often with anger about the suffering; in particular, if applicable, anger at the person who caused it. This can also be oneself, e.g. when forgetting something or doing something one deems to be stupid.
It is a form of stress, but conversely, if one is stressed by unrelated matters, mild imperfections can cause more irritation than usual: one is irritable; see also sensitivity (human).
In more basic organisms, assigning irritation the status of pain is the perception of the being stimulated - which is not observable although it may be shared (see gate control theory of pain).
It is not proven that oysters can feel pain, but it is known that they react to irritation. When an irritating object becomes trapped within an oyster's shell, it deposits layers of calcium carbonate (CaCO3), slowly increasing in size and producing a pearl. This serves no purpose to the oyster, pearls do not attract mates for the oyster or perform any other function. It seems impossible to find an evolutionary advantage for the ability to produce the pearl, thus it can be explained only as a reaction to an irritation.
It has also been observed that an amoeba avoids being prodded with a pin, but there is not enough evidence to suggest how much it feels this. Irritation is apparently the only universal sense shared by even single-celled creatures.
It is postulated that most such beings also feel pain, but this is a projection - empathy. Some philosophers, notably René Descartes, denied it entirely, even for such higher mammals as dogs or primates like monkeys - Descartes considered intelligence a pre-requisite for the feeling of pain. | Irritation
# Overview
Irritation or exacerbation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant. Irritants are typically thought of as chemical agents (for example phenol and capsaicin) but mechanical, thermal (heat) and radiative stimuli (for example ultraviolet light or ionising radiations) can also cause irritation.
Irritation also has non-clinical usages referring to bothersome physical or psychological pain or discomfort.
# Irritation in organisms
In higher organisms, the allergic response may be cause of irritation. An allergen is defined distinctly from an irritant, however, as allergy requires a specific interaction with the immune system and is thus dependent on the (possibly unique) sensitivity of the organism involved while an irritant, classically, acts in a non-specific manner.
In humans, it is a mild form of suffering, often with anger about the suffering; in particular, if applicable, anger at the person who caused it. This can also be oneself, e.g. when forgetting something or doing something one deems to be stupid.
It is a form of stress, but conversely, if one is stressed by unrelated matters, mild imperfections can cause more irritation than usual: one is irritable; see also sensitivity (human).
In more basic organisms, assigning irritation the status of pain is the perception of the being stimulated - which is not observable although it may be shared (see gate control theory of pain).
It is not proven that oysters can feel pain, but it is known that they react to irritation. When an irritating object becomes trapped within an oyster's shell, it deposits layers of calcium carbonate (CaCO3), slowly increasing in size and producing a pearl. This serves no purpose to the oyster, pearls do not attract mates for the oyster or perform any other function. It seems impossible to find an evolutionary advantage for the ability to produce the pearl, thus it can be explained only as a reaction to an irritation.
It has also been observed that an amoeba avoids being prodded with a pin, but there is not enough evidence to suggest how much it feels this. Irritation is apparently the only universal sense shared by even single-celled creatures.
It is postulated that most such beings also feel pain, but this is a projection - empathy. Some philosophers, notably René Descartes, denied it entirely, even for such higher mammals as dogs or primates like monkeys - Descartes considered intelligence a pre-requisite for the feeling of pain. | https://www.wikidoc.org/index.php/Irritable | |
61944de6e717b9ba02073963b459f544476fd4a5 | wikidoc | Isepamicin | Isepamicin
Synonyms and keywords: Isepamycin
# Overview
Isepamicin is an aminoglycoside antibiotic. It has been used in the treatment of skin, upper respiratory tract, lower respiratory tract, and urinary tract infections caused by Gram-negative bacteria (including Pseudomonas aeruginosa, Proteobacteria, and Escherichia coli).
# Category
Aminoglycoside
# Brand Names
EXACIN®, ISEPACIN®, ISEPACINE®, ISEPALLINE® (not currently available in the U.S.)
# Prescribing Information
### Clinical Pharmacology
General pharmacological properties of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, were studied in animals and the results obtained were summarized below. Intramuscular injections of HAPA-B at doses of 500 mg/kg inhibited the writing response induced by acetic acid, and at doses of 1,000 mg/kg, caused muscle relaxation, respiratory depression, suppression of spontaneous motor activity and prolongation of thiopental anesthesia. Anticonvulsive action and the effect on the rectal temperature were not observed.
Intravenous Intravenous HAPA-B showed no significant effect on the general behavior and the function of the central nervous system at doses of 100 mg/kg. Intravenous injections of HAPA-B to anesthetized dogs resulted increases in the femoral arterial blood flow at doses of 12.5 mg/kg, decrease in the blood pressure and increase in the respiratory rate at doses of 25 mg/kg, and increase in the carotid arterial blood flow at doses of 50 mg/kg. Apparent changes were not recognized in the heart rate and electrocardiograms. In conscious rabbits, intravenous HAPA-B produced increases in the heart rate without significant changes of the blood pressure and electrocardiograms at doses of 100 mg/kg. Spontaneous beatings of isolated atria were depressed by HAPA-B in concentrations of 3 X 10(-4) to 10(-3) g/ml. The HAPA-B inhibited the gastric secretion at intramuscular doses of 500 mg/kg or intravenous doses of 100 mg/kg, and depressed charcoal transport through small intestine and the spontaneous movement of isolated ileum at intramuscular doses of 1,000 mg/kg and at concentrations of 3 X 10(-4) to 10(-3) g/ml, respectively. No irritative effect was found on the gastric mucous membrane. Intravenous HAPA-B inhibited the response of nictitating membrane to pre and post ganglionic stimulations of cervical sympathetic nerve at doses of 100 mg/kg. In in vitro test, HAPA-B inhibited nonspecifically the constrictive responses of trachea, aorta, stomach, ileum and vas deferens to various agonists in concentrations of 3 X 10(-4) to 10(-3) g/ml. Spontaneous movements of uteri of estrous or pregnant animals were depressed by HAPA-B at intravenous doses of 50 to 100 mg/kg and in in vitro at concentrations of 10(-4) to 3 X 10(-4) g/ml. Antidiuretic effect was also observed at intramuscular doses of 250 mg/kg. HAPA-B increased the length of the whole blood clotting time and raised the plasma glucose level at intramuscular doses of 1,000 mg/kg and inhibited the platelet aggregation induced by ADP in vitro at concentrations of 10(-3) g/ml.
### Chemical Structure
Molecular Formula: C22H45N5O16S
### Reported Use
Treatment of susceptible bacterial infections
### Dosage
- Adults: I.M., I.V.: 8-15 mg/kg daily in 2 divided doses; maximum: 1.5 g/day
### Dosage Forms
Injection, solution: 250 mg/mL (1 mL, 2 mL)
# Mechanism of Action
Isepamicin is an aminoglycoside which inhibits bacterial protein synthesis by binding to 30S and 50S ribosomal subunits in susceptible micro-organisms. | Isepamicin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Isepamycin
# Overview
Isepamicin is an aminoglycoside antibiotic. It has been used in the treatment of skin, upper respiratory tract, lower respiratory tract, and urinary tract infections caused by Gram-negative bacteria (including Pseudomonas aeruginosa, Proteobacteria, and Escherichia coli).
# Category
Aminoglycoside
# Brand Names
EXACIN®, ISEPACIN®, ISEPACINE®, ISEPALLINE® (not currently available in the U.S.)
# Prescribing Information
### Clinical Pharmacology
General pharmacological properties of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, were studied in animals and the results obtained were summarized below. Intramuscular injections of HAPA-B at doses of 500 mg/kg inhibited the writing response induced by acetic acid, and at doses of 1,000 mg/kg, caused muscle relaxation, respiratory depression, suppression of spontaneous motor activity and prolongation of thiopental anesthesia. Anticonvulsive action and the effect on the rectal temperature were not observed.
Intravenous Intravenous HAPA-B showed no significant effect on the general behavior and the function of the central nervous system at doses of 100 mg/kg. Intravenous injections of HAPA-B to anesthetized dogs resulted increases in the femoral arterial blood flow at doses of 12.5 mg/kg, decrease in the blood pressure and increase in the respiratory rate at doses of 25 mg/kg, and increase in the carotid arterial blood flow at doses of 50 mg/kg. Apparent changes were not recognized in the heart rate and electrocardiograms. In conscious rabbits, intravenous HAPA-B produced increases in the heart rate without significant changes of the blood pressure and electrocardiograms at doses of 100 mg/kg. Spontaneous beatings of isolated atria were depressed by HAPA-B in concentrations of 3 X 10(-4) to 10(-3) g/ml. The HAPA-B inhibited the gastric secretion at intramuscular doses of 500 mg/kg or intravenous doses of 100 mg/kg, and depressed charcoal transport through small intestine and the spontaneous movement of isolated ileum at intramuscular doses of 1,000 mg/kg and at concentrations of 3 X 10(-4) to 10(-3) g/ml, respectively. No irritative effect was found on the gastric mucous membrane. Intravenous HAPA-B inhibited the response of nictitating membrane to pre and post ganglionic stimulations of cervical sympathetic nerve at doses of 100 mg/kg. In in vitro test, HAPA-B inhibited nonspecifically the constrictive responses of trachea, aorta, stomach, ileum and vas deferens to various agonists in concentrations of 3 X 10(-4) to 10(-3) g/ml. Spontaneous movements of uteri of estrous or pregnant animals were depressed by HAPA-B at intravenous doses of 50 to 100 mg/kg and in in vitro at concentrations of 10(-4) to 3 X 10(-4) g/ml. Antidiuretic effect was also observed at intramuscular doses of 250 mg/kg. HAPA-B increased the length of the whole blood clotting time and raised the plasma glucose level at intramuscular doses of 1,000 mg/kg and inhibited the platelet aggregation induced by ADP in vitro at concentrations of 10(-3) g/ml.[1]
### Chemical Structure
Molecular Formula: C22H45N5O16S[1]
### Reported Use
Treatment of susceptible bacterial infections[1]
### Dosage
- Adults: I.M., I.V.: 8-15 mg/kg daily in 2 divided doses; maximum: 1.5 g/day[1]
### Dosage Forms
Injection, solution: 250 mg/mL (1 mL, 2 mL)[1]
# Mechanism of Action
Isepamicin is an aminoglycoside which inhibits bacterial protein synthesis by binding to 30S and 50S ribosomal subunits in susceptible micro-organisms. | https://www.wikidoc.org/index.php/Isepamicin | |
41057e64c818542a1d09b83789217763d97d1ed1 | wikidoc | Isocyanate | Isocyanate
Isocyanate is the functional group of atoms –N=C=O (1 nitrogen, 1 carbon, 1 oxygen), not to be confused with the cyanate functional group which is arranged as –O–C≡N. Any organic compound which contains an isocyanate group may also be referred to in brief as an isocyanate. An isocyanate may have more than one isocyanate group. An isocyanate that has two isocyanate groups is known as a diisocyanate. Diisocyanates are manufactured for reaction with polyols in the production of polyurethanes.
# Synthesis
The normal industrial route to the manufacture of diisocyanates, is to synthesise the desired molecular structure with amine functional groups at the positions to be occupied by the isocyanate groups. Reaction with phosgene replaces the amine groups with isocyanate groups.
Common methods for the synthesis of isocyanates in the laboratory are the Curtius rearrangement of acyl azides and the Lossen rearrangement of hydroxamic acids.
# Chemistry
The isocyanate group reacts with the hydroxyl functional group to form a urethane linkage. If a diisocyanate is reacted with a compound containing two or more hydroxyl groups (a polyol), long polymer chains are formed, known as polyurethanes.
The isocyanate group also reacts with the amine functional group. Reaction between a diisocyanate and a compound containing two or more amine groups, produces long polymer chains known as polyureas.
The isocyanate group can react with itself. Aliphatic diisocyanates can form trimers, known as biurets.
# Common compounds
A monofunctional isocyanate of industrial significance is methyl isocyanate (MIC), which is used in the manufacture of pesticides.
The global market for diisocyanates in the year 2000 was 4.4 million tonnes, of which 61.3% was methylene diphenyl diisocyanate (MDI), 34.1% was toluene diisocyanate (TDI), 3.4% was the total for hexamethylene diisocyanate (HDI) and isophorone diisocyanate (IPDI), and 1.2% was the total for various others.
# Hazards
The reactivity of isocyanates makes them harmful to living tissue. They are toxic and are known to cause asthma in humans, both through inhalation exposure and dermal contact. Exposure to isocyanates and their vapors should be avoided. | Isocyanate
Isocyanate is the functional group of atoms –N=C=O (1 nitrogen, 1 carbon, 1 oxygen), not to be confused with the cyanate functional group which is arranged as –O–C≡N. Any organic compound which contains an isocyanate group may also be referred to in brief as an isocyanate. An isocyanate may have more than one isocyanate group. An isocyanate that has two isocyanate groups is known as a diisocyanate. Diisocyanates are manufactured for reaction with polyols in the production of polyurethanes.
# Synthesis
The normal industrial route to the manufacture of diisocyanates, is to synthesise the desired molecular structure with amine functional groups at the positions to be occupied by the isocyanate groups. Reaction with phosgene replaces the amine groups with isocyanate groups.[1]
Common methods for the synthesis of isocyanates in the laboratory are the Curtius rearrangement of acyl azides and the Lossen rearrangement of hydroxamic acids.
# Chemistry
The isocyanate group reacts with the hydroxyl functional group to form a urethane linkage. If a diisocyanate is reacted with a compound containing two or more hydroxyl groups (a polyol), long polymer chains are formed, known as polyurethanes.
The isocyanate group also reacts with the amine functional group. Reaction between a diisocyanate and a compound containing two or more amine groups, produces long polymer chains known as polyureas.
The isocyanate group can react with itself. Aliphatic diisocyanates can form trimers, known as biurets.
# Common compounds
A monofunctional isocyanate of industrial significance is methyl isocyanate (MIC), which is used in the manufacture of pesticides.
The global market for diisocyanates in the year 2000 was 4.4 million tonnes, of which 61.3% was methylene diphenyl diisocyanate (MDI), 34.1% was toluene diisocyanate (TDI), 3.4% was the total for hexamethylene diisocyanate (HDI) and isophorone diisocyanate (IPDI), and 1.2% was the total for various others.[1]
# Hazards
The reactivity of isocyanates makes them harmful to living tissue. They are toxic and are known to cause asthma in humans, both through inhalation exposure and dermal contact. Exposure to isocyanates and their vapors should be avoided. | https://www.wikidoc.org/index.php/Isocyanate | |
83be56ce43c7735b34cf0b409466f542c35dc369 | wikidoc | Isoetarine | Isoetarine
# Overview
Isoetarine (INN) or isoetharine (USAN), trade names Bronkosol and Bronkometer, is a selective beta2-adrenergic receptor agonist. It can be called the "granddaughter of adrenalin" in the line of beta-two agonists that gave quick relief for bronchospasm and asthma. Adrenalin or epinephrine was the first of these, and next came Isuprel. Isoetharine was the third drug in this line, thus the third generation or granddaughter of the original.
In the western US it was the drug of choice in the late 1970s and early 1980s for nebulization ("breathing treatment") to relieve airway spasm. It generally gave sharp relief of shortness of breath, starting within two to five minutes after the patient began breathing the nebulized mist. This rapid onset is not as clearly present in later drugs.
All of the early beta-two agonist catecholamines used for bronchospasm had strong side effects, with increase in heart rate as the most common and most problematic. This came because its "beta-two effect" was not quite as selective as might be hoped. Beta-one receptors appeared to also be stimulated in some patients, causing cardiac and other CNS side effects. With Bronkosol this effect tended to be transient and usually went away within a matter of minutes after the end of the treatment. Increase in blood pressure also occurred in a small but significant percentage of cases, but also was almost invariably transient.
By the late 1980s isoetharine was largely replaced in the marketplace by Alupent/metaproterenol, which seemed to have slightly less cardiac side effect and lasted a couple of hours longer. Alupent in turn was replaced by albuterol. Some practitioners still believe that these later aerosolized bronchodilators never gave quite as quick of relief from asthmatic shortness of breath as did Bronkosol. Thus they see a continued specialty role in treatment of severe shortness of breath that does not improve in the first five minutes of albuterol treatment. | Isoetarine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Isoetarine (INN) or isoetharine (USAN), trade names Bronkosol and Bronkometer, is a selective beta2-adrenergic receptor agonist. It can be called the "granddaughter of adrenalin" in the line of beta-two agonists that gave quick relief for bronchospasm and asthma.[1] Adrenalin or epinephrine was the first of these, and next came Isuprel. Isoetharine was the third drug in this line, thus the third generation or granddaughter of the original.
In the western US it was the drug of choice in the late 1970s and early 1980s for nebulization ("breathing treatment") to relieve airway spasm. It generally gave sharp relief of shortness of breath, starting within two to five minutes after the patient began breathing the nebulized mist. This rapid onset is not as clearly present in later drugs.
All of the early beta-two agonist catecholamines used for bronchospasm had strong side effects, with increase in heart rate as the most common and most problematic. This came because its "beta-two effect" was not quite as selective as might be hoped. Beta-one receptors appeared to also be stimulated in some patients, causing cardiac and other CNS side effects. With Bronkosol this effect tended to be transient and usually went away within a matter of minutes after the end of the treatment. Increase in blood pressure also occurred in a small but significant percentage of cases, but also was almost invariably transient.
By the late 1980s isoetharine was largely replaced in the marketplace by Alupent/metaproterenol, which seemed to have slightly less cardiac side effect and lasted a couple of hours longer. Alupent in turn was replaced by albuterol. Some practitioners still believe that these later aerosolized bronchodilators never gave quite as quick of relief from asthmatic shortness of breath as did Bronkosol. Thus they see a continued specialty role in treatment of severe shortness of breath that does not improve in the first five minutes of albuterol treatment. | https://www.wikidoc.org/index.php/Isoetarine | |
c1fdd5abcbc10e4cb56e1427cf89d21575445c25 | wikidoc | Osmolarity | Osmolarity
# Overview
In chemistry, the osmole (Osm) is a non-SI unit of measurement that defines the number of moles of a chemical compound that contribute to a solution's osmotic pressure.
Osmolarity is a measure of the osmoles of solute per liter of solution, while the osmolality is a measure of the osmoles of solute per kilogram of solvent. Molarity and Osmolarity are not commonly used in osmometry because they are temperature dependent; that is, water changes its volume with temperature. However, if the concentration is very low, osmolarity and osmolality are considered equivalent. In calculations for these two measurements, salts are presumed to dissociate into their component ions. For example, a mole of glucose in solution is one osmole, whereas a mole of sodium chloride in solution is two osmoles (one mole of sodium and one mole of chloride). Both sodium and chloride ions affect the osmotic pressure of the solution.
The equation to determine the osmolality of a solution is given by
Osm = \phi\ n C
where
- Φ is the osmotic coefficient, which accounts for the degree of non-ideality of the solution. In the simplest case it is the degree of dissociation of the solute. Then, Φ is between 0 and 1 where 1 indicates 100% dissociation. However, Φ can also be larger than 1 (e.g. for sucrose). For salts, electrostatic effects cause Φ to be smaller than 1 even if 100% dissociation occurs (see Debye-Hückel equation).
- n is the number of particles (ions) into which a molecule dissociates. For example: Glucose equals 1 and NaCl equals 2.
- C is the molal concentration of the solution
The units are Osm/kg
Osmolality can be measured using an osmometer which measures colligative properties, such as Freezing-point depression, Vapor pressure, or Boiling-point elevation.
# Osmolality/osmolarity vs. tonicity
While similar, osmolarity and tonicity are not the same. The key difference between the two is that tonicity implies a membrane that is impermeable to the solutes on either side of it. This is not a necessary condition in the case of osmolarity. Osmolarity is a measure of the osmotically active particles in a solution and in fact makes no explicit assertion with respect to the solute permeability of any involved membranes.
The derivatives of the term: isosmotic, hyperosmotic, and hypoosmotic, should not be confused with istonic, hypertonic and hypotonic.
Example: A urea solution that is isosmotic with respect to the cytosol of an erythrocyte is nonetheless not isotonic respective to the same erythrocyte. Urea freely diffuses across cellular membranes and is also an osmotically active particle. Normally, urea is present in a lower concentration in the nju of an erythrocyte than in an urea solution. Because urea is freely permeable to cell membranes and the concentration of urea is normally lower in the erythrocytes than in a urea solution, urea will diffuse down its concentration gradient into an erythrocyte placed into a urea solution. However, because urea is osmotically active, urea increases the solute concentration in the erythrocyte, which will then induce the osmosis of water into the cell. This can ultimately result in cell lysis. In retrospect, the isosmotic urea solution was in fact hypotonic with respect to the blood cell. Interestingly, even if the urea solution is hypoosmotic to the erythrocyte, urea will still diffuse into the cell along its concentration gradient. | Osmolarity
# Overview
In chemistry, the osmole (Osm) is a non-SI unit of measurement that defines the number of moles of a chemical compound that contribute to a solution's osmotic pressure.
Osmolarity is a measure of the osmoles of solute per liter of solution, while the osmolality is a measure of the osmoles of solute per kilogram of solvent. Molarity and Osmolarity are not commonly used in osmometry because they are temperature dependent; that is, water changes its volume with temperature. However, if the concentration is very low, osmolarity and osmolality are considered equivalent. In calculations for these two measurements, salts are presumed to dissociate into their component ions. For example, a mole of glucose in solution is one osmole, whereas a mole of sodium chloride in solution is two osmoles (one mole of sodium and one mole of chloride). Both sodium and chloride ions affect the osmotic pressure of the solution.
The equation to determine the osmolality of a solution is given by
<math> Osm = \phi\ n C </math>
where
- Φ is the osmotic coefficient, which accounts for the degree of non-ideality of the solution. In the simplest case it is the degree of dissociation of the solute. Then, Φ is between 0 and 1 where 1 indicates 100% dissociation. However, Φ can also be larger than 1 (e.g. for sucrose). For salts, electrostatic effects cause Φ to be smaller than 1 even if 100% dissociation occurs (see Debye-Hückel equation).
- n is the number of particles (ions) into which a molecule dissociates. For example: Glucose equals 1 and NaCl equals 2.
- C is the molal concentration of the solution
The units are Osm/kg
Osmolality can be measured using an osmometer which measures colligative properties, such as Freezing-point depression, Vapor pressure, or Boiling-point elevation.
# Osmolality/osmolarity vs. tonicity
While similar, osmolarity and tonicity are not the same. The key difference between the two is that tonicity implies a membrane that is impermeable to the solutes on either side of it. This is not a necessary condition in the case of osmolarity. Osmolarity is a measure of the osmotically active particles in a solution and in fact makes no explicit assertion with respect to the solute permeability of any involved membranes.
The derivatives of the term: isosmotic, hyperosmotic, and hypoosmotic, should not be confused with istonic, hypertonic and hypotonic.
Example: A urea solution that is isosmotic with respect to the cytosol of an erythrocyte is nonetheless not isotonic respective to the same erythrocyte. Urea freely diffuses across cellular membranes and is also an osmotically active particle. Normally, urea is present in a lower concentration in the nju of an erythrocyte than in an urea solution. Because urea is freely permeable to cell membranes and the concentration of urea is normally lower in the erythrocytes than in a urea solution, urea will diffuse down its concentration gradient into an erythrocyte placed into a urea solution. However, because urea is osmotically active, urea increases the solute concentration in the erythrocyte, which will then induce the osmosis of water into the cell. This can ultimately result in cell lysis. In retrospect, the isosmotic urea solution was in fact hypotonic with respect to the blood cell. Interestingly, even if the urea solution is hypoosmotic to the erythrocyte, urea will still diffuse into the cell along its concentration gradient. | https://www.wikidoc.org/index.php/Isosmotic | |
28b55610c7056015ec0c3e16e954368880dc141b | wikidoc | Ivabradine | Ivabradine
# 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
Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that is FDA approved for the prevention of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Common adverse reactions include bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes) ( ≥ 1%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Ivabradine FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ivabradine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
There is limited information regarding Ivabradine Contraindications in the drug label.
# Warnings
There is limited information regarding Ivabradine Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Ivabradine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Ivabradine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ivabradine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Ivabradine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ivabradine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ivabradine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Ivabradine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Ivabradine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Ivabradine in geriatric settings.
### Gender
There is no FDA guidance on the use of Ivabradine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ivabradine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ivabradine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ivabradine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ivabradine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ivabradine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ivabradine Administration in the drug label.
### Monitoring
There is limited information regarding Ivabradine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ivabradine and IV administrations.
# Overdosage
There is limited information regarding Ivabradine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Ivabradine Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Ivabradine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Ivabradine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Ivabradine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Ivabradine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Ivabradine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Ivabradine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Ivabradine How Supplied in the drug label.
## Storage
There is limited information regarding Ivabradine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ivabradine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ivabradine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Ivabradine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ivabradine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ivabradine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [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
Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that is FDA approved for the prevention of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Common adverse reactions include bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes) ( ≥ 1%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Ivabradine FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ivabradine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
There is limited information regarding Ivabradine Contraindications in the drug label.
# Warnings
There is limited information regarding Ivabradine Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Ivabradine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Ivabradine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ivabradine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Ivabradine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ivabradine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ivabradine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Ivabradine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Ivabradine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Ivabradine in geriatric settings.
### Gender
There is no FDA guidance on the use of Ivabradine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ivabradine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ivabradine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ivabradine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ivabradine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ivabradine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ivabradine Administration in the drug label.
### Monitoring
There is limited information regarding Ivabradine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ivabradine and IV administrations.
# Overdosage
There is limited information regarding Ivabradine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Ivabradine Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Ivabradine Mechanism of Action in the drug label.
## Structure
There is limited information regarding Ivabradine Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Ivabradine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Ivabradine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Ivabradine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Ivabradine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Ivabradine How Supplied in the drug label.
## Storage
There is limited information regarding Ivabradine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ivabradine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ivabradine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Ivabradine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ivabradine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ivabradine | |
4ef9cbd26889decec64f08b7b8967ba6cadfa356 | wikidoc | Ivosidenib | Ivosidenib
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# Black Box Warning
# Overview
Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor that is FDA approved for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in adult patients with newly-diagnosed AML who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and adult patients with relapsed or refractory AML. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis, electrocardiogram QT prolonged, rash, cough, decreased appetite, myalgia, constipation, and pyrexia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Ivosidenib is indicated for the treatment of newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adult patients who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
- Ivosidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
Dosage
- The recommended dose of ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of ivosidenib in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with ivosidenib experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with ivosidenib included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of ivosidenib. Differentiation syndrome occurred as early as 1 day and up to 3 months after ivosidenib initiation and has been observed with or without concomitant leukocytosis.
- If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt ivosidenib until signs and symptoms are no longer severe.
- Patients treated with ivosidenib can develop QT (QTc) prolongation and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with ivosidenib in the clinical trial, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to ivosidenib. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.
- Concomitant use of ivosidenib with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes.
- In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.
- Interrupt ivosidenib if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce ivosidenib if QTc increases to greater than 500 msec. Permanently discontinue ivosidenib in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
- Guillain-Barré syndrome occurred in < 1% (2/258) of patients treated with ivosidenib in the clinical study. Monitor patients taking ivosidenib for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue ivosidenib in patients who are diagnosed with Guillain-Barré syndrome.
# 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 safety of ivosidenib as a single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001. The median age of ivosidenib treated patients was 68 (range 18-87) with 68% ≥ 65 years, 51% male, 66% White, 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5% American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who received ivosidenib, 37% were exposed for 6 months or longer and 14% were exposed for 12 months or longer. The most common adverse reactions including laboratory abnormalities in ≥ 20% of 213 patients who received ivosidenib were hemoglobin decreased, fatigue, arthralgia, calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema, nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased, mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and pyrexia.
Newly-Diagnosed AML
- The safety profile of single-agent ivosidenib was studied in 28 adults with newly-diagnosed AML treated with 500 mg daily. The median duration of exposure to ivosidenib was 4.3 months (range 0.3 to 40.9 months). Ten patients (36%) were exposed to ivosidenib for at least 6 months and 6 patients (21%) were exposed for at least 1 year.
- Common (≥ 5%) serious adverse reactions included differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
- Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT prolonged (14%) and differentiation syndrome (11%). Two (7%) patients required a dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES.
- The most common adverse reactions reported in the trial are shown in TABLE 2.
- Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in TABLE 3.
Relapsed or Refractory AML
- The safety profile of single-agent ivosidenib was studied in 179 adults with relapsed or refractory AML treated with 500 mg daily.
- The median duration of exposure to ivosidenib was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to ivosidenib for at least 6 months and 16 patients (9%) were exposed for at least 1 year.
- Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
- The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).
- The most common adverse reactions reported in the trial are shown in TABLE 4.
- Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in TABLE 5.
## Postmarketing Experience
There is limited information regarding Ivosidenib Postmarketing Experience in the drug label.
# Drug Interactions
- Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates. Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during ivosidenib treatment. Do not administer ivosidenib with itraconazole or ketoconazole (CYP3A4 substrates) due to expected loss of antifungal efficacy. Co-administration of ivosidenib may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving ivosidenib. If co-administration of ivosidenib with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Based on animal embryo-fetal toxicity studies, ivosidenib may cause fetal harm when administered to a pregnant woman. There are no available data on ivosidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Animal Data
- Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily.
- In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ivosidenib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ivosidenib during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with ivosidenib and for at least 1 month after the last dose.
### Pediatric Use
- The safety and effectiveness of ivosidenib in pediatric patients have not been established.
### Geriatic Use
- Thirty-three (97%) of the 34 patients with newly diagnosed AML in the clinical study were 65 years of age or older, and 19 patients (56%) were 75 years or older. One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients with relapsed or refractory AML who were 65 years and older and younger patients.
### Gender
There is no FDA guidance on the use of Ivosidenib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ivosidenib with respect to specific racial populations.
### Renal Impairment
- No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis are unknown. For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with ivosidenib.
### Hepatic Impairment
- No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment. The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with ivosidenib.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ivosidenib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ivosidenib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Select patients for the treatment of AML with ivosidenib based on the presence of IDH1 mutations in the blood or bone marrow. Patients without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment and at relapse. Information on FDA-approved tests for the detection of IDH1 mutations in AML is available at HTTP.
- The recommended dose of ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.
- Administer ivosidenib with or without food. Do not administer ivosidenib with a high-fat meal because of an increase in ivosidenib concentration. Do not split or crush ivosidenib tablets. Administer ivosidenib tablets orally about the same time each day. If a dose of ivosidenib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of ivosidenib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.
Patients with the Comorbidities of Severe Renal or Severe Hepatic Impairment
- Treatment with ivosidenib has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with ivosidenib.
- If a strong CYP3A4 inhibitor must be coadministered, reduce the ivosidenib dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the ivosidenib dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.
### Monitoring
- Assess blood counts and blood chemistries prior to the initiation of ivosidenib, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. Monitor electrocardiograms (ECGs) at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly.
- Interrupt dosing or reduce dose for toxicities. See TABLE 1 for dose modification guidelines.
# IV Compatibility
There is limited information regarding the compatibility of Ivosidenib and IV administrations.
# Overdosage
There is limited information regarding Ivosidenib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions.
- Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.
## Structure
- The molecular formula is C28H22C1F3N6O3 and the molecular weight is 583.0 g/mol. Ivosidenib is practically insoluble in aqueous solutions between pH 1.2 and 7.4. The chemical structure is:
## Pharmacodynamics
- Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.
Cardiac Electrophysiology
- A concentration-dependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.7, 19.7) was observed at the steady-state Cmax following a 500 mg daily dose based on an analysis of 171 patients with advanced hematologic malignances and an IDH1 mutation, including 26 patients with newly diagnosed AML and 136 patients with relapsed or refractory AML, who received ivosidenib 500 mg daily. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.
## Pharmacokinetics
- The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady-state), unless otherwise specified. The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML and patients with relapsed or refractory AML.
- The mean peak plasma concentration (Cmax) is 4,503 ng/mL after a single dose, and 6,551 ng/mL (%CV: 44) at steady-state. The steady-state area under the concentration time curve (AUC) is 117,348 ng·hr/mL (%CV: 50).
- The AUC and Cmax of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for Cmax over one month. Steady-state plasma levels are reached within 14 days.
Absorption
- The median time to Cmax is approximately 3 hours.
Effect of Food
- Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%.
Distribution
- The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (%CV: 47). Protein binding of ivosidenib ranges from 92 to 96% in vitro.
Elimination
- Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance (CL/F) of 4.3 L/hour (%CV: 50).
Metabolism
- Ivosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.
Excretion
- After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).
Specific Populations
- No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, or mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m2, MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis is unknown.
Patients with Hepatic Impairment
- Following a single dose of ivosidenib 500 mg, the geometric mean ratio (90% confidence interval) of ivosidenib systemic exposure (AUC0-INF) in subjects with mild hepatic impairment (Child-Pugh A) was 0.85 (0.62, 1.15) and moderate hepatic impairment (Child-Pugh B) was 0.71 (0.48, 1.05) as compared to that in subjects with normal hepatic function. The pharmacokinetics of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) is unknown.
Drug Interaction Studies
Clinical Studies and Model-Based Approaches
Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib
- Itraconazole was used as a strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in a drug-drug interaction study in healthy subjects. Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax. In regards to multiple-dosing, note that because ivosidenib induces the metabolism of CYP3A4 substrates following ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with ivosidenib in patients.
- Based on physiologically-based pharmacokinetic modeling, co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control with no change in Cmax. In regards to multiple-dosing, co-administration with ivosidenib and fluconazole is predicted to increase ivosidenib steady-state Cmax to 152% of control and AUC to 190% of control.
Effect of Strong CYP3A4 Inducers on Ivosidenib
- Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33%.
Effect of Ivosidenib on CYP3A4 Substrates
- Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent.
Effect of Gastric Acid Reducing Agents on Ivosidenib
- Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations.
In vitro Studies
Metabolic Pathways
- Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes.
Drug Transporter Systems
- Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.
- Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with ivosidenib. Ivosidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Ivosidenib was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with ivosidenib. In repeat-dose toxicity studies up to 90 days in duration with twice daily oral administration of ivosidenib in rats, uterine atrophy was reported in females at non-tolerated dose levels.
# Clinical Studies
- The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly-diagnosed AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime™ IDH1 Assay. The cohort included patients who were age 75 years or older or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, or creatinine clearance < 45 mL/min. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Two (7%) of the 28 patients went on to stem cell transplantation following ivosidenib treatment.
- The baseline demographic and disease characteristics are shown in TABLE 6.
- Efficacy was established on the basis of the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 7. The median follow-up was 8.1 months (range, 0.6 to 40.9 months) and median treatment duration was 4.3 months (range, 0.3 to 40.9 months).
- For patients who achieved a CR or CRh, the median time to CR or CRh was 2.8 months (range, 1.9 to 12.9 months). Of the 12 patients who achieved a best response of CR or CRh, 11 (92%) achieved a first response of CR or CRh within 6 months of initiating ivosidenib.
- Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period.
- The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime™ IDH1 Assay. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Twenty-one (12%) of the 174 patients went on to stem cell transplantation following ivosidenib treatment.
- The baseline demographic and disease characteristics are shown in TABLE 8.
- Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 9. The median follow-up was 8.3 months (range, 0.2 to 39.5 months) and median treatment duration was 4.1 months (range, 0.1 to 39.5 months).
- For patients who achieved a CR or CRh, the median time to CR or CRh was 2 months (range, 0.9 to 5.6 months). Of the 57 patients who achieved a best response of CR or CRh, all achieved a first response of CR or CRh within 6 months of initiating ivosidenib.
- Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.
# How Supplied
- 250 mg tablet: Blue oval-shaped film-coated tablet debossed “IVO” on one side and “250” on the other side.
- 60-count bottles of 250 mg tablets with a desiccant canister.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Differentiation Syndrome
- Advise patients of the risks of developing differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation.
QTc Interval Prolongation
- Inform patients of symptoms that may be indicative of significant QTc interval prolongation including dizziness, lightheadedness, and fainting. Advise patients to report these symptoms and the use of all medications to their healthcare provider.
Drug Interactions
- Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products.
Guillain-Barré Syndrome
- Inform patients of symptoms that may be indicative of Guillain-Barré syndrome, including new signs or symptoms of motor and/or sensory neuropathy, such as weakness or tingling sensation in the legs, arms, or upper body, numbness and pain on one side or both sides of the body, changes to any sensory function, or burning or prickling sensation, or difficulty breathing. Advise patients to report these symptoms to their healthcare provider.
Tumor Lysis Syndrome
- Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values.
Gastrointestinal Adverse Reactions
- Advise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite and abdominal pain. Ask patients to report these events to their healthcare provider, and advise patients how to manage them.
Lactation
- Advise women not to breastfeed during treatment with ivosidenib and for at least 1 month after the final dose
Dosing and Storage Instructions
- Advise patients to swallow tablets whole and to not split, crush, or chew ivosidenib tablets.
- Advise patients to avoid taking ivosidenib with a high-fat meal.
- Instruct patients that if a dose of ivosidenib is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If a dose of ivosidenib is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.
- Store ivosidenib at room temperature from 20°C to 25°C (68°F to 77°F).
# Precautions with Alcohol
Alcohol-Ivosidenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Tibsovo
# Look-Alike Drug Names
There is limited information regarding Ivosidenib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ivosidenib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Black Box Warning
# Overview
Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor that is FDA approved for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in adult patients with newly-diagnosed AML who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and adult patients with relapsed or refractory AML. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, dyspnea, mucositis, electrocardiogram QT prolonged, rash, cough, decreased appetite, myalgia, constipation, and pyrexia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Ivosidenib is indicated for the treatment of newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adult patients who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
- Ivosidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
Dosage
- The recommended dose of ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of ivosidenib in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ivosidenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with ivosidenib experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with ivosidenib included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of ivosidenib. Differentiation syndrome occurred as early as 1 day and up to 3 months after ivosidenib initiation and has been observed with or without concomitant leukocytosis.
- If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt ivosidenib until signs and symptoms are no longer severe.
- Patients treated with ivosidenib can develop QT (QTc) prolongation and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with ivosidenib in the clinical trial, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to ivosidenib. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.
- Concomitant use of ivosidenib with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes.
- In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.
- Interrupt ivosidenib if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce ivosidenib if QTc increases to greater than 500 msec. Permanently discontinue ivosidenib in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
- Guillain-Barré syndrome occurred in < 1% (2/258) of patients treated with ivosidenib in the clinical study. Monitor patients taking ivosidenib for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue ivosidenib in patients who are diagnosed with Guillain-Barré syndrome.
# 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 safety of ivosidenib as a single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001. The median age of ivosidenib treated patients was 68 (range 18-87) with 68% ≥ 65 years, 51% male, 66% White, 6% Black or African American, 3% Asian, 0.5% Native Hawaiian or other Pacific Islander, 0.5% American Indian or Alaska Native, and 24% other/not provided. Among the 213 patients who received ivosidenib, 37% were exposed for 6 months or longer and 14% were exposed for 12 months or longer. The most common adverse reactions including laboratory abnormalities in ≥ 20% of 213 patients who received ivosidenib were hemoglobin decreased, fatigue, arthralgia, calcium decreased, sodium decreased, leukocytosis, diarrhea, magnesium decreased, edema, nausea, dyspnea, uric acid increased, potassium decreased, alkaline phosphatase increased, mucositis, aspartate aminotransferase increased, phosphatase decreased, electrocardiogram QT prolonged, rash, creatinine increased, cough, decreased appetite, myalgia, constipation, and pyrexia.
Newly-Diagnosed AML
- The safety profile of single-agent ivosidenib was studied in 28 adults with newly-diagnosed AML treated with 500 mg daily. The median duration of exposure to ivosidenib was 4.3 months (range 0.3 to 40.9 months). Ten patients (36%) were exposed to ivosidenib for at least 6 months and 6 patients (21%) were exposed for at least 1 year.
- Common (≥ 5%) serious adverse reactions included differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
- Common (≥ 10%) adverse reactions leading to dose interruption included electrocardiogram QT prolonged (14%) and differentiation syndrome (11%). Two (7%) patients required a dose reduction due to electrocardiogram QT prolonged. One patient each required permanent discontinuation due to diarrhea and PRES.
- The most common adverse reactions reported in the trial are shown in TABLE 2.
- Changes in selected post-baseline laboratory values that were observed in patients with newly diagnosed AML are shown in TABLE 3.
Relapsed or Refractory AML
- The safety profile of single-agent ivosidenib was studied in 179 adults with relapsed or refractory AML treated with 500 mg daily.
- The median duration of exposure to ivosidenib was 3.9 months (range 0.1 to 39.5 months). Sixty-five patients (36%) were exposed to ivosidenib for at least 6 months and 16 patients (9%) were exposed for at least 1 year.
- Serious adverse reactions (≥ 5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
- The most common adverse reactions leading to dose interruption were electrocardiogram QT prolonged (7%), differentiation syndrome (3%), leukocytosis (3%) and dyspnea (3%). Five out of 179 patients (3%) required a dose reduction due to an adverse reaction. Adverse reactions leading to a dose reduction included electrocardiogram QT prolonged (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Adverse reactions leading to permanent discontinuation included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increased (1%).
- The most common adverse reactions reported in the trial are shown in TABLE 4.
- Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in TABLE 5.
## Postmarketing Experience
There is limited information regarding Ivosidenib Postmarketing Experience in the drug label.
# Drug Interactions
- Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates. Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during ivosidenib treatment. Do not administer ivosidenib with itraconazole or ketoconazole (CYP3A4 substrates) due to expected loss of antifungal efficacy. Co-administration of ivosidenib may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving ivosidenib. If co-administration of ivosidenib with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Based on animal embryo-fetal toxicity studies, ivosidenib may cause fetal harm when administered to a pregnant woman. There are no available data on ivosidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Animal Data
- Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily.
- In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ivosidenib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ivosidenib during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with ivosidenib and for at least 1 month after the last dose.
### Pediatric Use
- The safety and effectiveness of ivosidenib in pediatric patients have not been established.
### Geriatic Use
- Thirty-three (97%) of the 34 patients with newly diagnosed AML in the clinical study were 65 years of age or older, and 19 patients (56%) were 75 years or older. One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients with relapsed or refractory AML who were 65 years and older and younger patients.
### Gender
There is no FDA guidance on the use of Ivosidenib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ivosidenib with respect to specific racial populations.
### Renal Impairment
- No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis are unknown. For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with ivosidenib.
### Hepatic Impairment
- No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment. The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with ivosidenib.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ivosidenib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ivosidenib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Select patients for the treatment of AML with ivosidenib based on the presence of IDH1 mutations in the blood or bone marrow. Patients without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during treatment and at relapse. Information on FDA-approved tests for the detection of IDH1 mutations in AML is available at HTTP://WWW.FDA.GOV/COMPANIONDIAGNOSTICS.
- The recommended dose of ivosidenib is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.
- Administer ivosidenib with or without food. Do not administer ivosidenib with a high-fat meal because of an increase in ivosidenib concentration. Do not split or crush ivosidenib tablets. Administer ivosidenib tablets orally about the same time each day. If a dose of ivosidenib is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of ivosidenib is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.
Patients with the Comorbidities of Severe Renal or Severe Hepatic Impairment
- Treatment with ivosidenib has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with ivosidenib.
- If a strong CYP3A4 inhibitor must be coadministered, reduce the ivosidenib dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the ivosidenib dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.
### Monitoring
- Assess blood counts and blood chemistries prior to the initiation of ivosidenib, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. Monitor electrocardiograms (ECGs) at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly.
- Interrupt dosing or reduce dose for toxicities. See TABLE 1 for dose modification guidelines.
# IV Compatibility
There is limited information regarding the compatibility of Ivosidenib and IV administrations.
# Overdosage
There is limited information regarding Ivosidenib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions.
- Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.
## Structure
- The molecular formula is C28H22C1F3N6O3 and the molecular weight is 583.0 g/mol. Ivosidenib is practically insoluble in aqueous solutions between pH 1.2 and 7.4. The chemical structure is:
## Pharmacodynamics
- Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.
Cardiac Electrophysiology
- A concentration-dependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.7, 19.7) was observed at the steady-state Cmax following a 500 mg daily dose based on an analysis of 171 patients with advanced hematologic malignances and an IDH1 mutation, including 26 patients with newly diagnosed AML and 136 patients with relapsed or refractory AML, who received ivosidenib 500 mg daily. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.
## Pharmacokinetics
- The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady-state), unless otherwise specified. The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML and patients with relapsed or refractory AML.
- The mean peak plasma concentration (Cmax) is 4,503 ng/mL [% coefficient of variation (%CV: 38)] after a single dose, and 6,551 ng/mL (%CV: 44) at steady-state. The steady-state area under the concentration time curve (AUC) is 117,348 ng·hr/mL (%CV: 50).
- The AUC and Cmax of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for Cmax over one month. Steady-state plasma levels are reached within 14 days.
Absorption
- The median time to Cmax is approximately 3 hours.
Effect of Food
- Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib Cmax by 98% (90% CI: 79%, 119%) and AUCinf by approximately 25%.
Distribution
- The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (%CV: 47). Protein binding of ivosidenib ranges from 92 to 96% in vitro.
Elimination
- Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance (CL/F) of 4.3 L/hour (%CV: 50).
Metabolism
- Ivosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.
Excretion
- After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).
Specific Populations
- No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, or mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m2, MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis is unknown.
Patients with Hepatic Impairment
- Following a single dose of ivosidenib 500 mg, the geometric mean ratio (90% confidence interval) of ivosidenib systemic exposure (AUC0-INF) in subjects with mild hepatic impairment (Child-Pugh A) was 0.85 (0.62, 1.15) and moderate hepatic impairment (Child-Pugh B) was 0.71 (0.48, 1.05) as compared to that in subjects with normal hepatic function. The pharmacokinetics of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) is unknown.
Drug Interaction Studies
Clinical Studies and Model-Based Approaches
Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib
- Itraconazole was used as a strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in a drug-drug interaction study in healthy subjects. Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in Cmax. In regards to multiple-dosing, note that because ivosidenib induces the metabolism of CYP3A4 substrates following ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with ivosidenib in patients.
- Based on physiologically-based pharmacokinetic modeling, co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control with no change in Cmax. In regards to multiple-dosing, co-administration with ivosidenib and fluconazole is predicted to increase ivosidenib steady-state Cmax to 152% of control and AUC to 190% of control.
Effect of Strong CYP3A4 Inducers on Ivosidenib
- Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33%.
Effect of Ivosidenib on CYP3A4 Substrates
- Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent.
Effect of Gastric Acid Reducing Agents on Ivosidenib
- Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations.
In vitro Studies
Metabolic Pathways
- Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes.
Drug Transporter Systems
- Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.
- Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with ivosidenib. Ivosidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Ivosidenib was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with ivosidenib. In repeat-dose toxicity studies up to 90 days in duration with twice daily oral administration of ivosidenib in rats, uterine atrophy was reported in females at non-tolerated dose levels.
# Clinical Studies
- The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly-diagnosed AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime™ IDH1 Assay. The cohort included patients who were age 75 years or older or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, or creatinine clearance < 45 mL/min. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Two (7%) of the 28 patients went on to stem cell transplantation following ivosidenib treatment.
- The baseline demographic and disease characteristics are shown in TABLE 6.
- Efficacy was established on the basis of the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 7. The median follow-up was 8.1 months (range, 0.6 to 40.9 months) and median treatment duration was 4.3 months (range, 0.3 to 40.9 months).
- For patients who achieved a CR or CRh, the median time to CR or CRh was 2.8 months (range, 1.9 to 12.9 months). Of the 12 patients who achieved a best response of CR or CRh, 11 (92%) achieved a first response of CR or CRh within 6 months of initiating ivosidenib.
- Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period.
- The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime™ IDH1 Assay. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Twenty-one (12%) of the 174 patients went on to stem cell transplantation following ivosidenib treatment.
- The baseline demographic and disease characteristics are shown in TABLE 8.
- Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 9. The median follow-up was 8.3 months (range, 0.2 to 39.5 months) and median treatment duration was 4.1 months (range, 0.1 to 39.5 months).
- For patients who achieved a CR or CRh, the median time to CR or CRh was 2 months (range, 0.9 to 5.6 months). Of the 57 patients who achieved a best response of CR or CRh, all achieved a first response of CR or CRh within 6 months of initiating ivosidenib.
- Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.
# How Supplied
- 250 mg tablet: Blue oval-shaped film-coated tablet debossed “IVO” on one side and “250” on the other side.
- 60-count bottles of 250 mg tablets with a desiccant canister.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Differentiation Syndrome
- Advise patients of the risks of developing differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation.
QTc Interval Prolongation
- Inform patients of symptoms that may be indicative of significant QTc interval prolongation including dizziness, lightheadedness, and fainting. Advise patients to report these symptoms and the use of all medications to their healthcare provider.
Drug Interactions
- Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products.
Guillain-Barré Syndrome
- Inform patients of symptoms that may be indicative of Guillain-Barré syndrome, including new signs or symptoms of motor and/or sensory neuropathy, such as weakness or tingling sensation in the legs, arms, or upper body, numbness and pain on one side or both sides of the body, changes to any sensory function, or burning or prickling sensation, or difficulty breathing. Advise patients to report these symptoms to their healthcare provider.
Tumor Lysis Syndrome
- Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values.
Gastrointestinal Adverse Reactions
- Advise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite and abdominal pain. Ask patients to report these events to their healthcare provider, and advise patients how to manage them.
Lactation
- Advise women not to breastfeed during treatment with ivosidenib and for at least 1 month after the final dose
Dosing and Storage Instructions
- Advise patients to swallow tablets whole and to not split, crush, or chew ivosidenib tablets.
- Advise patients to avoid taking ivosidenib with a high-fat meal.
- Instruct patients that if a dose of ivosidenib is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If a dose of ivosidenib is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.
- Store ivosidenib at room temperature from 20°C to 25°C (68°F to 77°F).
# Precautions with Alcohol
Alcohol-Ivosidenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Tibsovo
# Look-Alike Drug Names
There is limited information regarding Ivosidenib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ivosidenib | |
c45e38fc91b7fa6c1f5dbf8fead7799fcc03816a | wikidoc | Ixekizumab | Ixekizumab
# 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
Ixekizumab is a humanized anti-interleukin-17 monoclonal antibody that is FDA approved for the treatment of of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Common adverse reactions include injection site reactions, upper respiratory tract infections, nausea, and tinea infections (≥1%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ixekizumab is administered by subcutaneous injection. The recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Ixekizumab.
There are two presentations for Ixekizumab (i.e., autoinjector and prefilled syringe).
Ixekizumab is intended for use under the guidance and supervision of a physician. Patients may self-inject after training in subcutaneous injection technique using the autoinjector or prefilled syringe. Administer each injection at a different anatomic location (such as upper arms, thighs or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of Ixekizumab in the upper, outer arm may be performed by a caregiver or healthcare provider.
If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
Before injection, remove Ixekizumab autoinjector or Ixekizumab prefilled syringe from the refrigerator and allow Ixekizumab to reach room temperature (30 minutes) without removing the needle cap.
Inspect Ixekizumab formulation visually for particulate matter and discoloration prior to administration. Ixekizumab formulation is a clear and colorless to slightly yellow solution. Do not use if the liquid contains visible particles, is discolored or cloudy (other than clear and colorless to slightly yellow). Ixekizumab formulation does not contain preservatives, therefore discard any unused product remaining in the autoinjector or prefilled syringe.
Instruct patients using the autoinjector or prefilled syringe to inject the full amount (1 mL), which provides 80 mg of Ixekizumab, according to the directions.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixekizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixekizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Ixekizumab contains no information regarding Pediatric Indications and Dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixekizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixekizumab in pediatric patients.
# Contraindications
Ixekizumab is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.
# Warnings
Ixekizumab may increase the risk of infection. In clinical trials, the Ixekizumab treated group had a higher rate of infections than the placebo group (27% vs. 23%). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Ixekizumab treated group than in the placebo group.
Instruct patients treated with Ixekizumab to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Ixekizumab until the infection resolves.
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Ixekizumab. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Ixekizumab. Consider anti-TB therapy prior to initiating Ixekizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Ixekizumab should be monitored closely for signs and symptoms of active TB during and after treatment.
Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Ixekizumab group in clinical trials. If a serious hypersensitivity reaction occurs, discontinue Ixekizumab immediately and initiate appropriate therapy.
Crohn's disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Ixekizumab group (Crohn's disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period. During Ixekizumab treatment, monitor for onset or exacerbation of inflammatory bowel disease.
Prior to initiating therapy with Ixekizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Ixekizumab. No data are available on the response to live or inactive vaccines.
# Adverse Reactions
## Clinical Trials Experience
The following adverse drug reactions are discussed in greater detail in other sections of the label:
- Infections
- Hypersensitivity Reactions
- Inflammatory Bowel Disease
Because clinical trials are conducted under widely varying and controlled 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.
### Weeks 0 to 12:
Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Ixekizumab compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Ixekizumab (160 mg at Week 0, 80 mg every two weeks for 12 weeks) subcutaneously. In two of the trials, the safety of Ixekizumab (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept.
In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Ixekizumab Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the Ixekizumab group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).
Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Ixekizumab group than in the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.
Adverse reactions that occurred at rates less than 1% in the Ixekizumab group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema.
### Weeks 13 to 60:
A total of 332 subjects received the recommended maintenance regimen of Ixekizumab 80 mg dosed every 4 weeks.
During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Ixekizumab (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Ixekizumab (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.
### Weeks 0 to 60:
Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Ixekizumab (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Ixekizumab (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).
### Specific Adverse Drug Reactions
The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Ixekizumab.
In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Ixekizumab (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Ixekizumab (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up).
During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Ixekizumab (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Ixekizumab (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.
Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Ixekizumab (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Ixekizumab (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).
- Neutropenia
Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Ixekizumab (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Ixekizumab, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.
In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Ixekizumab group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Ixekizumab 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Ixekizumab 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to ˂2,000 cells/mm3). Neutropenia in the Ixekizumab group was not associated with an increased rate of infection compared to the placebo group.
- Thrombocytopenia
Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Ixekizumab 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with Ixekizumab was not associated with an increased rate of bleeding compared to subjects treated with placebo.
In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S. approved etanercept and 2% for Ixekizumab 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Ixekizumab 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Ixekizumab 80 mg Q2W. The rate of serious infections was 0.3% for both Ixekizumab 80 mg Q2W and U.S. approved etanercept.
## Immunogenicity
As with all therapeutic proteins there is the potential for immunogenicity with Ixekizumab. By Week 12, approximately 9% of subjects treated with Ixekizumab every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Ixekizumab at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.
Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Ixekizumab at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.
However, the assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.
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, comparison of incidence of antibodies to Ixekizumab with the incidences of antibodies to other products may be misleading.
## Postmarketing Experience
FDA Package Insert for Ixekizumab contains no information regarding Adverse Reactions.
# Drug Interactions
Avoid use of live vaccines in patients treated with Ixekizumab.
The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, Ixekizumab, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.
Therefore, upon initiation or discontinuation of Ixekizumab in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There are no available data on Ixekizumab use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, Ixekizumab may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD. The clinical significance of these nonclinical findings is unknown.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
- Animal Data
An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.
In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ixekizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ixekizumab during labor and delivery.
### Nursing Mothers
There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ixekizumab and any potential adverse effects on the breastfed infant from Ixekizumab or from the underlying maternal condition.
### Pediatric Use
The safety and effectiveness of Ixekizumab in pediatric patients (<18 years of age) have not been evaluated.
### Geriatic Use
Of the 4204 psoriasis subjects exposed to Ixekizumab, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ixekizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ixekizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ixekizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ixekizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ixekizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ixekizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ixekizumab Administration in the drug label.
### Monitoring
There is limited information regarding Ixekizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ixekizumab and IV administrations.
# Overdosage
In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.
## Structure
There is limited information regarding Ixekizumab Structure in the drug label.
## Pharmacodynamics
No formal pharmacodynamic studies have been conducted with Ixekizumab.
## Pharmacokinetics
Following a single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (±SD) serum concentrations (Cmax) of 16.2 ±6.6 mcg/mL by approximately 4 days post dose.
Steady-state concentrations were achieved by Week 8 following the 160 mg starting dose and 80 mg every 2 weeks dosing regimen; the mean ±SD steady-state trough concentration was 9.3 ±5.3 mcg/mL. Steady-state concentrations were achieved approximately 10 weeks after switching from the 80 mg every 2 weeks dosing regimen to the 80 mg every 4 weeks dosing regimen at Week 12. The mean ±SD steady-state trough concentration was 3.5 ±2.5 mcg/mL.
In studies of subjects with plaque psoriasis, ixekizumab bioavailability ranged from 60% to 81% following subcutaneous injection. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.
The mean (geometric CV%) volume of distribution at steady-state was 7.11 L (29%) in subjects with plaque psoriasis.
The metabolic pathway of ixekizumab has not been characterized. As a humanized IgG4 monoclonal antibody ixekizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
The mean systemic clearance was 0.39 L/day (37%) and the mean (geometric CV%) half life was 13 days (40%) in subjects with plaque psoriasis.
- Weight
Ixekizumab clearance and volume of distribution increase as body weight increases.
- Dose Linearity
Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg (not the recommended dose) to 160 mg following subcutaneous administration.
## Nonclinical Toxicology
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of Ixekizumab. Moreover published literature is mixed on potential effects on malignancy risk due to the inhibition of IL-17A activity, the pharmacological action of Ixekizumab. Some published literature suggests that IL-17A directly promotes cancer cell invasion, suggesting a potential beneficial effect by Ixekizumab, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection, suggesting a potential adverse effect by Ixekizumab. However, neutralization of IL-17A with Ixekizumab has not been studied in these models. Depletion of IL-17A with a neutralizing antibody inhibited tumor development in mice, suggesting a potential beneficial effect by Ixekizumab. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown.
No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature cynomolgus monkeys that were administered ixekizumab for 13 weeks at a subcutaneous dose of 50 mg/kg/week (19 times the MRHD on a mg/kg basis). The monkeys were not mated to evaluate fertility.
# Clinical Studies
Three multicenter, randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a total of 3866 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, a Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy.
In all three trials, subjects were randomized to either placebo or Ixekizumab (80 mg every two weeks ) for 12 weeks, following a 160 mg starting dose. In the two active comparator trials (Trials 2 and 3), subjects were also randomized to receive U.S. approved etanercept 50 mg twice weekly for 12 weeks.
All three trials assessed the changes from baseline to Week 12 in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema and scaling) within the affected regions, and 2) sPGA of “0” (clear) or “1” (minimal), the proportion of subjects with an sPGA 0 or 1 and at least a 2-point improvement.
Other evaluated outcomes included the proportion of subjects with an sPGA score of 0 (clear), a reduction of at least 90% in PASI (PASI 90), a reduction of 100% in PASI (PASI 100), and an improvement of itch severity as measured by a reduction of at least 4 points on an 11-point itch Numeric Rating Scale.
Subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline sPGA score was severe or very severe in 51% of subjects in Trial 1, 50% in Trial 2, and 48% in Trial 3.
Of all subjects, 44% had received prior phototherapy, 49% had received prior conventional systemic therapy, and 26% had received prior biologic therapy for the treatment of psoriasis. Of the subjects who had received prior biologic therapy, 15% had received at least one anti-TNF alpha agent, and 9% had received an anti-IL 12/IL23. A total of 23% of study subjects had a history of psoriatic arthritis.
The results of Trials 1, 2, and 3 are presented in Table 2.
Examination of age, gender, race, body weight, and previous treatment with a biologic did not identify differences in response to Ixekizumab among these subgroups at Week 12.
Subjects treated with Ixekizumab 80 mg Q2W experienced improvement in itch severity when compared to placebo at Week 12.
An integrated analysis of the U.S. sites in the two active comparator studies using U.S. approved etanercept, Ixekizumab demonstrated superiority to U.S. approved etanercept (50 mg twice weekly) on sPGA and PASI scores during the 12 week treatment period. The respective response rates for Ixekizumab 80 mg Q2W and U.S. approved etanercept 50 mg twice weekly were: sPGA of 0 or 1 (73% and 27%); PASI 75 (87% and 41%); sPGA of 0 (34% and 5%); PASI 90 (64% and 18%), and PASI 100 (34% and 4%).
To evaluate the maintenance and durability of response, subjects originally randomized to Ixekizumab and who were responders at Week 12 (i.e., sPGA of 0 or 1) in Trial 1 and Trial 2 were re-randomized to an additional 48 weeks of either a maintenance dose of Ixekizumab 80 mg Q4W (every four weeks) or placebo. Non-responders (sPGA >1) at Week 12 and subjects who relapsed (sPGA ≥3) during the maintenance period were placed on Ixekizumab 80 mg Q4W.
For responders at Week 12, the percentage of subjects who maintained this response (sPGA 0 or 1) at Week 60 (48 weeks following re-randomization) in the integrated trials (Trial 1 and Trial 2) was higher for subjects treated with Ixekizumab 80 mg Q4W (75%) compared to those treated with placebo (7%).
For responders at Week 12 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to relapse (sPGA ≥3) was 164 days in the integrated trials. Among these subjects, 66% regained a response of at least 0 or 1 on the sPGA within 12 weeks of restarting treatment with Ixekizumab 80 mg Q4W.
# How Supplied
Ixekizumab injection is a sterile, preservative free, clear and colorless to slightly yellow solution available in a single-dose prefilled autoinjector or a single-dose prefilled syringe to deliver 80 mg ixekizumab.
Ixekizumab is supplied as:
## Storage
Ixekizumab is sterile and preservative-free. Discard any unused portion.
- Ixekizumab must be protected from light until use.
- Store refrigerated at 2°C to 8°C (36°F to 46°F).
- Do not freeze. Do not use Ixekizumab if it has been frozen.
- Do not shake.
- Discard the Ixekizumab single-dose autoinjector or syringe after use in a puncture-resistant container.
- Not made with natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Ixekizumab, and each time the prescription is renewed, as there may be new information they need to know.
- Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly.
- Infection: Inform patients that Ixekizumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection.
- Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.
# Precautions with Alcohol
Alcohol-Ixekizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Ixekizumab Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ixekizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ixekizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shankar Kumar, 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.
# Overview
Ixekizumab is a humanized anti-interleukin-17 monoclonal antibody that is FDA approved for the treatment of of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Common adverse reactions include injection site reactions, upper respiratory tract infections, nausea, and tinea infections (≥1%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ixekizumab is administered by subcutaneous injection. The recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Ixekizumab.
There are two presentations for Ixekizumab (i.e., autoinjector and prefilled syringe).
Ixekizumab is intended for use under the guidance and supervision of a physician. Patients may self-inject after training in subcutaneous injection technique using the autoinjector or prefilled syringe. Administer each injection at a different anatomic location (such as upper arms, thighs or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of Ixekizumab in the upper, outer arm may be performed by a caregiver or healthcare provider.
If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
Before injection, remove Ixekizumab autoinjector or Ixekizumab prefilled syringe from the refrigerator and allow Ixekizumab to reach room temperature (30 minutes) without removing the needle cap.
Inspect Ixekizumab formulation visually for particulate matter and discoloration prior to administration. Ixekizumab formulation is a clear and colorless to slightly yellow solution. Do not use if the liquid contains visible particles, is discolored or cloudy (other than clear and colorless to slightly yellow). Ixekizumab formulation does not contain preservatives, therefore discard any unused product remaining in the autoinjector or prefilled syringe.
Instruct patients using the autoinjector or prefilled syringe to inject the full amount (1 mL), which provides 80 mg of Ixekizumab, according to the directions.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixekizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixekizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Ixekizumab contains no information regarding Pediatric Indications and Dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixekizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixekizumab in pediatric patients.
# Contraindications
Ixekizumab is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.
# Warnings
Ixekizumab may increase the risk of infection. In clinical trials, the Ixekizumab treated group had a higher rate of infections than the placebo group (27% vs. 23%). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Ixekizumab treated group than in the placebo group.
Instruct patients treated with Ixekizumab to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Ixekizumab until the infection resolves.
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Ixekizumab. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Ixekizumab. Consider anti-TB therapy prior to initiating Ixekizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Ixekizumab should be monitored closely for signs and symptoms of active TB during and after treatment.
Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Ixekizumab group in clinical trials. If a serious hypersensitivity reaction occurs, discontinue Ixekizumab immediately and initiate appropriate therapy.
Crohn's disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Ixekizumab group (Crohn's disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period. During Ixekizumab treatment, monitor for onset or exacerbation of inflammatory bowel disease.
Prior to initiating therapy with Ixekizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Ixekizumab. No data are available on the response to live or inactive vaccines.
# Adverse Reactions
## Clinical Trials Experience
The following adverse drug reactions are discussed in greater detail in other sections of the label:
- Infections
- Hypersensitivity Reactions
- Inflammatory Bowel Disease
Because clinical trials are conducted under widely varying and controlled 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.
### Weeks 0 to 12:
Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Ixekizumab compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Ixekizumab (160 mg at Week 0, 80 mg every two weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of Ixekizumab (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept.
In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Ixekizumab Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the Ixekizumab group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).
Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Ixekizumab group than in the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.
Adverse reactions that occurred at rates less than 1% in the Ixekizumab group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema.
### Weeks 13 to 60:
A total of 332 subjects received the recommended maintenance regimen of Ixekizumab 80 mg dosed every 4 weeks.
During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Ixekizumab (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Ixekizumab (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.
### Weeks 0 to 60:
Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Ixekizumab (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Ixekizumab (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).
### Specific Adverse Drug Reactions
The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Ixekizumab.
In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Ixekizumab (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Ixekizumab (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up).
During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Ixekizumab (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Ixekizumab (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.
Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Ixekizumab (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Ixekizumab (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).
- Neutropenia
Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Ixekizumab (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Ixekizumab, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.
In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Ixekizumab group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Ixekizumab 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Ixekizumab 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to ˂2,000 cells/mm3). Neutropenia in the Ixekizumab group was not associated with an increased rate of infection compared to the placebo group.
- Thrombocytopenia
Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Ixekizumab 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with Ixekizumab was not associated with an increased rate of bleeding compared to subjects treated with placebo.
In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S. approved etanercept and 2% for Ixekizumab 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Ixekizumab 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Ixekizumab 80 mg Q2W. The rate of serious infections was 0.3% for both Ixekizumab 80 mg Q2W and U.S. approved etanercept.
## Immunogenicity
As with all therapeutic proteins there is the potential for immunogenicity with Ixekizumab. By Week 12, approximately 9% of subjects treated with Ixekizumab every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Ixekizumab at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.
Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Ixekizumab at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.
However, the assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.
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, comparison of incidence of antibodies to Ixekizumab with the incidences of antibodies to other products may be misleading.
## Postmarketing Experience
FDA Package Insert for Ixekizumab contains no information regarding Adverse Reactions.
# Drug Interactions
Avoid use of live vaccines in patients treated with Ixekizumab.
The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, Ixekizumab, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.
Therefore, upon initiation or discontinuation of Ixekizumab in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There are no available data on Ixekizumab use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, Ixekizumab may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD. The clinical significance of these nonclinical findings is unknown.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
- Animal Data
An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.
In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ixekizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ixekizumab during labor and delivery.
### Nursing Mothers
There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ixekizumab and any potential adverse effects on the breastfed infant from Ixekizumab or from the underlying maternal condition.
### Pediatric Use
The safety and effectiveness of Ixekizumab in pediatric patients (<18 years of age) have not been evaluated.
### Geriatic Use
Of the 4204 psoriasis subjects exposed to Ixekizumab, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ixekizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ixekizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ixekizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ixekizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ixekizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ixekizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ixekizumab Administration in the drug label.
### Monitoring
There is limited information regarding Ixekizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ixekizumab and IV administrations.
# Overdosage
In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.
## Structure
There is limited information regarding Ixekizumab Structure in the drug label.
## Pharmacodynamics
No formal pharmacodynamic studies have been conducted with Ixekizumab.
## Pharmacokinetics
Following a single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (±SD) serum concentrations (Cmax) of 16.2 ±6.6 mcg/mL by approximately 4 days post dose.
Steady-state concentrations were achieved by Week 8 following the 160 mg starting dose and 80 mg every 2 weeks dosing regimen; the mean ±SD steady-state trough concentration was 9.3 ±5.3 mcg/mL. Steady-state concentrations were achieved approximately 10 weeks after switching from the 80 mg every 2 weeks dosing regimen to the 80 mg every 4 weeks dosing regimen at Week 12. The mean ±SD steady-state trough concentration was 3.5 ±2.5 mcg/mL.
In studies of subjects with plaque psoriasis, ixekizumab bioavailability ranged from 60% to 81% following subcutaneous injection. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.
The mean (geometric CV%) volume of distribution at steady-state was 7.11 L (29%) in subjects with plaque psoriasis.
The metabolic pathway of ixekizumab has not been characterized. As a humanized IgG4 monoclonal antibody ixekizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
The mean systemic clearance was 0.39 L/day (37%) and the mean (geometric CV%) half life was 13 days (40%) in subjects with plaque psoriasis.
- Weight
Ixekizumab clearance and volume of distribution increase as body weight increases.
- Dose Linearity
Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg (not the recommended dose) to 160 mg following subcutaneous administration.
## Nonclinical Toxicology
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of Ixekizumab. Moreover published literature is mixed on potential effects on malignancy risk due to the inhibition of IL-17A activity, the pharmacological action of Ixekizumab. Some published literature suggests that IL-17A directly promotes cancer cell invasion, suggesting a potential beneficial effect by Ixekizumab, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection, suggesting a potential adverse effect by Ixekizumab. However, neutralization of IL-17A with Ixekizumab has not been studied in these models. Depletion of IL-17A with a neutralizing antibody inhibited tumor development in mice, suggesting a potential beneficial effect by Ixekizumab. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown.
No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature cynomolgus monkeys that were administered ixekizumab for 13 weeks at a subcutaneous dose of 50 mg/kg/week (19 times the MRHD on a mg/kg basis). The monkeys were not mated to evaluate fertility.
# Clinical Studies
Three multicenter, randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a total of 3866 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, a Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy.
In all three trials, subjects were randomized to either placebo or Ixekizumab (80 mg every two weeks [Q2W]) for 12 weeks, following a 160 mg starting dose. In the two active comparator trials (Trials 2 and 3), subjects were also randomized to receive U.S. approved etanercept 50 mg twice weekly for 12 weeks.
All three trials assessed the changes from baseline to Week 12 in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema and scaling) within the affected regions, and 2) sPGA of “0” (clear) or “1” (minimal), the proportion of subjects with an sPGA 0 or 1 and at least a 2-point improvement.
Other evaluated outcomes included the proportion of subjects with an sPGA score of 0 (clear), a reduction of at least 90% in PASI (PASI 90), a reduction of 100% in PASI (PASI 100), and an improvement of itch severity as measured by a reduction of at least 4 points on an 11-point itch Numeric Rating Scale.
Subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline sPGA score was severe or very severe in 51% of subjects in Trial 1, 50% in Trial 2, and 48% in Trial 3.
Of all subjects, 44% had received prior phototherapy, 49% had received prior conventional systemic therapy, and 26% had received prior biologic therapy for the treatment of psoriasis. Of the subjects who had received prior biologic therapy, 15% had received at least one anti-TNF alpha agent, and 9% had received an anti-IL 12/IL23. A total of 23% of study subjects had a history of psoriatic arthritis.
The results of Trials 1, 2, and 3 are presented in Table 2.
Examination of age, gender, race, body weight, and previous treatment with a biologic did not identify differences in response to Ixekizumab among these subgroups at Week 12.
Subjects treated with Ixekizumab 80 mg Q2W experienced improvement in itch severity when compared to placebo at Week 12.
An integrated analysis of the U.S. sites in the two active comparator studies using U.S. approved etanercept, Ixekizumab demonstrated superiority to U.S. approved etanercept (50 mg twice weekly) on sPGA and PASI scores during the 12 week treatment period. The respective response rates for Ixekizumab 80 mg Q2W and U.S. approved etanercept 50 mg twice weekly were: sPGA of 0 or 1 (73% and 27%); PASI 75 (87% and 41%); sPGA of 0 (34% and 5%); PASI 90 (64% and 18%), and PASI 100 (34% and 4%).
To evaluate the maintenance and durability of response, subjects originally randomized to Ixekizumab and who were responders at Week 12 (i.e., sPGA of 0 or 1) in Trial 1 and Trial 2 were re-randomized to an additional 48 weeks of either a maintenance dose of Ixekizumab 80 mg Q4W (every four weeks) or placebo. Non-responders (sPGA >1) at Week 12 and subjects who relapsed (sPGA ≥3) during the maintenance period were placed on Ixekizumab 80 mg Q4W.
For responders at Week 12, the percentage of subjects who maintained this response (sPGA 0 or 1) at Week 60 (48 weeks following re-randomization) in the integrated trials (Trial 1 and Trial 2) was higher for subjects treated with Ixekizumab 80 mg Q4W (75%) compared to those treated with placebo (7%).
For responders at Week 12 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to relapse (sPGA ≥3) was 164 days in the integrated trials. Among these subjects, 66% regained a response of at least 0 or 1 on the sPGA within 12 weeks of restarting treatment with Ixekizumab 80 mg Q4W.
# How Supplied
Ixekizumab injection is a sterile, preservative free, clear and colorless to slightly yellow solution available in a single-dose prefilled autoinjector or a single-dose prefilled syringe to deliver 80 mg ixekizumab.
Ixekizumab is supplied as:
## Storage
Ixekizumab is sterile and preservative-free. Discard any unused portion.
- Ixekizumab must be protected from light until use.
- Store refrigerated at 2°C to 8°C (36°F to 46°F).
- Do not freeze. Do not use Ixekizumab if it has been frozen.
- Do not shake.
- Discard the Ixekizumab single-dose autoinjector or syringe after use in a puncture-resistant container.
- Not made with natural rubber latex.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Ixekizumab, and each time the prescription is renewed, as there may be new information they need to know.
- Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly.
- Infection: Inform patients that Ixekizumab may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection.
- Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.
# Precautions with Alcohol
Alcohol-Ixekizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Ixekizumab Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ixekizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ixekizumab | |
4ebce2194565f225c9f53357c2a0133d4b05b665 | wikidoc | IκB kinase | IκB kinase
The IκB kinase (IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation.
The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor of kappa B) protein inactivates the NF-κB transcription factor by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm. Specifically, IKK phosphorylates the inhibitory IκBα protein. This phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is now free, migrates into the nucleus and activates the expression of at least 150 genes; some of which are anti-apoptotic.
# Catalyzed reaction
In enzymology, an IκB kinase (EC 2.7.11.10) is an enzyme that catalyzes the chemical reaction:
Thus, the two substrates of this enzyme are ATP and IκB protein, whereas its two products are ADP and IκB phosphoprotein.
This enzyme belongs to the family of transferases, specifically those transferring a phosphate group to the sidechain oxygen atom of serine or threonine residues in proteins (protein-serine/threonine kinases). The systematic name of this enzyme class is ATP: phosphotransferase.
# Structure
The IκB kinase complex is composed of three subunits each encoded by a separate gene:
- IKK-α (also known as IKK1) (CHUK)
- IKK-β (also known as IKK2) (IKBKB)
- IKK-γ (also known as NEMO) (IKBKG)
The α- and β-subunits together are catalytically active whereas the γ-subunit serves a regulatory function.
The IKK-α and IKK-β kinase subunits are homologous in structure, composed of a kinase domain, as well as leucine zipper and helix-loop-helix dimerization domains, and a carboxy-terminal NEMO-binding domain (NBD). Mutational studies have revealed the identity of the NBD amino acid sequence as leucine-aspartate-tryptophan-serine-tryptophan-leucine, encoded by residues 737-742 and 738-743 of IKK-α and IKK-β, respectively. The regulatory IKK-γ subunit, or NEMO, is composed of two coiled coil domains, a leucine zipper dimerization domain, and a zinc finger-binding domain. Specifically, the NH2-terminus of NEMO binds to the NBD sequences on IKK-α and IKK-β, leaving the rest of NEMO accessible for interacting with regulatory proteins.
# Function
IκB kinase activity is essential for activation of members of the nuclear factor-kB (NF-κB) family of transcription factors, which play a fundamental role in lymphocyte immunoregulation. Activation of the canonical, or classical, NF-κB pathway begins in response to stimulation by various pro-inflammatory stimuli, including lipopolysaccharide (LPS) expressed on the surface of pathogens, or the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1). Following immune cell stimulation, a signal transduction cascade leads to the activation of the IKK complex, an event characterized by the binding of NEMO to the homologous kinase subunits IKK-α and IKK-β. The IKK complex phosphorylates serine residues (S32 and S36) within the amino-terminal domain of inhibitor of NF-κB (IκBα) upon activation, consequently leading to its ubiquitination and subsequent degradation by the proteasome. Degradation of IκBα releases the prototypical p50-p65 dimer for translocation to the nucleus, where it binds to κB sites and directs NF-κB-dependent transcriptional activity. NF-κB target genes can be differentiated by their different functional roles within lymphocyte immunoregulation and include positive cell-cycle regulators, anti-apoptotic and survival factors, and pro-inflammatory genes. Collectively, activation of these immunoregulatory factors promotes lymphocyte proliferation, differentiation, growth, and survival.
# Regulation
Activation of the IKK complex is dependent on phosphorylation of serine residues within the kinase domain of IKK-β, though IKK-α phosphorylation occurs concurrently in endogenous systems. Recruitment of IKK kinases by the regulatory domains of NEMO leads to the phosphorylation of two serine residues within the activation loop of IKK-β, moving the activation loop away from the catalytic pocket, thus allowing access to ATP and IκBα peptide substrates. Furthermore, the IKK complex is capable of undergoing trans-autophosphorylation, where the activated IKK-β kinase subunit phosphorylates its adjacent IKK-α subunit, as well as other inactive IKK complexes, thus resulting in high levels of IκB kinase activity. Following IKK-mediated phosphorylation of IκBα and the subsequent decrease in IκB abundance, the activated IKK kinase subunits undergo extensive carboxy-terminal autophosphorylation, reaching a low activity state that is further susceptible to complete inactivation by phosphatases once upstream inflammatory signaling diminishes.
# Deregulation and disease
Though functionally adaptive in response to inflammatory stimuli, deregulation of NF-κB signaling has been exploited in various disease states. Increased NF-κB activity as a result of constitutive IKK-mediated phosphorylation of IκBα has been observed in the development of atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. Specifically, constitutive NF-κB activity promotes continuous inflammatory signaling at the molecular level that translates to chronic inflammation phenotypically. Furthermore, the ability of NF-κB to simultaneously suppress apoptosis and promote continuous lymphocyte growth and proliferation explains its intimate connection with many types of cancer.
# Clinical significance
This enzyme participates in 15 pathways related to metabolism: MapK signaling, apoptosis, Toll-like receptor signaling, T-cell receptor signaling, B-cell receptor signaling, insulin signaling, adipokine signaling, Type 2 diabetes mellitus, epithelial cell signaling in helicobacter pylori, pancreatic cancer, prostate cancer, chronic myeloid leukemia, acute myeloid leukemia, and small cell lung cancer.
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer. The small-molecule inhibitor of IKK-β SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis. | IκB kinase
The IκB kinase (IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation.[1]
The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor of kappa B) protein inactivates the NF-κB transcription factor by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.[2][3][4] Specifically, IKK phosphorylates the inhibitory IκBα protein.[5] This phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is now free, migrates into the nucleus and activates the expression of at least 150 genes; some of which are anti-apoptotic.
# Catalyzed reaction
In enzymology, an IκB kinase (EC 2.7.11.10) is an enzyme that catalyzes the chemical reaction:
Thus, the two substrates of this enzyme are ATP and IκB protein, whereas its two products are ADP and IκB phosphoprotein.
This enzyme belongs to the family of transferases, specifically those transferring a phosphate group to the sidechain oxygen atom of serine or threonine residues in proteins (protein-serine/threonine kinases). The systematic name of this enzyme class is ATP:[IκB protein] phosphotransferase.
# Structure
The IκB kinase complex is composed of three subunits each encoded by a separate gene:
- IKK-α (also known as IKK1) (CHUK)
- IKK-β (also known as IKK2) (IKBKB)
- IKK-γ (also known as NEMO) (IKBKG)
The α- and β-subunits together are catalytically active whereas the γ-subunit serves a regulatory function.
The IKK-α and IKK-β kinase subunits are homologous in structure, composed of a kinase domain, as well as leucine zipper and helix-loop-helix dimerization domains, and a carboxy-terminal NEMO-binding domain (NBD).[6] Mutational studies have revealed the identity of the NBD amino acid sequence as leucine-aspartate-tryptophan-serine-tryptophan-leucine, encoded by residues 737-742 and 738-743 of IKK-α and IKK-β, respectively.[7] The regulatory IKK-γ subunit, or NEMO, is composed of two coiled coil domains, a leucine zipper dimerization domain, and a zinc finger-binding domain.[6] Specifically, the NH2-terminus of NEMO binds to the NBD sequences on IKK-α and IKK-β, leaving the rest of NEMO accessible for interacting with regulatory proteins.[7]
# Function
IκB kinase activity is essential for activation of members of the nuclear factor-kB (NF-κB) family of transcription factors, which play a fundamental role in lymphocyte immunoregulation.[6][8] Activation of the canonical, or classical, NF-κB pathway begins in response to stimulation by various pro-inflammatory stimuli, including lipopolysaccharide (LPS) expressed on the surface of pathogens, or the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1). Following immune cell stimulation, a signal transduction cascade leads to the activation of the IKK complex, an event characterized by the binding of NEMO to the homologous kinase subunits IKK-α and IKK-β. The IKK complex phosphorylates serine residues (S32 and S36) within the amino-terminal domain of inhibitor of NF-κB (IκBα) upon activation, consequently leading to its ubiquitination and subsequent degradation by the proteasome.[5] Degradation of IκBα releases the prototypical p50-p65 dimer for translocation to the nucleus, where it binds to κB sites and directs NF-κB-dependent transcriptional activity.[8] NF-κB target genes can be differentiated by their different functional roles within lymphocyte immunoregulation and include positive cell-cycle regulators, anti-apoptotic and survival factors, and pro-inflammatory genes. Collectively, activation of these immunoregulatory factors promotes lymphocyte proliferation, differentiation, growth, and survival.[9]
# Regulation
Activation of the IKK complex is dependent on phosphorylation of serine residues within the kinase domain of IKK-β, though IKK-α phosphorylation occurs concurrently in endogenous systems. Recruitment of IKK kinases by the regulatory domains of NEMO leads to the phosphorylation of two serine residues within the activation loop of IKK-β, moving the activation loop away from the catalytic pocket, thus allowing access to ATP and IκBα peptide substrates. Furthermore, the IKK complex is capable of undergoing trans-autophosphorylation, where the activated IKK-β kinase subunit phosphorylates its adjacent IKK-α subunit, as well as other inactive IKK complexes, thus resulting in high levels of IκB kinase activity. Following IKK-mediated phosphorylation of IκBα and the subsequent decrease in IκB abundance, the activated IKK kinase subunits undergo extensive carboxy-terminal autophosphorylation, reaching a low activity state that is further susceptible to complete inactivation by phosphatases once upstream inflammatory signaling diminishes.[5]
# Deregulation and disease
Though functionally adaptive in response to inflammatory stimuli, deregulation of NF-κB signaling has been exploited in various disease states.[5][6][7][8][9][10] Increased NF-κB activity as a result of constitutive IKK-mediated phosphorylation of IκBα has been observed in the development of atherosclerosis, asthma, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis.[8][10] Specifically, constitutive NF-κB activity promotes continuous inflammatory signaling at the molecular level that translates to chronic inflammation phenotypically. Furthermore, the ability of NF-κB to simultaneously suppress apoptosis and promote continuous lymphocyte growth and proliferation explains its intimate connection with many types of cancer.[8][9]
# Clinical significance
This enzyme participates in 15 pathways related to metabolism: MapK signaling, apoptosis, Toll-like receptor signaling, T-cell receptor signaling, B-cell receptor signaling, insulin signaling, adipokine signaling, Type 2 diabetes mellitus, epithelial cell signaling in helicobacter pylori, pancreatic cancer, prostate cancer, chronic myeloid leukemia, acute myeloid leukemia, and small cell lung cancer.
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[11] The small-molecule inhibitor of IKK-β SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.[11][12] | https://www.wikidoc.org/index.php/I%CE%BAB_kinase | |
ce9cd2edf42f2547d3f4cf13786e2747f9da2656 | wikidoc | Topiramate | Topiramate
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# Overview
Topiramate is an antiepileptic drug that is FDA approved for the {{{indicationType}}} of partial seizures, primary generalized tonic-clonic seizures and Lennox-Gastaut syndrome. Common adverse reactions include paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, cognitive problem, confusion, mood problems, fever, infection, and flushing.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Monotherapy Use
- The recommended dose for topiramate monotherapy in adults is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy in adults with partial onset seizures is 200 mg to 400 mg orally once daily.
- Monotherapy Use
- The recommended dose for topiramate monotherapy in adults is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total dose for adults with primary generalized tonic-clonic seizures is 400 mg orally once daily.
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy in adults with Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Topiramate in adult patients.
### Non–Guideline-Supported Use
- Topiramate therapy was started at 25 mg once daily, and increased at weekly intervals for 5 weeks to a total dose of 300 mg, divided twice daily. Patients remained on this dose from week 6 to the beginning of week 14, and then tapered off by week 16.
- Topiramate 25 mg daily titrated over an 8-week period to 400 mg/day or the maximum tolerated dose.
- Topiramate 25 mg/day for 1 week, with weekly titrations in increments of 25 or 50 mg/day up to 200 mg/day, then 100 mg/day weekly increments to a clinical response, up to a maximum of 400 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Monotherapy Use
- The recommended dose for topiramate monotherapy in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with partial onset seizures is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
- Monotherapy Use
- The recommended dose for topiramate monotherapy in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with primary generalized tonic-clonic seizures is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Topiramate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Topiramate in pediatric patients.
# Contraindications
- QUDEXY XR is contraindicated in patients with metabolic acidosis who are taking concomitant metformin.
# Warnings
### Precautions
- Acute Myopia and Secondary Angle Closure Glaucoma
- A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of QUDEXY XR as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of QUDEXY XR, may be helpful.
- Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
- Visual Field Defects
- Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
- Oligohydrosis and Hyperthermia
- Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.
- The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with QUDEXY XR should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when QUDEXY XR is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
- Metabolic Acidosis
- Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.
- Adults
- In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of less than 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg per day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in a controlled clinical trial for monotherapy was 15% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg per day and 7% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day.
- Pediatric Patients (2 years to 16 years of age)
- The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.
- In pediatric patients (6 years to 15 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day.
- Pediatric Patients (under 2 years of age)
- Although QUDEXY XR is not approved for use in patients less than 2 years of age with partial onset seizures, a study of topiramate as adjunctive use in patients under 2 years of age revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate less than 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day.
- Manifestations of Metabolic Acidosis
- Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sex-matched normative data, although these patients are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus.
- Risk Mitigation Strategies
- Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including QUDEXY XR, for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing QUDEXY XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Cognitive/Neuropsychiatric Adverse Reactions
- Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of QUDEXY XR were related to the central nervous system and were observed in the epilepsy population. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties), 2) Psychiatric/behavioral disturbances (e.g. depression or mood problems), and 3) Somnolence or fatigue.
- Adult Patients
- Cognitive Related Dysfunction
- The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment.
- In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200mg per day, 41% for 400mg per day, 52% for 600mg per day, 56% for 800 and 1,000 mg per day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.
- In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50mg per day and 26% for 400mg per day.
- Psychiatric/Behavioral Disturbances
- Psychiatric/behavioral disturbances (depression or mood) were dose-related for the epilepsy population treated with topiramate.
- Somnolence/Fatigue
- Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For other uses not approved for QUDEXY XR, somnolence and fatigue were more common in the titration phase.
- Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia.
- Pediatric Patients
- In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, the incidences of cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in the 50 mg per day and 400 mg per day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.
- No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per day group discontinued treatment due to any adverse events. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group.
- Fetal Toxicity
- Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.
- Consider the benefits and risks of topiramate when administering the drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.
- Withdrawal of Antiepileptic Drugs
- In patients with or without a history of seizures or epilepsy, antiepileptic drugs including QUDEXY XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In situations where rapid withdrawal of QUDEXY XR is medically required, appropriate monitoring is recommended.
- Hyperammonemia and Encephalopathy
- Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)
- Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs in very young pediatric patients (1 month to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy (8% for placebo, 10% for 5 mg/kg/day, 0% for 15 mg/kg/day, 9% for 25 mg/kg/day). QUDEXY XR is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (greater than 50% above upper limit of normal). The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.
- Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).
- Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)
- Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.
- Although QUDEXY XR is not indicated for use in infants/toddlers (1 month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate in these very young, pediatric patients.
- Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with valproic acid (VPA).
- The hyperammonemia associated with topiramate treatment appears to be more common when used concomitantly with VPA.
- Monitoring for Hyperammonemia
- Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or QUDEXY XR treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.
- In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
- Kidney Stones
- A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. QUDEXY XR is not approved for pediatric patients less than 2 years old.
- QUDEXY XR would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of QUDEXY XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.
- Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
- Hypothermia with Concomitant Valproic Acid Use
- Hypothermia, defined as an unintentional drop in body core temperature to less than 35ºC (95ºF) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
- Paresthesia
- Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials conducted with immediate-release topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation.
- Interaction with Other CNS Depressants
- Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Patients should be watched carefully when QUDEXY XR is co-administered with other CNS depressant drugs.
# 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 adverse reactions in the monotherapy controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group (incidence greater than or equal to 5%) and at a rate higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory .
- Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (greater than or equal to 2% more frequent than low-dose 50 mg per day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence and paresthesia.
- The adverse reactions in the controlled trial (Study 1) that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg per day topiramate group (incidence greater than or equal to 5%) and at a rate higher than in the 50 mg per day group were weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems .
- Approximately 12% of the 57 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (greater than 5%) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention.
- The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia . The most common dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease .
- Adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease .
- In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400mg per day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.
- Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200 mg to 1,600 mg per day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).
- Table 4 lists adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 7 lists adverse reactions that occurred in at least 1% of pediatric patients treated with 5 mg/kg to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.
- Other adverse reactions that occurred in more than 1% of adults treated with 200 mg to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.
- Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.
- The incidence of adverse reactions (Table 5) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.
- Topiramate decreases serum bicarbonate.
- Immediate-release topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Similar effects should be anticipated with use of QUDEXY XR.
- Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established.
- Changes in several clinical laboratory results (increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count and decreased potassium) have been observed in a clinical investigational program in very young (2 years and younger) pediatric patients who were treated with adjunctive topiramate for partial onset seizures.
- Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study. The incidence of these abnormal shifts was 4% for placebo, 4% for 50 mg, and 18% for 100 mg.
- Topiramate treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy.
- 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. In the QUDEXY XR study, a dose of 200 mg/day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience.
- The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the QUDEXY XR study.
- Table 8 displays the incidence of treatment-emergent adverse reactions that occurred in ≥2% of patients and numerically greater than placebo.
- In the controlled clinical study using QUDEXY XR, 8.9% of patients who received QUDEXY XR and 4.0% who received placebo discontinued as a result of treatment-emergent adverse reactions.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of topiramate. 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. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, and pemphigus.
# Drug Interactions
- Oral Contraceptives
- The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with QUDEXY XR. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.
- Antiepileptic Drugs
- Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate.
- Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.
- Numerous AEDs are substrates of the CYP enzyme system. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of QUDEXY XR.
- CNS Depressants and Alcohol
- Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Concomitant use of alcohol should be avoided.
- Other Carbonic Anhydrase Inhibitors
- Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when QUDEXY XR is given concomitantly with another carbonic anhydrase inhibitor.
- Metformin
- Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. The concomitant use of QUDEXY XR and metformin is contraindicated in patients with metabolic acidosis.
- Lithium
- In patients, there was an observed increase in systemic exposure of lithium following topiramate doses of up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus .
- Pregnancy Registry
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at /.
- Human Data
- Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% - 0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=CI 3.6-25.7) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%.
- Topiramate treatment can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.
- Animal Data
- Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20 mg/kg, 100 mg/kg, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400 mg per day on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.
- In rat studies (oral doses of 20 mg/kg, 100 mg/kg, and 500 mg/kg or 0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.
- In rabbit studies (20 mg/kg, 60 mg/kg, and 180 mg/kg or 10 mg/kg, 35 mg/kg, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.
- When female rats were treated during the latter part of gestation and throughout lactation (0.2 mg/kg, 4 mg/kg, 20 mg/kg, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre-and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.
- In a rat embryo/fetal development study with a postnatal component (0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2 basis) and higher.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Topiramate in women who are pregnant.
### Labor and Delivery
- Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor.
### Nursing Mothers
- Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when QUDEXY XR is administered to a nursing woman.
### Pediatric Use
- Seizures in Pediatric Patients 2 Years of Age and Older
- The safety and effectiveness of QUDEXY XR in pediatric patients is based on controlled trials with immediate-release topiramate.
- The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults.
- These include, but are not limited to:
- Oligohydrosis and hyperthermia.
- Dose-related increased incidence of metabolic acidosis.
- Dose-related increased incidence of hyperammonemia.
- Adjunctive Treatment for Epilepsy with Partial Onset Seizures in Infants and Toddlers (1 to 24 months)
- The following pediatric use information is based on studies conducted with immediate-release topiramate.
- Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures, was assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures.
- In general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications.
- These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older children.
- Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase. The significance of these findings is uncertain.
- Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain.
- Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference.
- In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease).
- In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known.
- Other Pediatric Studies
- Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study.
- Juvenile Animal Studies
- When topiramate (30 mg/kg/day, 90 mg/kg/day or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis.
### Geriatic Use
- Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment is necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m2. Estimate CrCl prior to dosing.
### Gender
- Evaluation of effectiveness and safety of topiramate in clinical trials has shown no gender-related effects.
### Race
- Evaluation of effectiveness and safety of topiramate in clinical trials has shown no race-related effects.
### Renal Impairment
- The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance less than 30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance greater than 70 mL/min/1.73m2). One-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Topiramate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be apprised of the potential hazard to the fetus from exposure to topiramate. If the decision is made to use topiramate, women who are not planning a pregnancy should use effective contraception. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
### Immunocompromised Patients
There is no FDA guidance one the use of Topiramate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Topiramate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Topiramate in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdoses of topiramate resulted in signs and symptoms which included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.
- Topiramate overdose has resulted in severe metabolic acidosis.
- A patient who ingested a dose between 96 g and 110 g of topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.
### Management
- Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of QUDEXY XR. Therefore, in acute QUDEXY XR overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Topiramate in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
## Structure
- Topiramate, USP, is a sulfamate-substituted monosaccharide. QUDEXY XR (topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg capsules for oral administration as whole capsules or opened and sprinkled onto a spoonful of soft food.
- Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:
- QUDEXY XR (topiramate) extended-release capsules contain beads of topiramate in a capsule. The inactive ingredients are microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate.
- In addition, the capsule shells for all strengths contain hypromellose 2910, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only).
## Pharmacodynamics
- Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.
## Pharmacokinetics
- Absorption and Distribution
- The pharmacokinetics of QUDEXY XR are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of QUDEXY XR are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.
- QUDEXY XR sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation.
- Following a single 200 mg oral dose of QUDEXY XR, peak plasma concentrations (Tmax) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of QUDEXY XR in subjects with normal renal function, with a Tmax of approximately 6 hours.
- At steady-state, the plasma exposure (AUC0-24hr, Cmax, and Cmin) of topiramate from QUDEXY XR administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for QUDEXY XR administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate.
- Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and Cmax) but delayed the Tmax by approximately 4 hours following a single dose of QUDEXY XR. QUDEXY XR can be taken without regard to meals.
- Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.
- Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate.
- Metabolism and Excretion
- Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of QUDEXY XR is approximately 56 hours. Steady-state is reached in about 5 days after QUDEXY XR dosing in subjects with normal renal function.
- Specific Populations
- Renal Impairment
- The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m2) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2) compared to subjects with normal renal function (creatinine clearance greater than70 mL/min/1.73 m2). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with creatinine clearance less than 70 mL/min/1.73 m2.
- Hemodialysis
- Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required.
- Hepatic Impairment
- In subjects with hepatic impairment, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.
- Age, Gender and Race
- The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance ) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. Because of this, dosage adjustment may be necessary.
- Clearance of topiramate in adults was not affected by gender or race.
- Pediatric Pharmacokinetics
- Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients aged 2 years to less than 16 years (95 pediatric patients less than 10 years of age).
- Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.
- As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.
- Drug-Drug Interaction Studies
- Antiepileptic Drugs
- Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of QUDEXY XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products.
- In Table 9, the second column (AED concentration) describes what happened to the concentration of the AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modified the concentration of topiramate in experimental settings when topiramate was given alone.
- In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy and hypothermia.
- CNS Depressants or Alcohol
- Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies.
- Oral Contraceptives
- In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200 to 800 mg per day, there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with QUDEXY XR. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.
- Digoxin
- In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.
- Hydrochlorothiazide
- A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to QUDEXY XR therapy may require an adjustment of the QUDEXY XR dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.
- Metformin
- Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. QUDEXY XR is expected to exhibit the same degree of metabolic acidosis as topiramate.
- A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin Cmax and AUC0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate QUDEXY XR pharmacokinetics is unclear.
- Pioglitazone
- A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUCτ,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is not known.
- When QUDEXY XR is added to pioglitazone therapy or pioglitazone is added to QUDEXY XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
- Glyburide
- A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in Cmax and 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced Cmax by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.
- Lithium
- In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR.
- Haloperidol
- The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).
- Amitriptyline
- There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of QUDEXY XR and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
- Sumatriptan
- Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).
- Risperidone
- When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9- hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.
- Propranolol
- Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg per day of topiramate.
- Dihydroergotamine
- Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study.
- Diltiazem
- Co-administration of diltiazem (240 mg) with topiramate (150 mg per day) resulted in a 10% decrease in Cmax and 25% decrease in diltiazem AUC, 27% decrease in Cmax and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate.
- Venlafaxine
- Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.
- Other Carbonic Anhydrase Inhibitors
- Concomitant use of QUDEXY XR, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if QUDEXY XR is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.
- Drug/Laboratory Tests Interactions
- There are no known interactions of QUDEXY XR with commonly used laboratory tests.
- Relative Bioavailability of QUDEXY XR Compared to Immediate-Release Topiramate in Healthy Volunteers
- QUDEXY XR, taken once daily, provides similar steady-state topiramate concentrations to immediate-release topiramate taken every 12 hours, when administered at the same total daily dose. In a healthy volunteer, multiple-dose crossover study, the 90% CI for the ratios of AUC0-24, Cmax and Cmin, as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose)) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 3 hours and at 8 hours post-dose, which is not expected to have a significant clinical impact.
- The effects of switching between QUDEXY XR and immediate-release topiramate were also evaluated in the same multiple-dose, crossover, comparative bioavailability study. In healthy subjects switched from immediate-release topiramate given every 12 hours to QUDEXY XR given once daily, similar concentrations were maintained immediately after the formulation switch. On the first day following the switch, there were no significant differences in AUC0-24, Cmax, and Cmin, as the 90% CI for the ratios were contained within the 80 to 125% equivalence limits.
## Nonclinical Toxicology
- Carcinogenesis
- An increase in urinary bladder tumors was observed in mice given topiramate (20 mg/kg, 75 mg/kg, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain.
- No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis).
- Mutagenesis
- Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.
- Impairment of Fertility
- No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).
# Clinical Studies
- Although a controlled clinical trial was performed (Study 11) , the basis for approval of the extended-release formulation (QUDEXY XR) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of QUDEXY XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points.
- Adults and Pediatric Patients 10 Years of Age and Older
- The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1).
- Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg per day or 400 mg per day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose of 400 mg per day for greater than 2 weeks, and patients who did not tolerate 150 mg per day were discontinued.
- The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg per day group over the topiramate 50 mg per day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.
- Adult Patients with Partial Onset Seizures
- The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
- Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.
- Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg per day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg per day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg per day until the target dose of 200 mg per day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10.
- Pediatric Patients Ages 2 to 16 Years with Partial Onset Seizures
- The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 to 16 years with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
- Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
- Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg per day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg per day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.
- The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo.
- Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
- Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg per day for four weeks; the dose was then increased by 50 mg to 150 mg per day increments every other week until the assigned dose of 175, 225 or 400 mg per day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.
- The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older (Study 10).
- Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.
- In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
- Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.
- In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated.
- The effectiveness of QUDEXY XR as an adjunctive treatment for adults (18 to 75 years of age) was evaluated in Study 11, a randomized, international, multi-center, double-blind, parallel-group, placebo-controlled trial in patients with a history of partial onset seizures, with or without secondary generalization.
- Patients with partial onset seizures on a stable dose of 1 to 3 AEDs entered into an 8 week baseline period. Patients who experienced at least 8 partial onset seizures, with or without secondary generalization, and no more than 21 consecutive seizure free days during the 8 week baseline phase were randomly assigned to placebo or QUDEXY XR administered once daily in addition to their concomitant AEDs. Following randomization, 249 patients began the double-blind treatment phase, which consisted of an initial 3 week titration period followed by an 8 week maintenance period. During the titration period, patients received QUDEXY XR or placebo beginning at 50 mg once daily; the dose was increased at weekly intervals by 50 mg once daily, or the placebo equivalent, until a final dose of 200 mg once daily was achieved. Patients than entered the maintenance period at the assigned dose of 200 mg once daily, or its placebo equivalent.
- The percent reduction in the frequency of partial-onset seizure, baseline period compared to the treatment phase, was the primary endpoint. Data was analyzed by the Wilcoxon rank-sum test, with the criteria of statistical significance of p<0.05. The results of the analysis are presented in Table 12. The median percent reduction in seizure rate was 39.5% in patients taking QUDEXY XR (N=124) and 21.7% in patients taking placebo (N=125). This difference was statistically significant.
- Figure 2 shows the change from baseline during titration plus maintenance (11 weeks) in partial-onset seizure frequency by category for patients treated with QUDEXY XR and placebo. Patients in whom the seizure frequency increased are shown as "worse." Patients in whom the seizure frequency decreased are shown in four categories of reduction in seizure frequency.
# How Supplied
- QUDEXY XR (topiramate) extended-release capsules contain beads of topiramate in a capsule and are available in the following strengths and colors:
- 25 mg: light pink and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "25 mg" on the body in black ink. 25 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1071-30)
- Bottle of 90 count with desiccant (NDC 0245-1071-90)
- Bottle of 500 count with desiccant (NDC 0245-1071-15)
- 50 mg: golden yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "50 mg" on the body in black ink. 50 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1072-30)
- Bottle of 90 count with desiccant (NDC 0245-1072-90)
- Bottle of 500 count with desiccant (NDC 0245-1072-15)
- 100 mg: reddish brown and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "100 mg" on the body in black ink. 100 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1074-30)
- Bottle of 90 count with desiccant (NDC 0245-1074-90)
- Bottle of 500 count with desiccant (NDC 0245-1074-15)
- 150 mg: pale yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "150 mg" on the body in black ink. 150 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1075-30)
- Bottle of 90 count with desiccant (NDC 0245-1075-90)
- Bottle of 500 count with desiccant (NDC 0245-1075-15)
- 200 mg: brown and grey capsules, printed with "UPSHER-SMITH" on the cap in white ink and "200 mg" on the body in black ink. 200 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1073-30)
- Bottle of 90 count with desiccant (NDC 0245-1073-90)
- Bottle of 500 count with desiccant (NDC 0245-1073-15)
- Storage and Handling
- QUDEXY XR (topiramate) extended-release capsules should be stored in a tightly-closed container at 20 to 25°C (68 to 77°F). Excursions permitted 15 to 30°C (59 to 86°F). Protect from moisture.
## Storage
There is limited information regarding Topiramate Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Administration Instructions
- Instruct patients to take QUDEXY XR only as prescribed.
- Counsel patients to swallow QUDEXY XR capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food. This drug/food mixture should be swallowed immediately and not chewed. Do not store drug/food mixture for future use.
- Eye Disorders
- Advise patients taking QUDEXY XR to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain.
- Oligohydrosis and Hyperthermia
- Counsel patients, especially pediatric patients, that QUDEXY XR can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek immediate medical attention if this is noticed.
- Metabolic Acidosis
- Warn patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus.
- Suicidal Behavior and Ideation
- Counsel patients, their caregivers, and families that AEDs, including QUDEXY XR, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Interference with Cognitive and Motor Performance
- Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on QUDEXY XR to gauge whether it adversely affects their mental performance, motor performance, and/or vision.
- Advise patients that even when taking QUDEXY XR, or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking QUDEXY XR for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities.
- Fetal Toxicity
- Counsel pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. There may also be risks to the fetus from chronic metabolic acidosis with use of QUDEXY XR during pregnancy.
- When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options. This is particularly important when QUDEXY XR use is considered for a condition not usually associated with permanent injury or death. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.
- Encourage pregnant women using topiramate to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number, 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at /.
- Hyperammonemia and Encephalopathy
- Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status.
- Kidney Stones
- Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation.
- Hypothermia
- Counsel patients that QUDEXY XR can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction.
- Paresthesia
- Counsel patients that they may experience tingling in the arms and legs. If this symptom occurs, they should consult with their physician.
# Precautions with Alcohol
- Alcohol-Topiramate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- QUDEXY XR®
# Look-Alike Drug Names
- Topamax® — Toprol XL®
# Drug Shortage Status
# Price | Topiramate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Overview
Topiramate is an antiepileptic drug that is FDA approved for the {{{indicationType}}} of partial seizures, primary generalized tonic-clonic seizures and Lennox-Gastaut syndrome. Common adverse reactions include paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, cognitive problem, confusion, mood problems, fever, infection, and flushing.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Monotherapy Use
- The recommended dose for topiramate monotherapy in adults is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy in adults with partial onset seizures is 200 mg to 400 mg orally once daily.
- Monotherapy Use
- The recommended dose for topiramate monotherapy in adults is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total dose for adults with primary generalized tonic-clonic seizures is 400 mg orally once daily.
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy in adults with Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Topiramate in adult patients.
### Non–Guideline-Supported Use
- Topiramate therapy was started at 25 mg once daily, and increased at weekly intervals for 5 weeks to a total dose of 300 mg, divided twice daily. Patients remained on this dose from week 6 to the beginning of week 14, and then tapered off by week 16.[1]
- Topiramate 25 mg daily titrated over an 8-week period to 400 mg/day or the maximum tolerated dose.[2]
- Topiramate 25 mg/day for 1 week, with weekly titrations in increments of 25 or 50 mg/day up to 200 mg/day, then 100 mg/day weekly increments to a clinical response, up to a maximum of 400 mg/day.[3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Monotherapy Use
- The recommended dose for topiramate monotherapy in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with partial onset seizures is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
- Monotherapy Use
- The recommended dose for topiramate monotherapy in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule:
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with primary generalized tonic-clonic seizures is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
- Adjunctive Therapy Use
- The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Topiramate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Topiramate in pediatric patients.
# Contraindications
- QUDEXY XR is contraindicated in patients with metabolic acidosis who are taking concomitant metformin.
# Warnings
### Precautions
- Acute Myopia and Secondary Angle Closure Glaucoma
- A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of QUDEXY XR as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of QUDEXY XR, may be helpful.
- Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
- Visual Field Defects
- Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
- Oligohydrosis and Hyperthermia
- Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.
- The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with QUDEXY XR should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when QUDEXY XR is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
- Metabolic Acidosis
- Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.
- Adults
- In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of less than 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg per day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in a controlled clinical trial for monotherapy was 15% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg per day and 7% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day.
- Pediatric Patients (2 years to 16 years of age)
- The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.
- In pediatric patients (6 years to 15 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day.
- Pediatric Patients (under 2 years of age)
- Although QUDEXY XR is not approved for use in patients less than 2 years of age with partial onset seizures, a study of topiramate as adjunctive use in patients under 2 years of age revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate less than 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day.
- Manifestations of Metabolic Acidosis
- Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sex-matched normative data, although these patients are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus.
- Risk Mitigation Strategies
- Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including QUDEXY XR, for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing QUDEXY XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Cognitive/Neuropsychiatric Adverse Reactions
- Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of QUDEXY XR were related to the central nervous system and were observed in the epilepsy population. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties), 2) Psychiatric/behavioral disturbances (e.g. depression or mood problems), and 3) Somnolence or fatigue.
- Adult Patients
- Cognitive Related Dysfunction
- The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment.
- In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200mg per day, 41% for 400mg per day, 52% for 600mg per day, 56% for 800 and 1,000 mg per day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.
- In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50mg per day and 26% for 400mg per day.
- Psychiatric/Behavioral Disturbances
- Psychiatric/behavioral disturbances (depression or mood) were dose-related for the epilepsy population treated with topiramate.
- Somnolence/Fatigue
- Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For other uses not approved for QUDEXY XR, somnolence and fatigue were more common in the titration phase.
- Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia.
- Pediatric Patients
- In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, the incidences of cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in the 50 mg per day and 400 mg per day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.
- No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per day group discontinued treatment due to any adverse events. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group.
- Fetal Toxicity
- Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.
- Consider the benefits and risks of topiramate when administering the drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.
- Withdrawal of Antiepileptic Drugs
- In patients with or without a history of seizures or epilepsy, antiepileptic drugs including QUDEXY XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In situations where rapid withdrawal of QUDEXY XR is medically required, appropriate monitoring is recommended.
- Hyperammonemia and Encephalopathy
- Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)
- Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs in very young pediatric patients (1 month to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy (8% for placebo, 10% for 5 mg/kg/day, 0% for 15 mg/kg/day, 9% for 25 mg/kg/day). QUDEXY XR is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (greater than 50% above upper limit of normal). The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.
- Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).
- Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)
- Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.
- Although QUDEXY XR is not indicated for use in infants/toddlers (1 month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate in these very young, pediatric patients.
- Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with valproic acid (VPA).
- The hyperammonemia associated with topiramate treatment appears to be more common when used concomitantly with VPA.
- Monitoring for Hyperammonemia
- Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or QUDEXY XR treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.
- In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
- Kidney Stones
- A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. QUDEXY XR is not approved for pediatric patients less than 2 years old.
- QUDEXY XR would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of QUDEXY XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.
- Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
- Hypothermia with Concomitant Valproic Acid Use
- Hypothermia, defined as an unintentional drop in body core temperature to less than 35ºC (95ºF) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
- Paresthesia
- Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials conducted with immediate-release topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation.
- Interaction with Other CNS Depressants
- Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Patients should be watched carefully when QUDEXY XR is co-administered with other CNS depressant drugs.
# 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 adverse reactions in the monotherapy controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group (incidence greater than or equal to 5%) and at a rate higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory [see Table 2].
- Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (greater than or equal to 2% more frequent than low-dose 50 mg per day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence and paresthesia.
- The adverse reactions in the controlled trial (Study 1) that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg per day topiramate group (incidence greater than or equal to 5%) and at a rate higher than in the 50 mg per day group were weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see Table 3].
- Approximately 12% of the 57 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (greater than 5%) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention.
- The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see Table 4]. The most common dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 6].
- Adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 7].
- In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400mg per day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.
- Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200 mg to 1,600 mg per day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).
- Table 4 lists adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 7 lists adverse reactions that occurred in at least 1% of pediatric patients treated with 5 mg/kg to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.
- Other adverse reactions that occurred in more than 1% of adults treated with 200 mg to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.
- Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.
- The incidence of adverse reactions (Table 5) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.
- Topiramate decreases serum bicarbonate.
- Immediate-release topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Similar effects should be anticipated with use of QUDEXY XR.
- Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established.
- Changes in several clinical laboratory results (increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count and decreased potassium) have been observed in a clinical investigational program in very young (2 years and younger) pediatric patients who were treated with adjunctive topiramate for partial onset seizures.
- Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study. The incidence of these abnormal shifts was 4% for placebo, 4% for 50 mg, and 18% for 100 mg.
- Topiramate treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy.
- 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. In the QUDEXY XR study, a dose of 200 mg/day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience.
- The safety data presented below are from 249 patients with partial epilepsy on concomitant AEDs who participated in the QUDEXY XR study.
- Table 8 displays the incidence of treatment-emergent adverse reactions that occurred in ≥2% of patients and numerically greater than placebo.
- In the controlled clinical study using QUDEXY XR, 8.9% of patients who received QUDEXY XR and 4.0% who received placebo discontinued as a result of treatment-emergent adverse reactions.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of topiramate. 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. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, and pemphigus.
# Drug Interactions
- Oral Contraceptives
- The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with QUDEXY XR. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.
- Antiepileptic Drugs
- Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate.
- Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.
- Numerous AEDs are substrates of the CYP enzyme system. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that immediate-release topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. The same drug interactions can be expected with the use of QUDEXY XR.
- CNS Depressants and Alcohol
- Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Concomitant use of alcohol should be avoided.
- Other Carbonic Anhydrase Inhibitors
- Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when QUDEXY XR is given concomitantly with another carbonic anhydrase inhibitor.
- Metformin
- Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. The concomitant use of QUDEXY XR and metformin is contraindicated in patients with metabolic acidosis.
- Lithium
- In patients, there was an observed increase in systemic exposure of lithium following topiramate doses of up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus [see Use in Specific Populations (8.9)].
- Pregnancy Registry
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/.
- Human Data
- Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% - 0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=CI 3.6-25.7) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%.
- Topiramate treatment can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.
- Animal Data
- Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20 mg/kg, 100 mg/kg, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400 mg per day on a mg/m2 basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.
- In rat studies (oral doses of 20 mg/kg, 100 mg/kg, and 500 mg/kg or 0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.
- In rabbit studies (20 mg/kg, 60 mg/kg, and 180 mg/kg or 10 mg/kg, 35 mg/kg, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m2 basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.
- When female rats were treated during the latter part of gestation and throughout lactation (0.2 mg/kg, 4 mg/kg, 20 mg/kg, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre-and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.
- In a rat embryo/fetal development study with a postnatal component (0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2 basis) and higher.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Topiramate in women who are pregnant.
### Labor and Delivery
- Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor.
### Nursing Mothers
- Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when QUDEXY XR is administered to a nursing woman.
### Pediatric Use
- Seizures in Pediatric Patients 2 Years of Age and Older
- The safety and effectiveness of QUDEXY XR in pediatric patients is based on controlled trials with immediate-release topiramate.
- The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults.
- These include, but are not limited to:
- Oligohydrosis and hyperthermia.
- Dose-related increased incidence of metabolic acidosis.
- Dose-related increased incidence of hyperammonemia.
- Adjunctive Treatment for Epilepsy with Partial Onset Seizures in Infants and Toddlers (1 to 24 months)
- The following pediatric use information is based on studies conducted with immediate-release topiramate.
- Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures, was assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures.
- In general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications.
- These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older children.
- Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase. The significance of these findings is uncertain.
- Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain.
- Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference.
- In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease).
- In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known.
- Other Pediatric Studies
- Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study.
- Juvenile Animal Studies
- When topiramate (30 mg/kg/day, 90 mg/kg/day or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis.
### Geriatic Use
- Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment is necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m2. Estimate CrCl prior to dosing.
### Gender
- Evaluation of effectiveness and safety of topiramate in clinical trials has shown no gender-related effects.
### Race
- Evaluation of effectiveness and safety of topiramate in clinical trials has shown no race-related effects.
### Renal Impairment
- The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance less than 30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance greater than 70 mL/min/1.73m2). One-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Topiramate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be apprised of the potential hazard to the fetus from exposure to topiramate. If the decision is made to use topiramate, women who are not planning a pregnancy should use effective contraception. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
### Immunocompromised Patients
There is no FDA guidance one the use of Topiramate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Topiramate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Topiramate in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdoses of topiramate resulted in signs and symptoms which included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.
- Topiramate overdose has resulted in severe metabolic acidosis.
- A patient who ingested a dose between 96 g and 110 g of topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.
### Management
- Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of QUDEXY XR. Therefore, in acute QUDEXY XR overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Topiramate in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
## Structure
- Topiramate, USP, is a sulfamate-substituted monosaccharide. QUDEXY XR (topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg capsules for oral administration as whole capsules or opened and sprinkled onto a spoonful of soft food.
- Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:
- QUDEXY XR (topiramate) extended-release capsules contain beads of topiramate in a capsule. The inactive ingredients are microcrystalline cellulose, hypromellose 2910, ethylcellulose, diethyl phthalate.
- In addition, the capsule shells for all strengths contain hypromellose 2910, titanium dioxide, black iron oxide, red iron oxide and/or yellow iron oxide, black pharmaceutical ink, and white pharmaceutical ink (200 mg only).
## Pharmacodynamics
- Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.
## Pharmacokinetics
- Absorption and Distribution
- The pharmacokinetics of QUDEXY XR are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of QUDEXY XR are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.
- QUDEXY XR sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation.
- Following a single 200 mg oral dose of QUDEXY XR, peak plasma concentrations (Tmax) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of QUDEXY XR in subjects with normal renal function, with a Tmax of approximately 6 hours.
- At steady-state, the plasma exposure (AUC0-24hr, Cmax, and Cmin) of topiramate from QUDEXY XR administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for QUDEXY XR administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate.
- Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and Cmax) but delayed the Tmax by approximately 4 hours following a single dose of QUDEXY XR. QUDEXY XR can be taken without regard to meals.
- Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.
- Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate.
- Metabolism and Excretion
- Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of QUDEXY XR is approximately 56 hours. Steady-state is reached in about 5 days after QUDEXY XR dosing in subjects with normal renal function.
- Specific Populations
- Renal Impairment
- The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m2) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2) compared to subjects with normal renal function (creatinine clearance greater than70 mL/min/1.73 m2). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with creatinine clearance less than 70 mL/min/1.73 m2.
- Hemodialysis
- Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required.
- Hepatic Impairment
- In subjects with hepatic impairment, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.
- Age, Gender and Race
- The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. Because of this, dosage adjustment may be necessary.
- Clearance of topiramate in adults was not affected by gender or race.
- Pediatric Pharmacokinetics
- Pharmacokinetics of immediate-release topiramate were evaluated in patients ages 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients aged 2 years to less than 16 years (95 pediatric patients less than 10 years of age).
- Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.
- As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.
- Drug-Drug Interaction Studies
- Antiepileptic Drugs
- Potential interactions between immediate-release topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of QUDEXY XR and standard AEDs is not expected to differ from the experience with immediate-release topiramate products.
- In Table 9, the second column (AED concentration) describes what happened to the concentration of the AED listed in the first column when topiramate was added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modified the concentration of topiramate in experimental settings when topiramate was given alone.
- In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy and hypothermia.
- CNS Depressants or Alcohol
- Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies.
- Oral Contraceptives
- In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg per day to 800 mg per day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200 to 800 mg per day, there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with QUDEXY XR. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.
- Digoxin
- In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.
- Hydrochlorothiazide
- A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to QUDEXY XR therapy may require an adjustment of the QUDEXY XR dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.
- Metformin
- Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. QUDEXY XR is expected to exhibit the same degree of metabolic acidosis as topiramate.
- A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin Cmax and AUC0-12h increased by 17% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate QUDEXY XR pharmacokinetics is unclear.
- Pioglitazone
- A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUCτ,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is not known.
- When QUDEXY XR is added to pioglitazone therapy or pioglitazone is added to QUDEXY XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
- Glyburide
- A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with topiramate (150 mg per day). There was a 22% decrease in Cmax and 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced Cmax by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.
- Lithium
- In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR.
- Haloperidol
- The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).
- Amitriptyline
- There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg per day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of QUDEXY XR and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
- Sumatriptan
- Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).
- Risperidone
- When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of topiramate 400 mg per day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9- hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.
- Propranolol
- Multiple dosing of topiramate (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate at a dose of 200 mg per day of topiramate.
- Dihydroergotamine
- Multiple dosing of topiramate (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of topiramate in the same study.
- Diltiazem
- Co-administration of diltiazem (240 mg) with topiramate (150 mg per day) resulted in a 10% decrease in Cmax and 25% decrease in diltiazem AUC, 27% decrease in Cmax and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate.
- Venlafaxine
- Multiple dosing of topiramate (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.
- Other Carbonic Anhydrase Inhibitors
- Concomitant use of QUDEXY XR, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if QUDEXY XR is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.
- Drug/Laboratory Tests Interactions
- There are no known interactions of QUDEXY XR with commonly used laboratory tests.
- Relative Bioavailability of QUDEXY XR Compared to Immediate-Release Topiramate in Healthy Volunteers
- QUDEXY XR, taken once daily, provides similar steady-state topiramate concentrations to immediate-release topiramate taken every 12 hours, when administered at the same total daily dose. In a healthy volunteer, multiple-dose crossover study, the 90% CI for the ratios of AUC0-24, Cmax and Cmin, as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose)) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of topiramate plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 3 hours and at 8 hours post-dose, which is not expected to have a significant clinical impact.
- The effects of switching between QUDEXY XR and immediate-release topiramate were also evaluated in the same multiple-dose, crossover, comparative bioavailability study. In healthy subjects switched from immediate-release topiramate given every 12 hours to QUDEXY XR given once daily, similar concentrations were maintained immediately after the formulation switch. On the first day following the switch, there were no significant differences in AUC0-24, Cmax, and Cmin, as the 90% CI for the ratios were contained within the 80 to 125% equivalence limits.
## Nonclinical Toxicology
- Carcinogenesis
- An increase in urinary bladder tumors was observed in mice given topiramate (20 mg/kg, 75 mg/kg, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain.
- No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis).
- Mutagenesis
- Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.
- Impairment of Fertility
- No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).
# Clinical Studies
- Although a controlled clinical trial was performed (Study 11) [see Clinical Studies (14.6)], the basis for approval of the extended-release formulation (QUDEXY XR) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of QUDEXY XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points.
- Adults and Pediatric Patients 10 Years of Age and Older
- The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1).
- Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg per day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg per day or 400 mg per day of topiramate. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose of 400 mg per day for greater than 2 weeks, and patients who did not tolerate 150 mg per day were discontinued.
- The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg per day group over the topiramate 50 mg per day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.
- Adult Patients with Partial Onset Seizures
- The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
- Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.
- Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg per day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In Study 7, the 25 or 50 mg per day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg per day until the target dose of 200 mg per day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 10.
- Pediatric Patients Ages 2 to 16 Years with Partial Onset Seizures
- The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 to 16 years with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
- Patients in Study 8 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In Study 8, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
- Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg per day increments every other week until the assigned dosage of 125, 175, 225 or 400 mg per day based on patients' weight to approximate a dosage of 6 mg/kg/day per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.
- The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years old and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo.
- Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.
- Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg per day for four weeks; the dose was then increased by 50 mg to 150 mg per day increments every other week until the assigned dose of 175, 225 or 400 mg per day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.
- The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older (Study 10).
- Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4 week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.
- In all adjunctive topiramate trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 11. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
- Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.
- In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 mg per day to 100 mg per day in adults and over a 2- to 8-week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated.
- The effectiveness of QUDEXY XR as an adjunctive treatment for adults (18 to 75 years of age) was evaluated in Study 11, a randomized, international, multi-center, double-blind, parallel-group, placebo-controlled trial in patients with a history of partial onset seizures, with or without secondary generalization.
- Patients with partial onset seizures on a stable dose of 1 to 3 AEDs entered into an 8 week baseline period. Patients who experienced at least 8 partial onset seizures, with or without secondary generalization, and no more than 21 consecutive seizure free days during the 8 week baseline phase were randomly assigned to placebo or QUDEXY XR administered once daily in addition to their concomitant AEDs. Following randomization, 249 patients began the double-blind treatment phase, which consisted of an initial 3 week titration period followed by an 8 week maintenance period. During the titration period, patients received QUDEXY XR or placebo beginning at 50 mg once daily; the dose was increased at weekly intervals by 50 mg once daily, or the placebo equivalent, until a final dose of 200 mg once daily was achieved. Patients than entered the maintenance period at the assigned dose of 200 mg once daily, or its placebo equivalent.
- The percent reduction in the frequency of partial-onset seizure, baseline period compared to the treatment phase, was the primary endpoint. Data was analyzed by the Wilcoxon rank-sum test, with the criteria of statistical significance of p<0.05. The results of the analysis are presented in Table 12. The median percent reduction in seizure rate was 39.5% in patients taking QUDEXY XR (N=124) and 21.7% in patients taking placebo (N=125). This difference was statistically significant.
- Figure 2 shows the change from baseline during titration plus maintenance (11 weeks) in partial-onset seizure frequency by category for patients treated with QUDEXY XR and placebo. Patients in whom the seizure frequency increased are shown as "worse." Patients in whom the seizure frequency decreased are shown in four categories of reduction in seizure frequency.
# How Supplied
- QUDEXY XR (topiramate) extended-release capsules contain beads of topiramate in a capsule and are available in the following strengths and colors:
- 25 mg: light pink and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "25 mg" on the body in black ink. 25 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1071-30)
- Bottle of 90 count with desiccant (NDC 0245-1071-90)
- Bottle of 500 count with desiccant (NDC 0245-1071-15)
- 50 mg: golden yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "50 mg" on the body in black ink. 50 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1072-30)
- Bottle of 90 count with desiccant (NDC 0245-1072-90)
- Bottle of 500 count with desiccant (NDC 0245-1072-15)
- 100 mg: reddish brown and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "100 mg" on the body in black ink. 100 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1074-30)
- Bottle of 90 count with desiccant (NDC 0245-1074-90)
- Bottle of 500 count with desiccant (NDC 0245-1074-15)
- 150 mg: pale yellow and grey capsules, printed with "UPSHER-SMITH" on the cap in black ink and "150 mg" on the body in black ink. 150 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1075-30)
- Bottle of 90 count with desiccant (NDC 0245-1075-90)
- Bottle of 500 count with desiccant (NDC 0245-1075-15)
- 200 mg: brown and grey capsules, printed with "UPSHER-SMITH" on the cap in white ink and "200 mg" on the body in black ink. 200 mg capsules are available in the following package configurations:
- Bottle of 30 count with desiccant (NDC 0245-1073-30)
- Bottle of 90 count with desiccant (NDC 0245-1073-90)
- Bottle of 500 count with desiccant (NDC 0245-1073-15)
- Storage and Handling
- QUDEXY XR (topiramate) extended-release capsules should be stored in a tightly-closed container at 20 to 25°C (68 to 77°F). Excursions permitted 15 to 30°C (59 to 86°F). Protect from moisture.
## Storage
There is limited information regarding Topiramate Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Administration Instructions
- Instruct patients to take QUDEXY XR only as prescribed.
- Counsel patients to swallow QUDEXY XR capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food. This drug/food mixture should be swallowed immediately and not chewed. Do not store drug/food mixture for future use.
- Eye Disorders
- Advise patients taking QUDEXY XR to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain.
- Oligohydrosis and Hyperthermia
- Counsel patients, especially pediatric patients, that QUDEXY XR can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek immediate medical attention if this is noticed.
- Metabolic Acidosis
- Warn patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus.
- Suicidal Behavior and Ideation
- Counsel patients, their caregivers, and families that AEDs, including QUDEXY XR, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Interference with Cognitive and Motor Performance
- Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on QUDEXY XR to gauge whether it adversely affects their mental performance, motor performance, and/or vision.
- Advise patients that even when taking QUDEXY XR, or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking QUDEXY XR for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities.
- Fetal Toxicity
- Counsel pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. There may also be risks to the fetus from chronic metabolic acidosis with use of QUDEXY XR during pregnancy.
- When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options. This is particularly important when QUDEXY XR use is considered for a condition not usually associated with permanent injury or death. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.
- Encourage pregnant women using topiramate to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number, 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/.
- Hyperammonemia and Encephalopathy
- Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status.
- Kidney Stones
- Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation.
- Hypothermia
- Counsel patients that QUDEXY XR can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction.
- Paresthesia
- Counsel patients that they may experience tingling in the arms and legs. If this symptom occurs, they should consult with their physician.
# Precautions with Alcohol
- Alcohol-Topiramate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- QUDEXY XR®[4]
# Look-Alike Drug Names
- Topamax® — Toprol XL®[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/J%26j | |
087d7ee55fe1b754eca5197755de3a7606e274ca | wikidoc | JUB (gene) | JUB (gene)
Protein ajuba is a protein that in humans is encoded by the JUB gene.
# Function
JUB proteins contribute to cell fate determination and regulate cell proliferation and differentiation. Plays an important role in regulation of the kinase activity of AURKA/Aurora-A for mitotic commitment.
# Interactions
JUB (gene) has been shown to interact with Stratifin and SLC1A2. | JUB (gene)
Protein ajuba is a protein that in humans is encoded by the JUB gene.[1][2]
# Function
JUB proteins contribute to cell fate determination and regulate cell proliferation and differentiation. Plays an important role in regulation of the kinase activity of AURKA/Aurora-A for mitotic commitment.
# Interactions
JUB (gene) has been shown to interact with Stratifin[3] and SLC1A2.[4] | https://www.wikidoc.org/index.php/JUB_(gene) | |
d7b8312b7d4967a106c2ac8aa4985938bc8ea101 | wikidoc | Jacko test | Jacko test
### Preface
### How To Use This Book
### Alphabetical Index of all Pages in the Cardiology Textbook
# ANATOMY
# Cardiovascular Anatomy
Arteries | Coronary arteries | Head and Neck | Upper Limbs | Torso-Chest | Torso-Abdomen | Lower Limbs | All
Veins | Head and Neck | Upper Extremity | Torso | Lower Extremity
Atria | Atria | Left atrium | Right atrium | Interatrial septum | Musculi pectinati
Ventricles | Ventricles | Left ventricle | Right ventricle | Interventricular septum | Trabeculae carneae | Chordae tendinae | Papillary muscle
Valves | Valves | Aortic valve | Mitral valve | Pulmonic valve | Tricuspid valve | Cusps
Regions | Base | Apex
Grooves | Coronary/atrioventricular | Interatrial | Anterior interventricular | Posterior interventricular
Surfaces | Sternocostal | Diaphragmatic
Borders | Right | Left
Right heart | Vena cavae | Coronary sinus | Right atrium | Right auricle | Fossa ovalis | Limbus of fossa ovalis | Crista terminalis | Valve of the inferior vena cava | Valve of the coronary sinus | Tricuspid valve | Right ventricle | Conus arteriosus | Moderator band/septomarginal trabecula | Pulmonary valve | Pulmonary artery | Pulmonary circulation
Left heart | Pulmonary veins | Left atrium | Left Auricle | Mitral valve | Left ventricle | Aortic valve | Aortic sinus | Aorta | Systemic circulation
Pericardium | Pericardium | Fibrous pericardium | Serous pericardium | Pericardial cavity | Epicardium/visceral layer | Pericardial sinus
Myocardium | Myocardium | Endocardium | Cardiac skeleton | Fibrous trigone | Fibrous rings
Conduction system | Conduction system | Cardiac pacemaker | SA node | AV node | Bundle of His | Purkinje fibers
# PHYSIOLOGY
# Cardiovascular Physiology
Volumes | Preload | Afterload | End-systolic volume | End-diastolic volume | Frank-Starling law of the heart | Cardiac output
Interactions | Wiggers diagram | Pressure volume diagram
Tropism | Chronotropy | Dromotropy | Inotropy
Hemodynamics | Hemodynamics | Baroreflexes | Kinin-kallikrein system | Renin-angiotensin system | Vasoconstrictors | Vasodilators | Compliance | Vascular resistance
Conduction | Electrical conduction system of the heart | Cardiac action potential
Cardiopulmonary | Respiratory physiology | Blood | Pulmonary circulation | Perfusion (Q) | Hypoxic pulmonary vasoconstriction | Pulmonary shunt | Ventilation/perfusion scan | ventilation/perfusion ratio (V/Q) | Zones of the lung | Gas exchange | Pulmonary gas pressures | Alveolar gas equation | Hemoglobin | Oxygen-haemoglobin dissociation curve | 2,3-DPG | Bohr effect | Haldane effect | Carbonic anhydrase | Chloride shift | Oxyhemoglobin | Respiratory quotient | Arterial blood gas | Diffusion capacity | Dlco
# DEVELOPMENTAL BIOLOGY
# Cardiovascular Development
Arteries | Dorsal aorta | Aortic arches | Vitelline arteries | Ductus arteriosus | Umbilical artery
Veins | Cardinal veins | Ducts of Cuvier | Vitelline veins | Ductus venosus | Umbilical vein
Heart Development | Primitive heart tube | Truncus arteriosus | Bulbus cordis | Primitive ventricle | Primitive atrium | Sinus venosus | Septum primum | Ostium primum | Ostium secundum | Septum secundum | Foramen ovale | Endocardial cushions | Septum intermedium | Aorticopulmonary septum | Atrial canal
# BASIC SCIENCE
# Cardiovascular Biochemistry
Molecular Biology | Biochemistry | Organic Chemistry | Enzymes | Immunology
# DIAGNOSTIC MODALITIES IN CARDIOLOGY
# The Patient History in Cardiovascular Disease
Chest Pain | Claudication | Cough | Dyspnea | Orthopnea | Palpitations | Paroxysmal Nocturnal Dyspnea | Pedal Edema
# The Physical Examination in Cardiovascular Disease
The Pulse | The Neck | The Heart | Lungs |
The Extremities
# The Electrocardiogram
Intervals | PR Interval | QRS Interval | QT Interval | T Wave | U Wave
Hypertrophy | Electrocardiographic Findings in LVH | Electrocardiographic Findings in Right Ventricular Hypertrophy (RVH) | Biventricular Hypertrophy
Bundle Branch Block | LBBB | LAHB | RBBB | Trifascicular block
Atrial Arrhythmias | Premature Atrial Contractions (PACs) | Ectopic Atrial Rhythm | Paroxysmal Atrial Tachycardia (PAT) | Paroxysmal Atrial Tachycardia (PAT) with Block | Multifocal Atrial Tachycardia (MAT) | Atrial Flutter | Atrial Fibrillation
Ventricular Arrhythmias | Differential Diagnosis of Tachycardia with a Wide QRS Complex
Conduction Abnormalities | First Degree AV Block | Second Degree AV Block | Complete or Third-Degree AV Block | Concealed conduction | AV Junctional Rhythms | Wolff-Parkinson-White Syndrome
Electrocardiographic Abnormalities in Different Disease States | The EKG in the Patient with an Atrial Septal Defect (ASD) | EKG Changes of Hypothermia | EKG Abnormalities in CNS Disease | The EKG of Cardiac Transplantation | The EKG in a Patient with a Pacemaker | Electrocardiography of Traumatic Heart Disease
Drug Effects on the EKG | Digitalis | Quinidine | Procainamide | Disopyramide | Lidocaine | Tocainide and Mexiletine | Phenytoin | Encainide, Flecainide and Propafenone | β-blockers | Amiodarone | Bretylium | Ca Channel Blockers | Adenosine | Phenothiazines | Tricyclic Antidepressants | Lithium
EKG in Electrolyte Disturbances | The EKG in Hyperkalemia | The EKG in Hypokalemia | The EKG in Hypercalcemia | The EKG in Hypocalcemia | Nonspecific ST-Segment and T-Wave Changes
# Exercise Stress Testing
# Cardiac Electrophysiology
# Cardiac Biomarkers
Creatine Kinase | Cytokines and their receptors | Lipoprotein-associated phospholipase A2 (Lp-PLA2) | Metalloproteinases (MMPs) | Natriuretic peptides | Prothrombin fragment 1.2 (F1.2) | Prothrombin time (PT) | Soluble CD40 ligand (sCD40L) | Thrombus precursor protein (TpP) | Von Willebrand factor (vWF) | White blood cell (WBC) count
# An Overview of Cardiac Imaging
# The Chest X Ray in Cardiovascular Disease
# Echocardiography
# Nuclear Cardiology
# Coronary Angiography
# Cardiovascular Magnetic Resonance Imaging (CMR)
# CT Angiography
# Positron Emission Tomography
# CARDIAC DISEASE STATES
# The Genetic Basis of Heart Disease
# Congenital Heart Disease
Cardiac chambers and connections | Persistent truncus arteriosus | Double outlet right ventricle (Taussig-Bing syndrome) | Transposition of the great vessels (Dextro, Levo)
Cardiac Septa | Cardiac septa | Ventricular septal defect | Atrial septal defect (Lutembacher's syndrome) | Atrioventricular septal defect | (Ostium primum) | Tetralogy of Fallot | Eisenmenger's syndrome
Right sided pulmonary and tricuspid valve | Pulmonary valve (Stenosis Pulmonary valve insufficiency) | Tricuspid valve (Stenosis, Atresia) | Ebstein's anomaly
Left sided aortic and mitral valves | Aortic valve (Stenosis, insufficiency, bicuspid) | Mitral valve (stenosis, regurgitation) | Hypoplastic left heart syndrome
Other congenital malformations | Dextrocardia | Levocardia | Cor triatriatum |
Great arteries aorta (Patent ductus arteriosus | Aortic coarctation | Interrupted aortic arch | Overriding aorta | Aneurysm of sinus of Valsalva | Vascular ring) | Pulmonary atresia
Great veins | Persistent left superior vena cava | Total anomalous pulmonary venous connection | Scimitar syndrome
Other | Arteriovenous malformation (Cerebral arteriovenous malformation)
# Cardiac Disease in Pregnancy
# Cardiac Diseases in AIDS
# Diseases of the Pericardium
# Trauma and the Heart
# Diseases of the Valvular Structures
Aortic Stenosis | Aortic Regurgitation | Mitral Stenosis | Mitral Regurgitation | Mitral Valve Prolapse | Pulmonic Regurgitation | Pulmonic Stenosis | Tricuspid Valve Prolapse | Tricuspid Regurgitation | Tricuspid Stenosis | Infective Endocarditis
# Diseases of the Myocardium
Cardiomegaly | Cardiomyopathy | Congestive Heart Failure | Left Ventricular Hypertrophy | Myocarditis
# Cardiac Arrhythmias
# VASCULAR MEDICINE
# Vascular Medicine
# Diseases of the Aorta
# Peripheral Arterial Disease
# Sytemic Arterial Hypertension
# Hypotension
# Primary Cardiac Tumors
# The Heart in Oncologic Disease
# Endocrine Disease and the Heart
Hyperthyroidism | Hypothyroidism | Hypoparathyroidism | Acromegaly
# Renal Disease and the Heart
# Infectious Disease and the Heart
AIDS | Chagas'
# Autoimmune/Rheumatologic Disease and the Heart
Lupus | Psoriasis | Rheumatoid Arthritis | Scleroderma | Temporal Arteritis | Ulcerative Colitis | Wegener's Granulomatosis
# Pulmonary Embolism
# Pulmonary Hypertension
# Cor Pulmonale
# Pre-Operative Clearance
# HEMOCARDIOLOGY
# The Role of the Coagulation System in Heart Disease
# CORONARY ARTERY DISEASE
# Atherosclerosis Prevention and Risk Factor Modification
# Chronic Stable Angina
Introduction | Definition | Historical Perspective | Epidemiology | Pathophysiology | Presentation | Recognition of Clinical Subsets | Risk Factors | Diagnosis | Differential Diagnosis of Chest Pain | Treatment | Prognosis | Rehabilitation | Prevention
# Unstable Angina
# Non ST Elevation Myocardial Infarction
# ST Elevation Myocardial Infarction
Overview | Epidemiology and Demographics | Pathophysiology of Reperfusion | Risk Factors | Pathophysiology | Triggers | Classification
Diagnosis | Symptoms | Physical Examination | Electrocardiogram | Cardiac Markers | Coronary Angiography | Histopathology
Treatment | Pre-Hospital Care | Initial Care | Thrombolytic Therapy | Primary Percutaneous Coronary Intervention | Rescue Percutaneous Coronary Intervention | Facilitated Percutaneous Coronary Intervention | Coronary Artery Bypass Graft Surgery | Barriers to Implementing Clinical Guidelines
ST Elevation Myocardial Infarction Arrhythmia Monitoring | Secondary Prevention | Complications | Prognosis |
ST Elevation Myocardial Infarction | Cardiac Rehabilitation
# The Living Guidelines
# PHARMACOTHERAPY
# Cardiovascular Pharmacotherapy
## Adrenergic Agonists
Adrenergic Agonists Overview
Direct Acting | Dobutamine | Dopamine | Epinephrine | Formoterol | Isoproterenol | Metaproterenol | Methoxamine | Norepinephrine | Phenylephrine | Salmeterol | Tamsulosin | Terbutaline
Indirect Acting | Amphetamine | Tyramine
Mixed Action | Ephedrine
## Angiotensin-Renin Inhibitors (C09)
ACE Inhibitor Overview | Benazepril | Captopril | Enalapril | Fosinopril | Lisinopril | Perindopril | Quinapril | Ramipril | Spirapril | Trandolapril
Angiotensin II receptor antagonist Overview | Candesartan | Eprosartan | Irbesartan | Losartan | Olmesartan | Tasosartan | Telmisartan | Valsartan
Renin Inhibitors Overview | Aliskiren | Remikiren
## Antiarrhythmic agents
Antiarrhythmic Agents Overview (C01B)
Class Ia | Ajmaline | Disopyramide | Prajmaline | Procainamide | Quinidine | Sparteine
Class Ib | Aprindine | Lidocaine | Mexiletine | Tocainide
Class Ic | Encainide | Flecainide | Lorcainide | Moricizine | Propafenone
Class II | Propranolol | Metoprolol | Nadolol | Atenolol | Acebutolol | Pindolol see Beta blockers (C07)
Class III | Amiodarone | Bretylium tosylate | Bunaftine | Dofetilide | Ibutilide | Sotalol
Class IV | Verapamil | Diltiazem see Calcium channel blockers (C08)
Class V | Adenosine | Atropine | Digoxin
## Anticoagulants
Anticoagulants Overview
Vitamin K Antagonists Overview | Acenocoumarol | Clorindione | Coumatetralyl | Dicumarol (Dicoumarol) | Diphenadione | Ethyl biscoumacetate | Phenprocoumon | Phenindione | Tioclomarol | Warfarin
## Antihypertensives and Diuretics
Antihypertensive Overview (C02) and Diuretic Overview (C03)
Sympatholytic Agents Overview (including Alpha Blockers Overview)
Vasodilators Overview | Diazoxide | Hydralazine | Minoxidil | Nitroprusside | Phentolamine
Other antihypertensives
Low ceiling diuretics
High ceiling diuretics
## Antiplatelet Agents
Glycoprotein IIb/IIIa Inhibitors Overview | Abciximab | Eptifibatide | Tirofiban
ADP Receptor Antagonists | Clopidogrel | Ticlopidine | Prasugrel
Prostaglandin Analogues Overview | Beraprost | Prostacyclin | Iloprost | Treprostinil
Other Antiplatelet Agents Acetylsalicylic acid/Aspirin | Aloxiprin | Ditazole | Carbasalate calcium | Cloricromen | Dipyridamole | Indobufen | Picotamide | Triflusal
## Antithrombins
Direct Thrombin Inhibitors Overview | Argatroban | Bivalirudin | Dabigatran | Desirudin | Hirudin | Lepirudin | Melagatran | Ximelagatran
Indirect Thrombin Inhibitors
Other Antithrombotics | Defibrotide | Dermatan sulfate | Fondaparinux | Rivaroxaban
Non-Medicinal Antithrombins Overview | Citrate | EDTA | Oxalate
## Beta Blockers
Beta Blockers Overview (C07)
Non-selective β antagonists | Metipranolol | Nadolol | Oxprenolol | Penbutolol | Pindolol | Propranolol | Timolol | Sotalol
β1 antagonists (cardioselective) | Atenolol | Acebutolol | Betaxolol | Bisoprolol | Esmolol | Metoprolol | Nebivolol
Mixed α1/β antagonists | Carvedilol | Labetalol
## Calcium Channel Blockers
Calcium Channel Blocker Overview
Class I Phenylalkylamines (C08DA) | Verapamil
Class II Dihydropyridines (C08CA)
Class III Benzothiazepines (C08DB)
## Cardiac Glycosides
Cardiac Glycoside Overview (C01A)
Digitalis Glycosides Overview | Acetyldigitoxin | Acetyldigoxin | Digitalis leaves | Digitoxin | Digoxin | Lanatoside C | Deslanoside | Metildigoxin | Gitoformate
Scilla Glycosides Overview | Proscillaridin
Strophantus Glycosides Overview | G-strophanthin | Cymarin
Other Cardiac Glycosides | Peruvoside
## Cardiac Stimulants Excluding Cardiac Glycosides
Cardiac stimulants excluding cardiac glycosides (C01C)
Adrenergic Overview and Dopaminergic Overview agents |
Etilefrine | Isoprenaline | Norepinephrine | Dopamine | Norfenefrine | Phenylephrine | Dobutamine | Oxedrine | Metaraminol | Methoxamine | Mephentermine | Dimetofrine | Prenalterol | Dopexamine | Gepefrine | Ibopamine | Midodrine | Octopamine | Fenoldopam | Cafedrine | Arbutamine | Theodrenaline | Epinephrine
Phosphodiesterase Inhibitors Overview (PDE3I) | Amrinone | Milrinone | Enoximone | Bucladesine
Other cardiac stimulants | Angiotensinamide | Xamoterol | Levosimendan
## Fibrinolytics
Alteplase | Reteplase | Tenecteplase | Streptokinase, Urokinase | Saruplase | Anistreplase
## Hypolipidemic Agents
Statins Overview | Atorvastatin | Cerivastatin | Fluvastatin | Lovastatin | Mevastatin | Pitavastatin | Pravastatin | Rosuvastatin | Simvastatin
Fibrates Overview | Clofibrate | Bezafibrate | Aluminium clofibrate | Gemfibrozil | Fenofibrate | Simfibrate | Ronifibrate | Ciprofibrate | Etofibrate | Clofibride
Bile Acid Sequestrant Overview | Colestyramine | Colestipol | Colextran | Colesevelam
Niacin and Derivatives | Niceritrol | Niacin | Nicofuranose | Aluminium nicotinate | Nicotinyl alcohol | Acipimox
Other | Dextrothyroxine | Probucol | Tiadenol | Benfluorex | Meglutol | Omega-3-triglycerides | Magnesium pyridoxal 5-phosphate glutamate | Policosanol | Ezetimibe
## Nitrates
Nitrates Overview | Glyceryl trinitrate | Isosorbide dinitrate | Isosorbide mononitrate | Molsidomine | Pentaerythritol tetranitrate
## Pulmonary Artery Hypertension
Medications used in the management of pulmonary arterial hypertension Overview (B01, C02)
Prostacyclin Overview | Beraprost | Epoprostenol | Iloprost | Treprostinil
Endothelin Receptor Antagonists Overview | Ambrisentan | Bosentan | Sitaxsentan
PDE5 Inhibitors Overview | Sildenafil, Tadalafil
Adjunctive therapy | Calcium channel blockers | Diuretics | Digoxin | Oxygen therapy | Warfarin
## Vasodilators
Vasodilators Overview (C01D)
Quinolone Vasodilators Overview | Flosequinan
Other Vasodilators | Heptaminol | Molsidomine | Nicorandil | Nesiritide
# INTERVENTIONAL CARDIOLOGY
# Interventional Cardiology
Diagnostic Catheterization | Risk Stratification and the Benefits of PCI vs Medical Therapy | Conscious Sedation | Preparation of the Patient for Diagnostic Catheterization | Technical Aspects of the Cardiac Catheterization Laboratory | Obtaining Venous and Arterial Access | Equipment Used in Diagnostic Cardiac Catheterizaiton | Hemodynamic Assessment in the Cardiac Catheterization Laboratory | Radiation Safety
Assesement of coronary lesions | Coronary Fractional Flow Reserve (FFR)) | Coronary flow reserve(CFR) | Intravascular ultrasound (IVUS)
PCI | Preparation of the Patient for Percutaneous Coronary Intervention (PCI) | Percutaneous Coronary Intervention (PCI): Basic Principles and Guidelines | Equipment Used in Percutaneous Coronary Intervention | Pharmacotherapy to Support PCI | Antiplatelet therapy | Antithrombotic therapy | Angiography and PCI in Special Patient Populations | Management Of Specific Lesion Types | High Risk Percutaneous Coronary Intervention (PCI) | Vascular Closure Devices | Post PCI Medical Management of the Interventional Patient | Complications During and Following Cardiac Catheterization and Percutaneous Coronary Intervention | Coronary stent thrombosis
High Risk PCI | PCI in the Patient in Cardiogenic Shock | PCI in the Patient Requiring CPR and Refractory Ventricular Arrhythmias | PCI in the Patient with Severely Depressed Ventricular Function | PCI in the Patient with Critical Valve Stenosis | PCI in the Sole Remaining Conduit | PCI in the Unprotected Left Main Patient | Adjuncts for High Risk Percuatenous Coronary Intervention
Other TopicsNon Coronary Interventions in the Cardiac Catheterization Laboratory | Transfusion in ACS management | Revascularization in the "No Option" Patient
# Cardiac Surgery
# Vascular Surgery
# BIOSTATISTICS
# Biostatistics
# COST EFFECTIVENESS AND QUALITY OF LIFE
# Cost Effectiveness in Cardiovascular Disease | Jacko test
Template:WikiDoc Cardiology News
### Editorial Board
### Preface
### How To Use This Book
### Alphabetical Index of all Pages in the Cardiology Textbook
# ANATOMY
# Cardiovascular Anatomy
Arteries | Coronary arteries | Head and Neck | Upper Limbs | Torso-Chest | Torso-Abdomen | Lower Limbs | All
Veins | Head and Neck | Upper Extremity | Torso | Lower Extremity
Atria | Atria | Left atrium | Right atrium | Interatrial septum | Musculi pectinati
Ventricles | Ventricles | Left ventricle | Right ventricle | Interventricular septum | Trabeculae carneae | Chordae tendinae | Papillary muscle
Valves | Valves | Aortic valve | Mitral valve | Pulmonic valve | Tricuspid valve | Cusps
Regions | Base | Apex
Grooves | Coronary/atrioventricular | Interatrial | Anterior interventricular | Posterior interventricular
Surfaces | Sternocostal | Diaphragmatic
Borders | Right | Left
Right heart | Vena cavae | Coronary sinus | Right atrium | Right auricle | Fossa ovalis | Limbus of fossa ovalis | Crista terminalis | Valve of the inferior vena cava | Valve of the coronary sinus | Tricuspid valve | Right ventricle | Conus arteriosus | Moderator band/septomarginal trabecula | Pulmonary valve | Pulmonary artery | Pulmonary circulation
Left heart | Pulmonary veins | Left atrium | Left Auricle | Mitral valve | Left ventricle | Aortic valve | Aortic sinus | Aorta | Systemic circulation
Pericardium | Pericardium | Fibrous pericardium | Serous pericardium | Pericardial cavity | Epicardium/visceral layer | Pericardial sinus
Myocardium | Myocardium | Endocardium | Cardiac skeleton | Fibrous trigone | Fibrous rings
Conduction system | Conduction system | Cardiac pacemaker | SA node | AV node | Bundle of His | Purkinje fibers
# PHYSIOLOGY
# Cardiovascular Physiology
Volumes | Preload | Afterload | End-systolic volume | End-diastolic volume | Frank-Starling law of the heart | Cardiac output
Interactions | Wiggers diagram | Pressure volume diagram
Tropism | Chronotropy | Dromotropy | Inotropy
Hemodynamics | Hemodynamics | Baroreflexes | Kinin-kallikrein system | Renin-angiotensin system | Vasoconstrictors | Vasodilators | Compliance | Vascular resistance
Conduction | Electrical conduction system of the heart | Cardiac action potential
Cardiopulmonary | Respiratory physiology | Blood | Pulmonary circulation | Perfusion (Q) | Hypoxic pulmonary vasoconstriction | Pulmonary shunt | Ventilation/perfusion scan | ventilation/perfusion ratio (V/Q) | Zones of the lung | Gas exchange | Pulmonary gas pressures | Alveolar gas equation | Hemoglobin | Oxygen-haemoglobin dissociation curve | 2,3-DPG | Bohr effect | Haldane effect | Carbonic anhydrase | Chloride shift | Oxyhemoglobin | Respiratory quotient | Arterial blood gas | Diffusion capacity | Dlco
# DEVELOPMENTAL BIOLOGY
# Cardiovascular Development
Arteries | Dorsal aorta | Aortic arches | Vitelline arteries | Ductus arteriosus | Umbilical artery
Veins | Cardinal veins | Ducts of Cuvier | Vitelline veins | Ductus venosus | Umbilical vein
Heart Development | Primitive heart tube | Truncus arteriosus | Bulbus cordis | Primitive ventricle | Primitive atrium | Sinus venosus | Septum primum | Ostium primum | Ostium secundum | Septum secundum | Foramen ovale | Endocardial cushions | Septum intermedium | Aorticopulmonary septum | Atrial canal
# BASIC SCIENCE
# Cardiovascular Biochemistry
Molecular Biology | Biochemistry | Organic Chemistry | Enzymes | Immunology
# DIAGNOSTIC MODALITIES IN CARDIOLOGY
# The Patient History in Cardiovascular Disease
Chest Pain | Claudication | Cough | Dyspnea | Orthopnea | Palpitations | Paroxysmal Nocturnal Dyspnea | Pedal Edema
# The Physical Examination in Cardiovascular Disease
The Pulse | The Neck | The Heart | Lungs |
The Extremities
# The Electrocardiogram
Intervals | PR Interval | QRS Interval | QT Interval | T Wave | U Wave
Hypertrophy | Electrocardiographic Findings in LVH | Electrocardiographic Findings in Right Ventricular Hypertrophy (RVH) | Biventricular Hypertrophy
Bundle Branch Block | LBBB | LAHB | RBBB | Trifascicular block
Atrial Arrhythmias | Premature Atrial Contractions (PACs) | Ectopic Atrial Rhythm | Paroxysmal Atrial Tachycardia (PAT) | Paroxysmal Atrial Tachycardia (PAT) with Block | Multifocal Atrial Tachycardia (MAT) | Atrial Flutter | Atrial Fibrillation
Ventricular Arrhythmias | Differential Diagnosis of Tachycardia with a Wide QRS Complex
Conduction Abnormalities | First Degree AV Block | Second Degree AV Block | Complete or Third-Degree AV Block | Concealed conduction | AV Junctional Rhythms | Wolff-Parkinson-White Syndrome
Electrocardiographic Abnormalities in Different Disease States | The EKG in the Patient with an Atrial Septal Defect (ASD) | EKG Changes of Hypothermia | EKG Abnormalities in CNS Disease | The EKG of Cardiac Transplantation | The EKG in a Patient with a Pacemaker | Electrocardiography of Traumatic Heart Disease
Drug Effects on the EKG | Digitalis | Quinidine | Procainamide | Disopyramide | Lidocaine | Tocainide and Mexiletine | Phenytoin | Encainide, Flecainide and Propafenone | β-blockers | Amiodarone | Bretylium | Ca Channel Blockers | Adenosine | Phenothiazines | Tricyclic Antidepressants | Lithium
EKG in Electrolyte Disturbances | The EKG in Hyperkalemia | The EKG in Hypokalemia | The EKG in Hypercalcemia | The EKG in Hypocalcemia | Nonspecific ST-Segment and T-Wave Changes
# Exercise Stress Testing
# Cardiac Electrophysiology
# Cardiac Biomarkers
Creatine Kinase | Cytokines and their receptors | Lipoprotein-associated phospholipase A2 (Lp-PLA2) | Metalloproteinases (MMPs) | Natriuretic peptides | Prothrombin fragment 1.2 (F1.2) | Prothrombin time (PT) | Soluble CD40 ligand (sCD40L) | Thrombus precursor protein (TpP) | Von Willebrand factor (vWF) | White blood cell (WBC) count
# An Overview of Cardiac Imaging
# The Chest X Ray in Cardiovascular Disease
# Echocardiography
# Nuclear Cardiology
# Coronary Angiography
# Cardiovascular Magnetic Resonance Imaging (CMR)
# CT Angiography
# Positron Emission Tomography
# CARDIAC DISEASE STATES
# The Genetic Basis of Heart Disease
# Congenital Heart Disease
Cardiac chambers and connections | Persistent truncus arteriosus | Double outlet right ventricle (Taussig-Bing syndrome) | Transposition of the great vessels (Dextro, Levo)
Cardiac Septa | Cardiac septa | Ventricular septal defect | Atrial septal defect (Lutembacher's syndrome) | Atrioventricular septal defect | (Ostium primum) | Tetralogy of Fallot | Eisenmenger's syndrome
Right sided pulmonary and tricuspid valve | Pulmonary valve (Stenosis Pulmonary valve insufficiency) | Tricuspid valve (Stenosis, Atresia) | Ebstein's anomaly
Left sided aortic and mitral valves | Aortic valve (Stenosis, insufficiency, bicuspid) | Mitral valve (stenosis, regurgitation) | Hypoplastic left heart syndrome
Other congenital malformations | Dextrocardia | Levocardia | Cor triatriatum |
Great arteries aorta (Patent ductus arteriosus | Aortic coarctation | Interrupted aortic arch | Overriding aorta | Aneurysm of sinus of Valsalva | Vascular ring) | Pulmonary atresia
Great veins | Persistent left superior vena cava | Total anomalous pulmonary venous connection | Scimitar syndrome
Other | Arteriovenous malformation (Cerebral arteriovenous malformation)
# Cardiac Disease in Pregnancy
# Cardiac Diseases in AIDS
# Diseases of the Pericardium
# Trauma and the Heart
# Diseases of the Valvular Structures
Aortic Stenosis | Aortic Regurgitation | Mitral Stenosis | Mitral Regurgitation | Mitral Valve Prolapse | Pulmonic Regurgitation | Pulmonic Stenosis | Tricuspid Valve Prolapse | Tricuspid Regurgitation | Tricuspid Stenosis | Infective Endocarditis
# Diseases of the Myocardium
Cardiomegaly | Cardiomyopathy | Congestive Heart Failure | Left Ventricular Hypertrophy | Myocarditis
# Cardiac Arrhythmias
# VASCULAR MEDICINE
# Vascular Medicine
# Diseases of the Aorta
# Peripheral Arterial Disease
# Sytemic Arterial Hypertension
# Hypotension
# Primary Cardiac Tumors
# The Heart in Oncologic Disease
# Endocrine Disease and the Heart
Hyperthyroidism | Hypothyroidism | Hypoparathyroidism | Acromegaly
# Renal Disease and the Heart
# Infectious Disease and the Heart
AIDS | Chagas'
# Autoimmune/Rheumatologic Disease and the Heart
Lupus | Psoriasis | Rheumatoid Arthritis | Scleroderma | Temporal Arteritis | Ulcerative Colitis | Wegener's Granulomatosis
# Pulmonary Embolism
# Pulmonary Hypertension
# Cor Pulmonale
# Pre-Operative Clearance
# HEMOCARDIOLOGY
# The Role of the Coagulation System in Heart Disease
# CORONARY ARTERY DISEASE
# Atherosclerosis Prevention and Risk Factor Modification
# Chronic Stable Angina
Introduction | Definition | Historical Perspective | Epidemiology | Pathophysiology | Presentation | Recognition of Clinical Subsets | Risk Factors | Diagnosis | Differential Diagnosis of Chest Pain | Treatment | Prognosis | Rehabilitation | Prevention
# Unstable Angina
# Non ST Elevation Myocardial Infarction
# ST Elevation Myocardial Infarction
Overview | Epidemiology and Demographics | Pathophysiology of Reperfusion | Risk Factors | Pathophysiology | Triggers | Classification
Diagnosis | Symptoms | Physical Examination | Electrocardiogram | Cardiac Markers | Coronary Angiography | Histopathology
Treatment | Pre-Hospital Care | Initial Care | Thrombolytic Therapy | Primary Percutaneous Coronary Intervention | Rescue Percutaneous Coronary Intervention | Facilitated Percutaneous Coronary Intervention | Coronary Artery Bypass Graft Surgery | Barriers to Implementing Clinical Guidelines
ST Elevation Myocardial Infarction Arrhythmia Monitoring | Secondary Prevention | Complications | Prognosis |
ST Elevation Myocardial Infarction | Cardiac Rehabilitation
# The Living Guidelines
# PHARMACOTHERAPY
# Cardiovascular Pharmacotherapy
## Adrenergic Agonists
Adrenergic Agonists Overview
Direct Acting | Dobutamine | Dopamine | Epinephrine | Formoterol | Isoproterenol | Metaproterenol | Methoxamine | Norepinephrine | Phenylephrine | Salmeterol | Tamsulosin | Terbutaline
Indirect Acting | Amphetamine | Tyramine
Mixed Action | Ephedrine
## Angiotensin-Renin Inhibitors (C09)
ACE Inhibitor Overview | Benazepril | Captopril | Enalapril | Fosinopril | Lisinopril | Perindopril | Quinapril | Ramipril | Spirapril | Trandolapril
Angiotensin II receptor antagonist Overview | Candesartan | Eprosartan | Irbesartan | Losartan | Olmesartan | Tasosartan | Telmisartan | Valsartan
Renin Inhibitors Overview | Aliskiren | Remikiren
## Antiarrhythmic agents
Antiarrhythmic Agents Overview (C01B)
Class Ia | Ajmaline | Disopyramide | Prajmaline | Procainamide | Quinidine | Sparteine
Class Ib | Aprindine | Lidocaine | Mexiletine | Tocainide
Class Ic | Encainide | Flecainide | Lorcainide | Moricizine | Propafenone
Class II | Propranolol | Metoprolol | Nadolol | Atenolol | Acebutolol | Pindolol see Beta blockers (C07)
Class III | Amiodarone | Bretylium tosylate | Bunaftine | Dofetilide | Ibutilide | Sotalol
Class IV | Verapamil | Diltiazem see Calcium channel blockers (C08)
Class V | Adenosine | Atropine | Digoxin
## Anticoagulants
Anticoagulants Overview
Vitamin K Antagonists Overview | Acenocoumarol | Clorindione | Coumatetralyl | Dicumarol (Dicoumarol) | Diphenadione | Ethyl biscoumacetate | Phenprocoumon | Phenindione | Tioclomarol | Warfarin
## Antihypertensives and Diuretics
Antihypertensive Overview (C02) and Diuretic Overview (C03)
Sympatholytic Agents Overview (including Alpha Blockers Overview)
Vasodilators Overview | Diazoxide | Hydralazine | Minoxidil | Nitroprusside | Phentolamine
Other antihypertensives
Low ceiling diuretics
High ceiling diuretics
## Antiplatelet Agents
Glycoprotein IIb/IIIa Inhibitors Overview | Abciximab | Eptifibatide | Tirofiban
ADP Receptor Antagonists | Clopidogrel | Ticlopidine | Prasugrel
Prostaglandin Analogues Overview | Beraprost | Prostacyclin | Iloprost | Treprostinil
Other Antiplatelet Agents Acetylsalicylic acid/Aspirin | Aloxiprin | Ditazole | Carbasalate calcium | Cloricromen | Dipyridamole | Indobufen | Picotamide | Triflusal
## Antithrombins
Direct Thrombin Inhibitors Overview | Argatroban | Bivalirudin | Dabigatran | Desirudin | Hirudin | Lepirudin | Melagatran | Ximelagatran
Indirect Thrombin Inhibitors
Other Antithrombotics | Defibrotide | Dermatan sulfate | Fondaparinux | Rivaroxaban
Non-Medicinal Antithrombins Overview | Citrate | EDTA | Oxalate
## Beta Blockers
Beta Blockers Overview (C07)
Non-selective β antagonists | Metipranolol | Nadolol | Oxprenolol | Penbutolol | Pindolol | Propranolol | Timolol | Sotalol
β1 antagonists (cardioselective) | Atenolol | Acebutolol | Betaxolol | Bisoprolol | Esmolol | Metoprolol | Nebivolol
Mixed α1/β antagonists | Carvedilol | Labetalol
## Calcium Channel Blockers
Calcium Channel Blocker Overview
Class I Phenylalkylamines (C08DA) | Verapamil
Class II Dihydropyridines (C08CA)
Class III Benzothiazepines (C08DB)
## Cardiac Glycosides
Cardiac Glycoside Overview (C01A)
Digitalis Glycosides Overview | Acetyldigitoxin | Acetyldigoxin | Digitalis leaves | Digitoxin | Digoxin | Lanatoside C | Deslanoside | Metildigoxin | Gitoformate
Scilla Glycosides Overview | Proscillaridin
Strophantus Glycosides Overview | G-strophanthin | Cymarin
Other Cardiac Glycosides | Peruvoside
## Cardiac Stimulants Excluding Cardiac Glycosides
Cardiac stimulants excluding cardiac glycosides (C01C)
Adrenergic Overview and Dopaminergic Overview agents |
Etilefrine | Isoprenaline | Norepinephrine | Dopamine | Norfenefrine | Phenylephrine | Dobutamine | Oxedrine | Metaraminol | Methoxamine | Mephentermine | Dimetofrine | Prenalterol | Dopexamine | Gepefrine | Ibopamine | Midodrine | Octopamine | Fenoldopam | Cafedrine | Arbutamine | Theodrenaline | Epinephrine
Phosphodiesterase Inhibitors Overview (PDE3I) | Amrinone | Milrinone | Enoximone | Bucladesine
Other cardiac stimulants | Angiotensinamide | Xamoterol | Levosimendan
## Fibrinolytics
Alteplase | Reteplase | Tenecteplase | Streptokinase, Urokinase | Saruplase | Anistreplase
## Hypolipidemic Agents
Statins Overview | Atorvastatin | Cerivastatin | Fluvastatin | Lovastatin | Mevastatin | Pitavastatin | Pravastatin | Rosuvastatin | Simvastatin
Fibrates Overview | Clofibrate | Bezafibrate | Aluminium clofibrate | Gemfibrozil | Fenofibrate | Simfibrate | Ronifibrate | Ciprofibrate | Etofibrate | Clofibride
Bile Acid Sequestrant Overview | Colestyramine | Colestipol | Colextran | Colesevelam
Niacin and Derivatives | Niceritrol | Niacin | Nicofuranose | Aluminium nicotinate | Nicotinyl alcohol | Acipimox
Other | Dextrothyroxine | Probucol | Tiadenol | Benfluorex | Meglutol | Omega-3-triglycerides | Magnesium pyridoxal 5-phosphate glutamate | Policosanol | Ezetimibe
## Nitrates
Nitrates Overview | Glyceryl trinitrate | Isosorbide dinitrate | Isosorbide mononitrate | Molsidomine | Pentaerythritol tetranitrate
## Pulmonary Artery Hypertension
Medications used in the management of pulmonary arterial hypertension Overview (B01, C02)
Prostacyclin Overview | Beraprost | Epoprostenol | Iloprost | Treprostinil
Endothelin Receptor Antagonists Overview | Ambrisentan | Bosentan | Sitaxsentan
PDE5 Inhibitors Overview | Sildenafil, Tadalafil
Adjunctive therapy | Calcium channel blockers | Diuretics | Digoxin | Oxygen therapy | Warfarin
## Vasodilators
Vasodilators Overview (C01D)
Quinolone Vasodilators Overview | Flosequinan
Other Vasodilators | Heptaminol | Molsidomine | Nicorandil | Nesiritide
# INTERVENTIONAL CARDIOLOGY
# Interventional Cardiology
Diagnostic Catheterization | Risk Stratification and the Benefits of PCI vs Medical Therapy | Conscious Sedation | Preparation of the Patient for Diagnostic Catheterization | Technical Aspects of the Cardiac Catheterization Laboratory | Obtaining Venous and Arterial Access | Equipment Used in Diagnostic Cardiac Catheterizaiton | Hemodynamic Assessment in the Cardiac Catheterization Laboratory | Radiation Safety
Assesement of coronary lesions | Coronary Fractional Flow Reserve (FFR)) | Coronary flow reserve(CFR) | Intravascular ultrasound (IVUS)
PCI | Preparation of the Patient for Percutaneous Coronary Intervention (PCI) | Percutaneous Coronary Intervention (PCI): Basic Principles and Guidelines | Equipment Used in Percutaneous Coronary Intervention | Pharmacotherapy to Support PCI | Antiplatelet therapy | Antithrombotic therapy | Angiography and PCI in Special Patient Populations | Management Of Specific Lesion Types | High Risk Percutaneous Coronary Intervention (PCI) | Vascular Closure Devices | Post PCI Medical Management of the Interventional Patient | Complications During and Following Cardiac Catheterization and Percutaneous Coronary Intervention | Coronary stent thrombosis
High Risk PCI | PCI in the Patient in Cardiogenic Shock | PCI in the Patient Requiring CPR and Refractory Ventricular Arrhythmias | PCI in the Patient with Severely Depressed Ventricular Function | PCI in the Patient with Critical Valve Stenosis | PCI in the Sole Remaining Conduit | PCI in the Unprotected Left Main Patient | Adjuncts for High Risk Percuatenous Coronary Intervention
Other TopicsNon Coronary Interventions in the Cardiac Catheterization Laboratory | Transfusion in ACS management | Revascularization in the "No Option" Patient
# Cardiac Surgery
Template:Cardiac surgery
# Vascular Surgery
Template:Vascular surgery
# BIOSTATISTICS
# Biostatistics
# COST EFFECTIVENESS AND QUALITY OF LIFE
# Cost Effectiveness in Cardiovascular Disease
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Jacko_test | |
dc3b80c9bc033e25597a32049acc581810696690 | wikidoc | Jan Janský | Jan Janský
prof. MUDr. Jan Janský (Template:IPA2) (April 3 1873, Prague – September 8 1921, Černošice near Prague) was a Czech serologist, neurologist and psychiatrist. He is credited with the first classification of blood into the four types (A, B, AB, O) of the ABO blood group system.
Janský studied medicine at Charles University in Prague. From 1899 he worked in a psychiatric clinic in Prague. In 1914 he was named professor. During World War I Janský served two years as a doctor at the front until a heart attack disabled him. After the war he worked as a neuropsychiatrist in a military Hospital (Vojenská nemocnice). He had angina pectoralis and died of ischaemic heart disease.
Janský was also a proponent of voluntary blood donations.
# Blood classification
Through his psychiatric research, Janský tried to find a correlation between mental diseases and blood diseases. He found no such correlation existed and published a study, Hematologická studie u psychotiků (1907, Hematological study of psychotics), in which he classified blood into four groups I, II, III, IV. At the time this discovery passed almost unnoticed. In 1921 an American medical commission acknowledged Janský's classification (over that of Karl Landsteiner, who classified blood into only three groups; and was for this (blood types) discovery awarded the Nobel Prize in Physiology or Medicine in 1930). Janský's classification remains in use today. A similar classification was described by William Lorenzo Moss, except the I and IV of Moss were the opposite to that of Janský's, leading to confusion in blood transfusion until the use of A, B and O became standard.
# Legacy
- Frequent voluntary blood donors in The Czech Republic are awarded with Janský medal (Janského plaketa). | Jan Janský
prof. MUDr. Jan Janský (Template:IPA2) (April 3 1873, Prague – September 8 1921, Černošice near Prague) was a Czech serologist, neurologist and psychiatrist. He is credited with the first classification of blood into the four types (A, B, AB, O) of the ABO blood group system.
Janský studied medicine at Charles University in Prague. From 1899 he worked in a psychiatric clinic in Prague. In 1914 he was named professor. During World War I Janský served two years as a doctor at the front until a heart attack disabled him. After the war he worked as a neuropsychiatrist in a military Hospital (Vojenská nemocnice). He had angina pectoralis and died of ischaemic heart disease.
Janský was also a proponent of voluntary blood donations.
# Blood classification
Through his psychiatric research, Janský tried to find a correlation between mental diseases and blood diseases. He found no such correlation existed and published a study, Hematologická studie u psychotiků (1907, Hematological study of psychotics), in which he classified blood into four groups I, II, III, IV. At the time this discovery passed almost unnoticed. In 1921 an American medical commission acknowledged Janský's classification (over that of Karl Landsteiner, who classified blood into only three groups; and was for this (blood types) discovery awarded the Nobel Prize in Physiology or Medicine in 1930). Janský's classification remains in use today. A similar classification was described by William Lorenzo Moss, except the I and IV of Moss were the opposite to that of Janský's, leading to confusion in blood transfusion until the use of A, B and O became standard. [1]
# Legacy
- Frequent voluntary blood donors in The Czech Republic are awarded with Janský medal (Janského plaketa). | https://www.wikidoc.org/index.php/Jan_Jansky | |
0e7dc2df8d3bffa8a88d3064d8f833688d8b0f5a | wikidoc | Jill Stein | Jill Stein
Jill Stein (J-Lexington) is a physician and Green-Rainbow Party activist residing in Lexington, Massachusetts. She serves on the boards of Greater Boston Physicians for Social Responsibility and MassVoters for Fair Elections, and has been active recently with the Massachusetts Coalition for Healthy Communities.
# Electoral history
## Campaign for Governor, 2002
She was the Green-Rainbow Party candidate for governor of Massachusetts in 2002. She gained widespread approval for her strong performance in the debates, but this failed to translate into success at the ballot box, coming third in the field of five with 76,530 votes and about 3.5% of the vote.
## Campaign for Massachusetts House of Representatives, 2004
Following her defeat to Mitt Romney, she ran for state representative in 2004 for the Ninth Middlesex District, with the endorsement of State Representative Jay R. Kaufman. Stein received 21.3% of the vote, ahead of Republican Linda Fosburg, with 18.9% of the vote, but behind Democratic incumbent Thomas M. Stanley, who received 59.6% of the vote.
## Elected to Town Meeting Seat, 2005
Stein was elected to the Town Meeting Seat, Precinct 2 (N. Waltham, Middlesex County) in march 2005 local elections. She finished first of 16 candidates running for 7 seats receiving 539 votes, for 20.6% of the total vote.
# Campaign for Massachusetts Secretary of the Commonwealth, 2006
She was nominated for Secretary of the Commonwealth on March 4, 2006, at the Green-Rainbow Party state-wide nominating convention. Dr. Stein was the sole challenger to three-term incumbent Democrat Bill Galvin for the post. The general election was held on November 7, 2006. Jill Stein was able to capitalize of this head to head match up and received 353,551 votes for 18% of the total vote. Jill's 18% marks the best finish for a Green Party candidate running for Secretary of State in any state to date. | Jill Stein
Jill Stein (J-Lexington) is a physician and Green-Rainbow Party activist residing in Lexington, Massachusetts. She serves on the boards of Greater Boston Physicians for Social Responsibility and MassVoters for Fair Elections, and has been active recently with the Massachusetts Coalition for Healthy Communities.
# Electoral history
## Campaign for Governor, 2002
She was the Green-Rainbow Party candidate for governor of Massachusetts in 2002. She gained widespread approval for her strong performance in the debates, but this failed to translate into success at the ballot box, coming third in the field of five with 76,530 votes and about 3.5% of the vote.
## Campaign for Massachusetts House of Representatives, 2004
Following her defeat to Mitt Romney, she ran for state representative in 2004 for the Ninth Middlesex District, with the endorsement of State Representative Jay R. Kaufman.[citation needed] Stein received 21.3% of the vote, ahead of Republican Linda Fosburg, with 18.9% of the vote, but behind Democratic incumbent Thomas M. Stanley, who received 59.6% of the vote.[1]
## Elected to Town Meeting Seat, 2005
Stein was elected to the Town Meeting Seat, Precinct 2 (N. Waltham, Middlesex County) in march 2005 local elections. She finished first of 16 candidates running for 7 seats receiving 539 votes, for 20.6% of the total vote.
# Campaign for Massachusetts Secretary of the Commonwealth, 2006
She was nominated for Secretary of the Commonwealth on March 4, 2006, at the Green-Rainbow Party state-wide nominating convention. Dr. Stein was the sole challenger to three-term incumbent Democrat Bill Galvin for the post. The general election was held on November 7, 2006. Jill Stein was able to capitalize of this head to head match up and received 353,551 votes for 18% of the total vote.[1] Jill's 18% marks the best finish for a Green Party candidate running for Secretary of State in any state to date. | https://www.wikidoc.org/index.php/Jill_Stein | |
04f3280583ce3e7406636aa9c4b870fb99b33e0d | wikidoc | Jim Pankiw | Jim Pankiw
Dr. Jim Pankiw (born August 7, 1966) is a Canadian politician and former Member of Parliament.
Pankiw served two terms in the Canadian House of Commons, representing Saskatoon—Humboldt in Saskatchewan from 1997 until 2004 as a member of the Reform Party of Canada, the Canadian Alliance, the Democratic Representative Caucus and finally as an independent (politician) MP.
# Early life
Pankiw was raised by his father George Pankiw in Unity, Saskatchewan. His mother died when he was young. After training as a chiropractor, Pankiw was first elected to Canadian Parliament in the Canadian federal election, 1997 as a member of the Reform Party. He won a plurality of just 220 votes over Dennis Gruending of the New Democratic Party.
# Controversy
In 2000, Pankiw wrote a letter to the president of the University of Saskatchewan, Peter MacKinnon, condemning the university's affirmative action policies and comparing its supporters to those of the Ku Klux Klan. The letter led to a heated debate between Pankiw and Saskatchewan Liberal Party cabinet minister Jack Hilson on the university campus.
At the time of the Canadian federal election, 2000, Pankiw was a member of Reform's successor, the Canadian Alliance. He ran into opposition during his on-campus debate with the Liberal Party of Canada candidate, former MP Morris Bodnar. Owing to strong support from the rural areas of the constituency, Pankiw won re-election with a plurality of 6,360 votes.
# Expulsion
By 2001, Pankiw's relationship with much of the Alliance caucus and especially the leader, Stockwell Day, was reported to be strained. Pankiw eventually joined with a small group of MPs informally led by Chuck Strahl and called for Day's resignation. As a result, Pankiw was suspended and eventually expelled from the Alliance caucus and party. After joining with other expellees to form the Democratic Representative Caucus, Pankiw sat with other DRC members in the Progressive Conservative Party of Canada-DRC coalition.
The election of Stephen Harper as leader of the Alliance resulted in the dissolution of the PC-DRC coalition and in most of the DRC members returning to the Alliance fold. Pankiw also applied for re-admission. However, by this time he was involved in another controversy, after an aboriginal peoples of Canada lawyer alleged that an inebriated Pankiw had made lewd gestures to him in a Saskatoon bar, and challenged him to a fight.
Pankiw was denied re-admission to the Alliance. He was also refused membership in the new Conservative Party of Canada, and served the rest of his term as an independent MP.
# Mayoralty election
In 2003, Pankiw ran against the unpopular incumbent James Maddin for mayor of Saskatoon. Those opposed to him raised billboards that read "Racism-Free Zone — No Pankiw, Thank You". In response, Pankiw distributed flyers claiming that it was his opponents who were racist. The revelation that Pankiw had recently purchased a home outside the Saskatoon city limits also attracted criticism since his mayoral application said he resided in the Forest Grove area in northeast Saskatoon.
Pankiw finished ahead of Maddin in third place, behind runner-up Peter Zakreski. Don Atchison was elected mayor. Voter turnout exceeded 50 percent, a level almost unheard of in a Canadian municipal election.
# Reelection and return campaigns
Pankiw sought re-election in the Canadian federal election, 2004, against Conservative candidate Brad Trost, Liberal Patrick Wolfe and New Democrat Nettie Wiebe. He received 7,076 votes, achieving fourth place, 2,368 votes behind the winner, Trost.
Pankiw was defeated again in the Canadian federal election, 2006 in the Battlefords-Lloydminster constituency by Conservative Gerry Ritz. Ritz has represented Battlefords-Lloydminster since the 1997 election, which he won after defeating Pankiw's father George in a heated contest for the Reform Party nomination. | Jim Pankiw
Dr. Jim Pankiw (born August 7, 1966) is a Canadian politician and former Member of Parliament.
Pankiw served two terms in the Canadian House of Commons, representing Saskatoon—Humboldt in Saskatchewan from 1997 until 2004 as a member of the Reform Party of Canada, the Canadian Alliance, the Democratic Representative Caucus and finally as an independent (politician) MP.
# Early life
Pankiw was raised by his father George Pankiw in Unity, Saskatchewan. His mother died when he was young. After training as a chiropractor, Pankiw was first elected to Canadian Parliament in the Canadian federal election, 1997 as a member of the Reform Party. He won a plurality of just 220 votes over Dennis Gruending of the New Democratic Party.
# Controversy
In 2000, Pankiw wrote a letter to the president of the University of Saskatchewan, Peter MacKinnon, condemning the university's affirmative action policies and comparing its supporters to those of the Ku Klux Klan. The letter led to a heated debate between Pankiw and Saskatchewan Liberal Party cabinet minister Jack Hilson on the university campus.[1]
At the time of the Canadian federal election, 2000, Pankiw was a member of Reform's successor, the Canadian Alliance. He ran into opposition during his on-campus debate with the Liberal Party of Canada candidate, former MP Morris Bodnar. Owing to strong support from the rural areas of the constituency, Pankiw won re-election with a plurality of 6,360 votes.
# Expulsion
By 2001, Pankiw's relationship with much of the Alliance caucus and especially the leader, Stockwell Day, was reported to be strained.[citation needed] Pankiw eventually joined with a small group of MPs informally led by Chuck Strahl and called for Day's resignation. As a result, Pankiw was suspended and eventually expelled from the Alliance caucus and party. After joining with other expellees to form the Democratic Representative Caucus, Pankiw sat with other DRC members in the Progressive Conservative Party of Canada-DRC coalition.
The election of Stephen Harper as leader of the Alliance resulted in the dissolution of the PC-DRC coalition and in most of the DRC members returning to the Alliance fold. Pankiw also applied for re-admission. However, by this time he was involved in another controversy, after an aboriginal peoples of Canada lawyer alleged that an inebriated Pankiw had made lewd gestures to him in a Saskatoon bar, and challenged him to a fight.[2]
Pankiw was denied re-admission to the Alliance. He was also refused membership in the new Conservative Party of Canada, and served the rest of his term as an independent MP.
# Mayoralty election
In 2003, Pankiw ran against the unpopular incumbent James Maddin for mayor of Saskatoon. Those opposed to him raised billboards that read "Racism-Free Zone — No Pankiw, Thank You". In response, Pankiw distributed flyers claiming that it was his opponents who were racist. The revelation that Pankiw had recently purchased a home outside the Saskatoon city limits also attracted criticism since his mayoral application said he resided in the Forest Grove area in northeast Saskatoon.
Pankiw finished ahead of Maddin in third place, behind runner-up Peter Zakreski. Don Atchison was elected mayor. Voter turnout exceeded 50 percent, a level almost unheard of in a Canadian municipal election.[citation needed]
# Reelection and return campaigns
Pankiw sought re-election in the Canadian federal election, 2004, against Conservative candidate Brad Trost, Liberal Patrick Wolfe and New Democrat Nettie Wiebe. He received 7,076 votes, achieving fourth place, 2,368 votes behind the winner, Trost.
Pankiw was defeated again in the Canadian federal election, 2006 in the Battlefords-Lloydminster constituency by Conservative Gerry Ritz. Ritz has represented Battlefords-Lloydminster since the 1997 election, which he won after defeating Pankiw's father George in a heated contest for the Reform Party nomination. | https://www.wikidoc.org/index.php/Jim_Pankiw | |
9b1abd8e430561d906c60ae43db0051105d25587 | wikidoc | Jing (TCM) | Jing (TCM)
Jīng (Template:Zh-c; Wade-Giles: ching1) is the Chinese word for "essence", specifically kidney essence. Along with qì and shén, it is considered one of the Three Treasures Sanbao 三寶 of Traditional Chinese Medicine or TCM. Jīng is stored in the kidneys and is the most dense physical matter within the body (as opposed to shén which is the most volatile). It is said to be the material basis for the physical body and is yīn in nature, which means it nourishes, fuels, and cools the body. As such it is an important concept in the internal martial arts. Jīng is also believed by some to be the carrier of our heritage (similar to DNA). Production of semen, in the man, and menstrual blood (or pregnancy), in the woman, are believed to place the biggest strains on jīng. Because of this, some even equate jīng with semen, but this is inaccurate; the jīng circulates through the 8 extraordinary vessels and creates marrow and semen, among other functions.
One is said to be born with a set amount of jīng (pre-natal jīng, also sometimes called yuan qi) and also can acquire jīng from food and various forms of stimulation (exercise, study, meditation.) Theoretically, jīng is consumed continuously in life; by everyday stress, illness, substance abuse, sexual intemperance, etc. Pre-natal jīng by definition cannot be renewed, and it is said it is completely consumed upon dying.
So, this jīng is considered quite important for longevity in TCM. Many disciplines related to qìgōng are devoted to the replenishment of "lost" jīng by restoration of the post-natal jīng. In particular, the internal martial arts (esp. Tai chi chuan) and the Circle Walking of Baguazhang may be used to preserve pre-natal jīng and build post-natal jīng - if performed correctly. Commonplace in China is the sight of rénshēn on sale in herb shops, at a wide range of prices - Kung Fu classics fans may remember it used as a plot element at the start of Drunken Master 2. Rénshēn, particularly Korean and Chinese, is said to bolster the jīng and a common medicinal recipe is to add to porridge (of course congee in China) along with cinnamon, goji berries and ginger for a sweet, warming breakfast when the weather starts to turn cold in Autumn.
An early mention of the term in this sense is in a 4th century BCE chapter called "Inner Training" (內業) of a larger text compiled during the Han dynasty, the Guǎnzi (管子).
Jīng (精; essence) should not be confused with the related concept of jìn (勁; power), nor with jīng (經; classic/warp), which appears in many early Chinese book titles, such as the Nèi Jīng, yì jīng and Chá Jīng, the fundamental text on all the knowledge associated with tea.
The concept of Jing is employed in the animated series Avatar: The Last Airbender. | Jing (TCM)
Template:ChineseText
Jīng (Template:Zh-c; Wade-Giles: ching1) is the Chinese word for "essence", specifically kidney essence. Along with qì and shén, it is considered one of the Three Treasures Sanbao 三寶 of Traditional Chinese Medicine or TCM. Jīng is stored in the kidneys and is the most dense physical matter within the body (as opposed to shén which is the most volatile). It is said to be the material basis for the physical body and is yīn in nature, which means it nourishes, fuels, and cools the body. As such it is an important concept in the internal martial arts. Jīng is also believed by some to be the carrier of our heritage (similar to DNA). Production of semen, in the man, and menstrual blood (or pregnancy), in the woman, are believed to place the biggest strains on jīng. Because of this, some even equate jīng with semen, but this is inaccurate; the jīng circulates through the 8 extraordinary vessels and creates marrow and semen, among other functions.[1]
One is said to be born with a set amount of jīng (pre-natal jīng, also sometimes called yuan qi) and also can acquire jīng from food and various forms of stimulation (exercise, study, meditation.) Theoretically, jīng is consumed continuously in life; by everyday stress, illness, substance abuse, sexual intemperance, etc. Pre-natal jīng by definition cannot be renewed, and it is said it is completely consumed upon dying.
So, this jīng is considered quite important for longevity in TCM. Many disciplines related to qìgōng are devoted to the replenishment of "lost" jīng by restoration of the post-natal jīng. In particular, the internal martial arts (esp. Tai chi chuan) and the Circle Walking of Baguazhang may be used to preserve pre-natal jīng and build post-natal jīng - if performed correctly. Commonplace in China is the sight of rénshēn on sale in herb shops, at a wide range of prices - Kung Fu classics fans may remember it used as a plot element at the start of Drunken Master 2. Rénshēn, particularly Korean and Chinese, is said to bolster the jīng and a common medicinal recipe is to add to porridge (of course congee in China) along with cinnamon, goji berries and ginger for a sweet, warming breakfast when the weather starts to turn cold in Autumn.
An early mention of the term in this sense is in a 4th century BCE chapter called "Inner Training" (內業) of a larger text compiled during the Han dynasty, the Guǎnzi (管子)[2].
Jīng (精; essence) should not be confused with the related concept of jìn (勁; power), nor with jīng (經; classic/warp), which appears in many early Chinese book titles, such as the Nèi Jīng, yì jīng and Chá Jīng, the fundamental text on all the knowledge associated with tea[3].
The concept of Jing is employed in the animated series Avatar: The Last Airbender. | https://www.wikidoc.org/index.php/Jing_(TCM) | |
fd285c5f9086ebfde2946e6e4af004e831212e5a | wikidoc | Joel Brind | Joel Brind
Dr. Joel Brind is a pro-life born again Christian, scientist, and a leading advocate of the abortion-breast cancer hypothesis. He is a professor of biology and endocrinology at Baruch College and critiques abortion-breast cancer studies. Brind was an invitee to the National Cancer Institute's conference on the ABC issue where he filed the minority dissenting comment.
Brind has been mischaracterized by some pro-choice advocates and publications. In Joyce Arthur's article she incorrectly claims Brind believes "miscarriages are caused by a lack of pregnancy hormones." In fact, Brind and reproductive experts are aware miscarriages usually are not caused, but rather are characterized by a lack of hormones. (See also: ABC section) A Women's eNews article states that Brind wrote in a pro-life publication where he implies the term "recall bias" is manufactured. It was actually the evidence from the Rookus study that Brind considered "artificially manufactured."
However, many believe Brind overlooks methological weaknesses of some studies he uses as evidence for an abortion-breast cancer link. Furthermore, medical researchers note Brind overstates his findings since his own research shows a "barely statistically significant" increase in breast cancer rates. | Joel Brind
Dr. Joel Brind is a pro-life born again Christian, scientist, and a leading advocate of the abortion-breast cancer hypothesis.[1] He is a professor of biology and endocrinology at Baruch College and critiques abortion-breast cancer studies. Brind was an invitee to the National Cancer Institute's conference on the ABC issue[2] where he filed the minority dissenting comment.[3]
Brind has been mischaracterized by some pro-choice advocates and publications. In Joyce Arthur's article she incorrectly claims Brind believes "miscarriages are caused by a lack of pregnancy hormones."[4] In fact, Brind and reproductive experts are aware miscarriages usually are not caused, but rather are characterized by a lack of hormones.[5] (See also: ABC section) A Women's eNews article[6] states that Brind wrote in a pro-life publication where he implies the term "recall bias" is manufactured. It was actually the evidence from the Rookus study[7] that Brind considered "artificially manufactured."[8]
However, many believe Brind overlooks methological weaknesses of some studies he uses as evidence for an abortion-breast cancer link. Furthermore, medical researchers note Brind overstates his findings since his own research shows a "barely statistically significant" increase in breast cancer rates.[9] | https://www.wikidoc.org/index.php/Joel_Brind | |
d6e6a23a712132a59c5b841564b624616e4ebf9d | wikidoc | Juice Plus | Juice Plus
Juice Plus+ is a branded line of dietary supplements containing concentrated fruit and vegetable juice extracts fortified with added vitamins and nutrients. Introduced in 1993 and sold via direct or multi-level marketing, the supplements are advertised as "the next best thing to fruits and vegetables," a claim which has stirred considerable controversy.
Marketing claims made about Juice Plus products suggest that they can provide benefits such as reducing oxidative stress and promoting cardiovascular health. Critics have argued that there is no scientific proof that Juice Plus offers significant health benefits, and that deceptive claims are used in the product's marketing information. Studies which have set out to test the effects of Juice Plus have generated conflicting and controversial results.
# Product overview
Juice Plus is manufactured by Natural Alternatives International in San Marcos, CA and distributed by National Safety Associates (NSA; Collierville, TN) via direct or multi-level marketing. NSA was founded in 1970 and before introducing Juice Plus in 1993, was known for other multilevel-marketed products such as water filters, air filters, and fire-protection equipment. Naturopath Humbart "Smokey" Santillo is credited with having developed the Juice Plus “concept” and “nutritional philosophy” and for creating what has been described as the “original formula” for the product. According to Santillo, he has also worked with NSA to develop other Juice Plus products.
The primary products in the Juice Plus line are Orchard Blend (a fruit juice powder-based vitamin supplement) and Garden Blend (vegetable juice powder-based) capsules, which are sold together in 4-month supplies at a cost, in 2007, of approximately $160 USD. Other Juice Plus supplement products include gummie candies, chewable tablets, wafers, meal replacement powders, and a vitamin formulation for dogs and cats.
Nutrients used in the manufacture of Juice Plus are purchased from third-party suppliers, including the Henkel Corporation (now doing business as Cognis Corporation) and Schweizerhall Pharma, and added as fortifiers to the product's plant powders. According to the manufacturer, the additives are used to restore the levels of micronutrients lost during processing and to ensure uniformity. Juice Plus Gummies, a candy-like supplement for children, were shown to consist of 85% corn syrup and 10% beef gelatin, plus added nutrients.
Juice Plus products are marketed by individual distributors who receive sales commissions ranging from 6% (for enrolling five customers in 30 days) to 14% (for enrolling twenty customers in 30 days). Detailed sales figures for Juice Plus are not publicly available but NSA representatives claimed that Juice Plus achieved monthly sales of $6 million USD in 1993 and that it was the company’s most successful new product.
# Product research
National Safety Associates refers to Juice Plus as “the next best thing to eating fruits and vegetables” and describes the products as containing the “nutritional essence of 17 different fruits, vegetables, and grains”. NSA also claims that Juice Plus delivers key phytonutrients that are absorbed by the body, reduces oxidative stress, promotes cardiovascular wellness, supports a healthy immune system, and helps protect DNA. However, multiple studies of varying standards have produced conflicting results as to the truth of these claims.
Of the published peer-reviewed studies on Juice Plus products, seven were funded and/or authored by the manufacturer, NAI; four were funded by the main distributor, NSA; two were funded by individual Juice Plus distributors; and one was conducted independently. The products examined in most of the studies were Garden Blend and Orchard Blend; three studies were performed on Vineyard Blend (a berry juice powder-based version) taken with Garden and Orchard Blend, and one study was on Juice Plus Gummies.
## Nutrient absorption
Though Juice Plus contains some nutrients, concerns have been raised that these nutrients may not be bioavailable, meaning not effectively absorbed by the human body, and that some of the nutrients claimed to be in the products may not be present in significant amounts. Studies on nutrient absorption showed that subjects taking Juice Plus had elevated blood levels of folate and β-carotene but the effects on blood levels of vitamin E and vitamin C were inconsistent. Some studies have shown significant increases in vitamin E and C levels, while other studies have shown much weaker effects on vitamin E and C levels, and that the levels of the two vitamins are not significantly increased. Studies have also found that Juice Plus does not raise the blood levels of other key phytonutrients from fresh fruits and vegetables, such as lycopene, lutein, zeaxanthin, and β-cryptoxanthin.
## Antioxidant activity
NSA claims that Juice Plus is an effective antioxidant, and quotes a study that showed a 75% reduction in lipid peroxidation (an oxidative stress marker) in subjects that took Juice Plus for 7 to 28 days. Other studies have also reported reductions in lipid peroxidation and DNA oxidation. These three studies were not blinded or placebo-controlled, included few participants (in one case no more than 15), and did not include monitoring or control of the participants' food intake. One of the studies was criticized as “a particularly poor study” by Rosemary Stanton in the Australian journal, The Skeptic. Three other studies which were conducted under more rigorous conditions, meaning randomized, double-blind, placebo-controlled studies, longer in duration and with more subjects, found no significant reductions in lipid peroxidation, DNA oxidation, or other markers of oxidative stress.
One study, which used an in vitro test of antioxidant activity, found that 1 g of Juice Plus Garden Blend/Orchard Blend powder had the corresponding antioxidant capacity to approximately 10 g (fresh weight) of fruit or vegetable, amounting to 30 g (roughly one-third of a serving) per 4 capsules.
One placebo-controlled study conducted in 2002 found that Juice Plus Gummie candies did not significantly improve the antioxidant status of children, as indicated by negative results from 6 different antioxidant tests. The authors explained this by saying it was possible that the supplement did not contain enough of the proper antioxidants to make a significant difference or that the antioxidants extracted in the fruit/vegetable extract were not bioavailable.
## Cardiovascular effects
Several studies have examined the effects of Juice Plus capsules on biochemical parameters associated with cardiovascular function, again with conflicting results. One study, which was not double blinded or placebo controlled, found a 37% decrease in homocysteine levels. Other more rigorous studies, including two that were randomized, double-blind, placebo-controlled trials, found that homocysteine levels were not reduced or were reduced only marginally (7%). Two randomized, double-blind placebo controlled studies have examined the effect of Juice Plus on serum cholesterol and LDL levels. One study found that Juice Plus had no significant effects; the other found slight decreases in cholesterol (6%) and LDL (9%) in subjects that took Orchard/Garden Blend, but no reductions among subjects who took Juice Plus Vineyard blend in addition.
One study found that Juice Plus had no effect on blood pressure in healthy subjects. This study also reported that a combined regimen of Juice Plus Orchard Blend and Garden Blend significantly decreased the impairment of brachial artery vasoactivity caused by a high-fat meal; however, the addition of Vineyard Blend to this regimen had no additional effect on brachial artery vasoactivity and led to an increase in total lipoprotein and LDL.
## Immune effects
A non-randomized, non-blinded, non-controlled study in elderly cigarette smokers and non-smokers examined the effects of Juice Plus Orchard Blend and Garden Blend on 8 immunologic parameters, including stimulated T-cell cytokine production (IL-2, IL-6, TNF-α and IFN-γ) and the activity of various immune cells (peripheral blood monocytes, natural killer cells, T-helper cells, and cytotoxic T cells). Juice Plus significantly increased peripheral blood monocyte proliferation and NK cell cytotoxicity in non-smokers but not in smokers, and increased in vitro IL-2 production by stimulated monocytes in both smokers and non-smokers. None of the other 5 immune parameters were affected in either smokers or non-smokers. Memorial Sloan-Kettering Cancer Center noted several faults with this study including that it lacked placebo controls and was not blinded, that the results do not necessarily correlate with an overall increase in immunity, and that it would have been more informative had clinical parameters been measured, such as whether fewer patients became sick.
A double-blind, randomized, placebo-controlled study examined the effect of Juice Plus Orchard Blend and Garden Blend on T cell counts, lymphocyte cytokine production, Epstein-Barr virus (EBV) antibody titers, and the incidence of illness in healthy subjects. The percentage of circulating γδ-CD3+ T cells and αβ-CD3+ T cells did not change significantly in subjects who took Juice Plus; however, at the end of the supplementation period, subjects taking the supplement had a higher percentage of γδ-CD3+ T cells (7.2%) as compared with placebo (5.4%). IFN-γ produced by stimulated lymphocytes in vitro was reduced in the Juice Plus (68%) and placebo groups (41%), but the reduction was statistically significant only in the Juice Plus group. The levels of other cytokines (IL-4, IL-6, TGF-β) were unchanged and Juice Plus had no significant effect on the incidence and symptoms of illness or on EBV antibody titers.
## Adverse effects
Adverse effects of Juice Plus have been mentioned in three studies, none of which were randomized, blinded, or placebo-controlled. No monitoring of adverse effects was reported in other published Juice Plus studies. Memorial Sloan-Kettering Cancer Center noted that in one study, some subjects who took Orchard Blend and Garden Blend developed a hive-like rash. Another study in 2000 reported adverse effects (upper-respiratory tract, urinary, and musculoskeletal) in roughly a third of the participants who took the products for 7 days. However, these events resolved spontaneously and were deemed by the researchers to be unrelated to treatment. In a third study from 2007, some subjects withdrew due to gastrointestinal distress possibly caused by the Juice Plus regimen (a combination of Orchard Blend, Garden Blend, and Vineyard Blend).
# Juice Plus Children's Research Foundation
The Juice Plus Children's Research Foundation, founded in 1997, is a non-profit organization whose stated goal is to initiate and/or support programs that advance the principle that improved nutrition leads to healthier lifestyle and overall better health in children. The foundation is chaired by executives of National Safety Associates and operates from the company's head office in Collierville, Tennessee.
As of 2007, no research had been published by the Foundation, but it does conduct an ongoing survey which seems to link Juice Plus consumption to a general improvement in diet and lifestyle habits. Critics, including the University of California Berkeley Wellness Letter and Dr. Stephen Barrett of MLMWatch, question the survey's scientific value, and state that the Foundation is being used mainly as a marketing gimmick to get families to buy Juice Plus products.
# Criticism
According to Consumer Reports, in 2005, National Safety Associates used advertising featuring Dr. William Sears, which implied that Juice Plus Gummies are low in sugar and a nutritional alternative to fruits and vegetables. This claim resulted in consumer complaints to the Better Business Bureau's National Advertising Division (NAD). The BBB issued a complaint that NSA's claims were misleading, and as a result, NSA promised to modify its ads and stop calling Gummies “the next best thing to fruits and vegetables”. However, as of 2007, the Juice Plus homepage still advertises that the products are “the next best thing to fruits and vegetables”, though not specifically in reference to the Gummies.
University of California Berkeley Wellness Letter and MLMWatch also commented on the unreliability of Juice Plus testimonials provided by former professional athlete O.J. Simpson, who was tried and acquitted for the June 12, 1994 murder of his ex-wife Nicole Brown Simpson and her friend, Ronald Goldman. Simpson signed a multi-year six-figure contract with NSA in January 1994 and became an official celebrity endorser of Juice Plus. In March 1994, shortly before the murders took place, Simpson was videotaped telling 4,000 Juice Plus distributors at a sales meeting that the product had cured his arthritis, improved his golf game, and freed him from using anti-arthritic drugs. However, during his criminal trial in 1995 and civil trial in 1997 (and in his 2007 book If I Did It) Simpson claimed that he was too incapacitated by arthritis to have committed the murders and that he had continued to take a variety of potent anti-inflammatory drugs, including sulfasalazine and Motrin. After controversy surrounding Simpson erupted, NSA cancelled his endorsement contract and stopped using the Simpson videotape to promote Juice Plus.
Concerns have also been raised about the accuracy of product labeling. Three studies which included chemical analyses of Juice Plus have indicated nutrient amounts that differ from the amounts listed on the product labels.
Doubts have been raised about the benefits of Juice Plus by the Memorial Sloan-Kettering Cancer Center, the University of California Berkeley and other sources. Specific criticisms include: the product’s marketing being unsupported by research data, the product contains too little fruit and vegetable powder to offer significant clinical benefits, concerns that the effects can be attributed to the inclusion of added exogenous vitamins and micronutrients, and complaints that the products are excessively priced relative to their potential benefits. In a January 2007 article in the St. Louis Post Dispatch, dietitian Renee Schwendinger said, "the average person should eat actual fruits and vegetables, not take a supplement such as Juice Plus," and that barring that, "a single multivitamin will give you all the nutrition you need if your diet is lacking, and it's less expensive." Nutritionist Rosemary Stanton echoed similar sentiments, stating “Juice Plus…contains added vitamins, and as such may have some value, although regular vitamins cost only a fraction of the Juice Plus product" and that "there is no evidence the supplement has enough fruits and vegetables to provide an alternative to the real thing.” Registered dietician Kathleen Goodwin noted that “while there have been some clinical research studies about the effectiveness of Juice Plus, the evidence overall is inconclusive, the research flawed, and the funding provided by the manufacturer of the supplements themselves…Juice Plus supplements simply do not compare to the thousands of naturally occurring nutrients and phytochemicals we derive from the real thing.” The University of California Berkeley Wellness Letter claimed “no matter how compressed these capsules are, or what they contain, it’s impossible to deliver the nutrients of five to ten servings of fruits and vegetables in several capsules weighing 800 to 850 milligrams (about one-thirtieth of an ounce) each. It would take two dozen 800-milligram capsules just to provide all the nutrients in six ounces of carrot juice” and concluded “you don’t need Juice Plus”. Registered dietician Fudeko T. Maruyama and nutritional education specialist Mary P. Clarke of Kansas State University commented that “the promotional literature for Juice Plus, billed as a whole food concentrate, is a carefully worded blend of incorrect information, misleading health claims, and nonscientific jargon” and concluded that “Juice Plus probably won't harm you, but can hurt your pocketbook." Memorial Sloan-Kettering Cancer Clinic referred to Juice Plus as a ”pricey supplement” that is “distributed through a multi-tiered marketing scheme with exaggerated value and cost."
In a critique of Juice Plus, Stephen Barrett of MLMWatch remarked upon the previous association between two authors of a 1996 Juice Plus research study and United Sciences of America, Inc. (USAI), a multilevel marketing company that sold vitamin supplements with illegal claims that they could prevent many diseases. In 1986, lead author John A. Wise, who later co-authored several other Juice Plus research studies, was USAI's Executive Vice-President of Research and Development; and second author Robert J. Morin was a scientific advisor who helped design the products. State and federal enforcement actions drove USAI out of business in 1987. Wise became a consultant to Natural Alternatives International (NAI) in 1987 and a company executive (Vice-President of Research and Development) in 1992. Barrett noted that Wise was also an NAI shareholder and that production of Juice Plus for National Safety Associates (NSA) was responsible for 16% of NAIs sales in 1999. In 2006, NSA accounted for 38% of NAIs sales. Wise was appointed Chief Scientific Officer of NAI in 2002 and resigned from the company’s executive board on June 30, 2007. Wise then entered into a consultancy agreement with NAI stipulating a fee of $10,000 USD per month, and as of August, 2007, was listed as an NAI insider, with direct ownership of 59,600 shares of NAI stock and short-term vested options to purchase an additional 130,000 shares. | Juice Plus
Juice Plus+ is a branded line of dietary supplements containing concentrated fruit and vegetable juice extracts fortified with added vitamins and nutrients. Introduced in 1993[2] and sold via direct or multi-level marketing, the supplements are advertised as "the next best thing to fruits and vegetables," a claim which has stirred considerable controversy.
Marketing claims made about Juice Plus products suggest that they can provide benefits such as reducing oxidative stress and promoting cardiovascular health. Critics have argued that there is no scientific proof that Juice Plus offers significant health benefits, and that deceptive claims are used in the product's marketing information. Studies which have set out to test the effects of Juice Plus have generated conflicting and controversial results.
# Product overview
Juice Plus is manufactured by Natural Alternatives International in San Marcos, CA and distributed by National Safety Associates (NSA; Collierville, TN) via direct or multi-level marketing. NSA was founded in 1970 and before introducing Juice Plus in 1993, was known for other multilevel-marketed products such as water filters, air filters, and fire-protection equipment. Naturopath Humbart "Smokey" Santillo is credited with having developed the Juice Plus “concept” and “nutritional philosophy” and for creating what has been described as the “original formula” for the product.[3][4][5] According to Santillo, he has also worked with NSA to develop other Juice Plus products.[3]
The primary products in the Juice Plus line are Orchard Blend (a fruit juice powder-based vitamin supplement) and Garden Blend (vegetable juice powder-based) capsules, which are sold together in 4-month supplies at a cost, in 2007, of approximately $160 USD.[6] Other Juice Plus supplement products include gummie candies, chewable tablets, wafers, meal replacement powders, and a vitamin formulation for dogs and cats.
Nutrients used in the manufacture of Juice Plus are purchased from third-party suppliers,[7][8][9] including the Henkel Corporation (now doing business as Cognis Corporation)[10][11] and Schweizerhall Pharma,[12] and added as fortifiers to the product's plant powders.[13][14] According to the manufacturer, the additives are used to restore the levels of micronutrients lost during processing and to ensure uniformity.[14] Juice Plus Gummies, a candy-like supplement for children, were shown to consist of 85% corn syrup and 10% beef gelatin, plus added nutrients.[1]
Juice Plus products are marketed by individual distributors who receive sales commissions ranging from 6% (for enrolling five customers in 30 days) to 14% (for enrolling twenty customers in 30 days).[15] Detailed sales figures for Juice Plus are not publicly available but NSA representatives claimed that Juice Plus achieved monthly sales of $6 million USD in 1993[16] and that it was the company’s most successful new product.[17]
# Product research
National Safety Associates refers to Juice Plus as “the next best thing to eating fruits and vegetables” and describes the products as containing the “nutritional essence of 17 different fruits, vegetables, and grains”. NSA also claims that Juice Plus delivers key phytonutrients that are absorbed by the body, reduces oxidative stress, promotes cardiovascular wellness, supports a healthy immune system, and helps protect DNA.[6] However, multiple studies of varying standards have produced conflicting results as to the truth of these claims.
Of the published peer-reviewed studies on Juice Plus products, seven were funded and/or authored by the manufacturer, NAI;[18][7][8][19][20][21][22] four were funded by the main distributor, NSA;[19][23][24][1][25] two were funded by individual Juice Plus distributors;[26][27] and one was conducted independently.[28] The products examined in most of the studies were Garden Blend and Orchard Blend; three studies were performed on Vineyard Blend (a berry juice powder-based version) taken with Garden and Orchard Blend,[18][24][29] and one study was on Juice Plus Gummies.[1]
## Nutrient absorption
Though Juice Plus contains some nutrients, concerns have been raised that these nutrients may not be bioavailable, meaning not effectively absorbed by the human body, and that some of the nutrients claimed to be in the products may not be present in significant amounts.[13][1] Studies on nutrient absorption showed that subjects taking Juice Plus had elevated blood levels of folate and β-carotene[19][20][22] but the effects on blood levels of vitamin E and vitamin C were inconsistent. Some studies have shown significant increases in vitamin E[7][19] and C levels,[7][19][8] while other studies have shown much weaker effects on vitamin E[8][22] and C levels[22], and that the levels of the two vitamins are not significantly increased.[20][23] Studies have also found that Juice Plus does not raise the blood levels of other key phytonutrients from fresh fruits and vegetables, such as lycopene,[20][22] lutein,[20][22] zeaxanthin,[20][22][24] and β-cryptoxanthin.[20][21][22][24]
## Antioxidant activity
NSA claims that Juice Plus is an effective antioxidant, and quotes a study that showed a 75% reduction in lipid peroxidation (an oxidative stress marker) in subjects that took Juice Plus for 7 to 28 days.[7] Other studies have also reported reductions in lipid peroxidation[8] and DNA oxidation.[20] These three studies were not blinded or placebo-controlled, included few participants (in one case no more than 15), and did not include monitoring or control of the participants' food intake. One of the studies[7] was criticized as “a particularly poor study” by Rosemary Stanton[30] in the Australian journal, The Skeptic.[31] Three other studies which were conducted under more rigorous conditions, meaning randomized, double-blind, placebo-controlled studies, longer in duration and with more subjects, found no significant reductions in lipid peroxidation,[22][23] DNA oxidation, [23][19][24] or other markers of oxidative stress.[22][26]
One study, which used an in vitro test of antioxidant activity, found that 1 g of Juice Plus Garden Blend/Orchard Blend powder had the corresponding antioxidant capacity to approximately 10 g (fresh weight) of fruit or vegetable, amounting to 30 g (roughly one-third of a serving) per 4 capsules.[28]
One placebo-controlled study conducted in 2002 found that Juice Plus Gummie candies did not significantly improve the antioxidant status of children, as indicated by negative results from 6 different antioxidant tests.[1] The authors explained this by saying it was possible that the supplement did not contain enough of the proper antioxidants to make a significant difference or that the antioxidants extracted in the fruit/vegetable extract were not bioavailable.
## Cardiovascular effects
Several studies have examined the effects of Juice Plus capsules on biochemical parameters associated with cardiovascular function, again with conflicting results. One study, which was not double blinded or placebo controlled, found a 37% decrease in homocysteine levels.[27] Other more rigorous studies, including two that were randomized, double-blind, placebo-controlled trials, found that homocysteine levels were not reduced[18][26] or were reduced only marginally (7%).[22] Two randomized, double-blind placebo controlled studies have examined the effect of Juice Plus on serum cholesterol and LDL levels. One study found that Juice Plus had no significant effects;[22] the other found slight decreases in cholesterol (6%) and LDL (9%) in subjects that took Orchard/Garden Blend, but no reductions among subjects who took Juice Plus Vineyard blend in addition.[18]
One study found that Juice Plus had no effect on blood pressure in healthy subjects.[18] This study also reported that a combined regimen of Juice Plus Orchard Blend and Garden Blend significantly decreased the impairment of brachial artery vasoactivity caused by a high-fat meal; however, the addition of Vineyard Blend to this regimen had no additional effect on brachial artery vasoactivity and led to an increase in total lipoprotein and LDL.[32]
## Immune effects
A non-randomized, non-blinded, non-controlled study in elderly cigarette smokers and non-smokers examined the effects of Juice Plus Orchard Blend and Garden Blend on 8 immunologic parameters, including stimulated T-cell cytokine production (IL-2, IL-6, TNF-α and IFN-γ) and the activity of various immune cells (peripheral blood monocytes, natural killer [NK] cells, T-helper cells, and cytotoxic T cells).[21] Juice Plus significantly increased peripheral blood monocyte proliferation and NK cell cytotoxicity in non-smokers but not in smokers, and increased in vitro IL-2 production by stimulated monocytes in both smokers and non-smokers. None of the other 5 immune parameters were affected in either smokers or non-smokers. Memorial Sloan-Kettering Cancer Center noted several faults with this study including that it lacked placebo controls and was not blinded, that the results do not necessarily correlate with an overall increase in immunity, and that it would have been more informative had clinical parameters been measured, such as whether fewer patients became sick.[5]
A double-blind, randomized, placebo-controlled study examined the effect of Juice Plus Orchard Blend and Garden Blend on T cell counts, lymphocyte cytokine production, Epstein-Barr virus (EBV) antibody titers, and the incidence of illness in healthy subjects.[24] The percentage of circulating γδ-CD3+ T cells and αβ-CD3+ T cells did not change significantly in subjects who took Juice Plus; however, at the end of the supplementation period, subjects taking the supplement had a higher percentage of γδ-CD3+ T cells (7.2%) as compared with placebo (5.4%). IFN-γ produced by stimulated lymphocytes in vitro was reduced in the Juice Plus (68%) and placebo groups (41%), but the reduction was statistically significant only in the Juice Plus group. The levels of other cytokines (IL-4, IL-6, TGF-β) were unchanged and Juice Plus had no significant effect on the incidence and symptoms of illness or on EBV antibody titers.
## Adverse effects
Adverse effects of Juice Plus have been mentioned in three studies,[21][8][29] none of which were randomized, blinded, or placebo-controlled. No monitoring of adverse effects was reported in other published Juice Plus studies.[18][7][22][1][19][20][23][24][26][27] Memorial Sloan-Kettering Cancer Center noted[5] that in one study,[21] some subjects who took Orchard Blend and Garden Blend developed a hive-like rash. Another study in 2000 reported adverse effects (upper-respiratory tract, urinary, and musculoskeletal) in roughly a third of the participants who took the products for 7 days. However, these events resolved spontaneously and were deemed by the researchers to be unrelated to treatment.[8] In a third study from 2007, some subjects withdrew due to gastrointestinal distress possibly caused by the Juice Plus regimen (a combination of Orchard Blend, Garden Blend, and Vineyard Blend).[29]
# Juice Plus Children's Research Foundation
The Juice Plus Children's Research Foundation,[33] founded in 1997, is a non-profit organization whose stated goal is to initiate and/or support programs that advance the principle that improved nutrition leads to healthier lifestyle and overall better health in children. The foundation is chaired by executives of National Safety Associates and operates from the company's head office in Collierville, Tennessee.
As of 2007, no research had been published by the Foundation, but it does conduct an ongoing survey which seems to link Juice Plus consumption to a general improvement in diet and lifestyle habits. Critics, including the University of California Berkeley Wellness Letter and Dr. Stephen Barrett of MLMWatch, question the survey's scientific value, and state that the Foundation is being used mainly as a marketing gimmick to get families to buy Juice Plus products.[34][35]
# Criticism
According to Consumer Reports, in 2005, National Safety Associates used advertising featuring Dr. William Sears, which implied that Juice Plus Gummies are low in sugar and a nutritional alternative to fruits and vegetables. This claim resulted in consumer complaints to the Better Business Bureau's National Advertising Division (NAD). The BBB issued a complaint that NSA's claims were misleading, and as a result, NSA promised to modify its ads and stop calling Gummies “the next best thing to fruits and vegetables”.[36] However, as of 2007, the Juice Plus homepage still advertises that the products are “the next best thing to fruits and vegetables”, though not specifically in reference to the Gummies.[6]
University of California Berkeley Wellness Letter[37] and MLMWatch[2] also commented on the unreliability of Juice Plus testimonials provided by former professional athlete O.J. Simpson, who was tried and acquitted for the June 12, 1994 murder of his ex-wife Nicole Brown Simpson and her friend, Ronald Goldman. Simpson signed a multi-year six-figure contract with NSA in January 1994 and became an official celebrity endorser of Juice Plus. In March 1994, shortly before the murders took place, Simpson was videotaped telling 4,000 Juice Plus distributors at a sales meeting that the product had cured his arthritis, improved his golf game, and freed him from using anti-arthritic drugs.[38][39][40][2] However, during his criminal trial in 1995 and civil trial in 1997 (and in his 2007 book If I Did It)[41] Simpson claimed that he was too incapacitated by arthritis to have committed the murders and that he had continued to take a variety of potent anti-inflammatory drugs, including sulfasalazine and Motrin.[42][43][44][45][2] After controversy surrounding Simpson erupted, NSA cancelled his endorsement contract and stopped using the Simpson videotape to promote Juice Plus.[5][37]
Concerns have also been raised about the accuracy of product labeling. Three studies which included chemical analyses of Juice Plus have indicated nutrient amounts that differ from the amounts listed on the product labels.[18][46][47]
Doubts have been raised about the benefits of Juice Plus by the Memorial Sloan-Kettering Cancer Center, the University of California Berkeley and other sources.[13][5][37][35][48][31][2][49] Specific criticisms include: the product’s marketing being unsupported by research data, the product contains too little fruit and vegetable powder to offer significant clinical benefits,[37] concerns that the effects can be attributed to the inclusion of added exogenous vitamins and micronutrients, and complaints that the products are excessively priced relative to their potential benefits.[2][31][35][5][49][50] In a January 2007 article in the St. Louis Post Dispatch, dietitian Renee Schwendinger said, "the average person should eat actual fruits and vegetables, not take a supplement such as Juice Plus," and that barring that, "a single multivitamin will give you all the nutrition you need if your diet is lacking, and it's less expensive."[50] Nutritionist Rosemary Stanton[30] echoed similar sentiments, stating “Juice Plus…contains added vitamins, and as such may have some value, although regular vitamins cost only a fraction of the Juice Plus product" and that "there is no evidence the supplement has enough fruits and vegetables to provide an alternative to the real thing.”[31] Registered dietician Kathleen Goodwin noted that “while there have been some clinical research studies about the effectiveness of Juice Plus, the evidence overall is inconclusive, the research flawed, and the funding provided by the manufacturer of the supplements themselves…Juice Plus supplements simply do not compare to the thousands of naturally occurring nutrients and phytochemicals we derive from the real thing.”[48] The University of California Berkeley Wellness Letter claimed “no matter how compressed these capsules are, or what they contain, it’s impossible to deliver the nutrients of five to ten servings of fruits and vegetables in several capsules weighing 800 to 850 milligrams (about one-thirtieth of an ounce) each. It would take two dozen 800-milligram capsules just to provide all the nutrients in six ounces of carrot juice” and concluded “you don’t need Juice Plus”.[37] Registered dietician Fudeko T. Maruyama and nutritional education specialist Mary P. Clarke of Kansas State University commented that “the promotional literature for Juice Plus, billed as a whole food concentrate, is a carefully worded blend of incorrect information, misleading health claims, and nonscientific jargon” and concluded that “Juice Plus probably won't harm you, but can hurt your pocketbook."[49] Memorial Sloan-Kettering Cancer Clinic referred to Juice Plus as a ”pricey supplement” that is “distributed through a multi-tiered marketing scheme with exaggerated value and cost." [5]
In a critique of Juice Plus,[2] Stephen Barrett of MLMWatch remarked upon the previous association between two authors of a 1996 Juice Plus research study [7] and United Sciences of America, Inc. (USAI), a multilevel marketing company that sold vitamin supplements with illegal claims that they could prevent many diseases.[51][52][53][54][55][56] In 1986, lead author John A. Wise, who later co-authored several other Juice Plus research studies,[18][19][20][21] was USAI's Executive Vice-President of Research and Development; and second author Robert J. Morin was a scientific advisor who helped design the products. State and federal enforcement actions[51][52][53][54][55][56] drove USAI out of business in 1987.[51][53][56] Wise became a consultant to Natural Alternatives International (NAI) in 1987 and a company executive (Vice-President of Research and Development) in 1992. Barrett noted that Wise was also an NAI shareholder and that production of Juice Plus for National Safety Associates (NSA) was responsible for 16% of NAIs sales in 1999. In 2006, NSA accounted for 38% of NAIs sales. Wise was appointed Chief Scientific Officer of NAI in 2002 and resigned from the company’s executive board on June 30, 2007. Wise then entered into a consultancy agreement with NAI stipulating a fee of $10,000 USD per month,[57] and as of August, 2007, was listed as an NAI insider, with direct ownership of 59,600 shares of NAI stock[58] and short-term vested options to purchase an additional 130,000 shares.[59] | https://www.wikidoc.org/index.php/Juice_Plus | |
6a220740a5f50ee9ea70f6640672b7e2855cc994 | wikidoc | KIZ (gene) | KIZ (gene)
Kizuna centrosomal protein is a protein that in humans is encoded by the KIZ gene.
# Function
The protein encoded by this gene localizes to centrosomes, strengthening and stabilizing the pericentriolar region prior to spindle formation. The encoded protein usually remains with the mother centrosome after centrosomal duplication. Several transcript variants encoding different isoforms have been found for this gene. .
# Clinical significance
Mutations in KIZ cause Rod-cone dystrophy (RCD) . | KIZ (gene)
Kizuna centrosomal protein is a protein that in humans is encoded by the KIZ gene.[1]
# Function
The protein encoded by this gene localizes to centrosomes, strengthening and stabilizing the pericentriolar region prior to spindle formation. The encoded protein usually remains with the mother centrosome after centrosomal duplication. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013].
# Clinical significance
Mutations in KIZ cause Rod-cone dystrophy (RCD) .[2] | https://www.wikidoc.org/index.php/KIZ_(gene) | |
8fe77abf9d33bce7e31375ab2f48ede65bd8e31e | wikidoc | Keratin 14 | Keratin 14
Keratin 14 is a member of the type I keratin family of intermediate filament proteins. Keratin 14 was the first type I keratin sequence determined.
Keratin 14 is also known as cytokeratin-14 (CK-14) or keratin-14 (KRT14). In humans it is encoded by the KRT14 gene.
Keratin 14 is usually found as a heterodimer with type II keratin 5 and form the cytoskeleton of epithelial cells.
# Pathology
Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex and dermatopathia pigmentosa reticularis, both of which are autosomal dominant mutations. | Keratin 14
Keratin 14 is a member of the type I keratin family of intermediate filament proteins. Keratin 14 was the first type I keratin sequence determined.[1]
Keratin 14 is also known as cytokeratin-14 (CK-14) or keratin-14 (KRT14). In humans it is encoded by the KRT14 gene.[2][3][4]
Keratin 14 is usually found as a heterodimer with type II keratin 5 and form the cytoskeleton of epithelial cells.
# Pathology
Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex and dermatopathia pigmentosa reticularis, both of which are autosomal dominant mutations.[5] | https://www.wikidoc.org/index.php/KRT14 | |
a4ba3eec250ae70dc6122f8ae18a258c0cfb3369 | wikidoc | Kaempferol | Kaempferol
Kaempferol is a natural flavonoid which has been isolated from tea, broccoli, Delphinium, Witch-hazel, grapefruit, and other plant sources. Kaempferol is a yellow crystalline solid with a melting point of 276-278 °C. It is slightly soluble in water but soluble in hot ethanol and diethyl ether.
Many glycosides of kaempferol, such as kaemferitrin and astragalin, have been isolated as natural products from plants. Kaemphferol consumption in tea and broccoli has been associated with reduced risk of heart disease.
Kaempferol is what gives the flowers of Acacia decurrens and Acacia longifolia their color. | Kaempferol
Kaempferol is a natural flavonoid which has been isolated from tea[1], broccoli, Delphinium, Witch-hazel, grapefruit, and other plant sources. Kaempferol is a yellow crystalline solid with a melting point of 276-278 °C. It is slightly soluble in water but soluble in hot ethanol and diethyl ether.
Many glycosides of kaempferol, such as kaemferitrin and astragalin, have been isolated as natural products from plants. Kaemphferol consumption in tea and broccoli has been associated with reduced risk of heart disease.[2]
Kaempferol is what gives the flowers of Acacia decurrens and Acacia longifolia their color.[3] | https://www.wikidoc.org/index.php/Kaempferol | |
d1e82aa2ab691ae32775775ff0149ccb0362365c | wikidoc | Kallikrein | Kallikrein
Kallikreins (tissue and plasma kallikrein) are a subgroup of the serine protease family.
# Functions
They liberate kinins (BK and KD) from the kininogens.
It also generates plasmin from plasminogen:
Prekallikrein is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XII or other stimuli.
# Genes
There are 15 known kallikreins: KLK1, KLK2, KLK3, KLK4, KLK5, KLK6, KLK7, KLK8, KLK9, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15
# Clinical significance
Kallikreins are targets of active investigation by drug researchers as possible biomarkers for cancer.
Prostate-specific antigen (PSA; hk3, human kallikrein gene 3) and human glandular kallikrein (hK2) are used as tumor markers for prostate cancer. | Kallikrein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Kallikreins (tissue and plasma kallikrein) are a subgroup of the serine protease family.
# Functions
They liberate kinins (BK and KD) from the kininogens.[1]
It also generates plasmin from plasminogen:
Prekallikrein is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XII or other stimuli.
# Genes
There are 15 known kallikreins: KLK1, KLK2, KLK3, KLK4, KLK5, KLK6, KLK7, KLK8, KLK9, KLK10, KLK11, KLK12, KLK13, KLK14, KLK15
# Clinical significance
Kallikreins are targets of active investigation by drug researchers as possible biomarkers for cancer.[2][3]
Prostate-specific antigen (PSA; hk3, human kallikrein gene 3) and human glandular kallikrein (hK2) are used as tumor markers for prostate cancer. | https://www.wikidoc.org/index.php/Kallikrein | |
9ad82fadd434cd2e73aff6b58e511835cedec6b0 | wikidoc | Kaopectate | Kaopectate
Kaopectate, known medically as bismuth subsalicylate, is an orally taken medication from Chattem, Inc. for the treatment of mild diarrhoea. It is also sometimes used to treat indigestion, nausea and stomach ulcers.
# Ingredients
The active ingredient in Kaopectate has changed since its original creation. Originally, kaolinite was used as the adsorbent and pectin as the emollient. Attapulgite clay replaced the kaolinite, and since the mid-2000s, pink bismuth subsalicylate has been used.
# Side Effects
## Mild
- Constipation
- Dizziness/Lightheadedness
- Increased thirst
- Increased sweating
- Black stools
- Black tongue
## Severe
- Vomiting
- Stomach pains
- Involuntary movemements of the hands and lower arms
- Vision impairment
# Use on animals
The FDA does not have a clear stance on the administration of kaopectate on animals such as dogs and cats that are suffering from diarrhea.
Additionally it should be noted that Kaolin-pectate, the original compound, is approved by the OTC (Organic Trade Association) for use in animals being produced for food. | Kaopectate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Kaopectate, known medically as bismuth subsalicylate, is an orally taken medication from Chattem, Inc. for the treatment of mild diarrhoea. It is also sometimes used to treat indigestion, nausea and stomach ulcers.
# Ingredients
The active ingredient in Kaopectate has changed since its original creation. Originally, kaolinite was used as the adsorbent and pectin as the emollient. Attapulgite clay replaced the kaolinite, and since the mid-2000s, pink bismuth subsalicylate has been used.
# Side Effects
## Mild
- Constipation
- Dizziness/Lightheadedness
- Increased thirst
- Increased sweating
- Black stools
- Black tongue
## Severe
- Vomiting
- Stomach pains
- Involuntary movemements of the hands and lower arms
- Vision impairment
# Use on animals
The FDA does not have a clear stance on the administration of kaopectate on animals such as dogs and cats that are suffering from diarrhea.
Additionally it should be noted that Kaolin-pectate, the original compound, is approved by the OTC (Organic Trade Association) for use in animals being produced for food.
# External links
- Further in-depth information about Kaopectate
- Chattem, Inc. page for Kaopectate
- Kaopectate use in animals
Template:WikiDoc Sources
Template:Jb1 | https://www.wikidoc.org/index.php/Kaopectate | |
7a3d348edf5f7eb2eacd8ccbd3ee4256aa15af71 | wikidoc | Keratin 18 | Keratin 18
Keratin 18 is a type I cytokeratin. It is, together with its filament partner keratin 8, perhaps the most commonly found products of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene.
Keratin 18 is often used together with keratin 8 and keratin 19 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.
# Interactions
Keratin 18 has been shown to interact with Collagen, type XVII, alpha 1, DNAJB6, Pinin and TRADD. | Keratin 18
Keratin 18 is a type I cytokeratin. It is, together with its filament partner keratin 8, perhaps the most commonly found products of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene.[1]
Keratin 18 is often used together with keratin 8 and keratin 19 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.[2]
# Interactions
Keratin 18 has been shown to interact with Collagen, type XVII, alpha 1,[3] DNAJB6,[4] Pinin[5] and TRADD.[6] | https://www.wikidoc.org/index.php/Keratin_18 | |
415844b2303e4d2c5e18826fa981125df8ffcf48 | wikidoc | Keratin 19 | Keratin 19
Keratin, type I cytoskeletal 19 also known as cytokeratin-19 (CK-19) or keratin-19 (K19) is a 40 kDa protein that in humans is encoded by the KRT19 gene. Keratin 19 is a type I keratin.
# Function
Keratin 19 is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins.
Keratin 19 is a type I keratin. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically found in the periderm, the transiently superficial layer that envelops the developing epidermis. The type I cytokeratins are clustered in a region of chromosome 17q12-q21.
# Use as biomarker
KRT19 is also known as Cyfra 21-1.Due to its high sensitivity, KRT19 is the most used marker for the RT-PCR-mediated detection of tumor cells disseminated in lymph nodes, peripheral blood, and bone marrow of breast cancer patients. Depending on the assays, KRT19 has been shown to be both a specific and a non-specific marker. False positivity in such KRT19 RT-PCR studies include: illegitimate transcription (expression of small amounts of KRT19 mRNA by tissues in which it has no real physiological role), haematological disorders (KRT19 induction in peripheral blood cells by cytokines and growth factors, which circulate at higher concentrations in inflammatory conditions and neutropenia), the presence of pseudogenes (two KRT19 pseudogenes, KRT19a and KRT19b, have been identified, which have significant sequence homology to KRT19 mRNA. Subsequently, attempts to detect the expression of the authentic KRT19 may result in the detection of either or both of these pseudogenes), sample contamination (introduction of contaminating epithelial cells during peripheral blood sampling for subsequent RT-PCR analysis). Moreover, Ck-19 is widely applied as post-operative diagnostic marker of papillary thyroid carcinoma.
Keratin 19 is often used together with keratin 8 and keratin 18 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.
# Interactions
Keratin 19 has been shown to interact with Pinin. | Keratin 19
Keratin, type I cytoskeletal 19 also known as cytokeratin-19 (CK-19) or keratin-19 (K19) is a 40 kDa protein that in humans is encoded by the KRT19 gene.[1][2] Keratin 19 is a type I keratin.
# Function
Keratin 19 is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins.
Keratin 19 is a type I keratin. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically found in the periderm, the transiently superficial layer that envelops the developing epidermis. The type I cytokeratins are clustered in a region of chromosome 17q12-q21.[2]
# Use as biomarker
KRT19 is also known as Cyfra 21-1.[3]Due to its high sensitivity, KRT19 is the most used marker for the RT-PCR-mediated detection of tumor cells disseminated in lymph nodes, peripheral blood, and bone marrow of breast cancer patients. Depending on the assays, KRT19 has been shown to be both a specific and a non-specific marker. False positivity in such KRT19 RT-PCR studies include: illegitimate transcription (expression of small amounts of KRT19 mRNA by tissues in which it has no real physiological role), haematological disorders (KRT19 induction in peripheral blood cells by cytokines and growth factors, which circulate at higher concentrations in inflammatory conditions and neutropenia), the presence of pseudogenes (two KRT19 pseudogenes, KRT19a and KRT19b, have been identified, which have significant sequence homology to KRT19 mRNA. Subsequently, attempts to detect the expression of the authentic KRT19 may result in the detection of either or both of these pseudogenes), sample contamination (introduction of contaminating epithelial cells during peripheral blood sampling for subsequent RT-PCR analysis).[4] Moreover, Ck-19 is widely applied as post-operative diagnostic marker of papillary thyroid carcinoma.[5]
Keratin 19 is often used together with keratin 8 and keratin 18 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.[6]
# Interactions
Keratin 19 has been shown to interact with Pinin.[7] | https://www.wikidoc.org/index.php/Keratin_19 | |
816c411da48cfbea53ab43f0beaeac81fd8f9e64 | wikidoc | Keratin 20 | Keratin 20
Keratin 20, often abbreviated CK20, is a protein that in humans is encoded by the KRT20 gene.
Keratin 20 is a type I cytokeratin. It is a major cellular protein of mature enterocytes and goblet cells and is specifically found in the gastric and intestinal mucosa.
In immunohistochemistry, antibodies to CK20 can be used to identify a range of adenocarcinoma arising from epithelia that normally contain the CK20 protein. For example, the protein is commonly found in colorectal cancer, transitional cell carcinomas and in Merkel cell carcinoma, but is absent in lung cancer, prostate cancer, and non-mucinous ovarian cancer. It is often used in combination with antibodies to CK7 to distinguish different types of glandular tumour. | Keratin 20
Keratin 20, often abbreviated CK20, is a protein that in humans is encoded by the KRT20 gene.[1][2][3]
Keratin 20 is a type I cytokeratin. It is a major cellular protein of mature enterocytes and goblet cells and is specifically found in the gastric and intestinal mucosa.[4]
In immunohistochemistry, antibodies to CK20 can be used to identify a range of adenocarcinoma arising from epithelia that normally contain the CK20 protein. For example, the protein is commonly found in colorectal cancer, transitional cell carcinomas and in Merkel cell carcinoma, but is absent in lung cancer, prostate cancer, and non-mucinous ovarian cancer. It is often used in combination with antibodies to CK7 to distinguish different types of glandular tumour.[5] | https://www.wikidoc.org/index.php/Keratin_20 | |
5825e9aa25b22b32707ef700ea7c1f2582b3a07a | wikidoc | Keratin 6A | Keratin 6A
Keratin 6A is one of the 27 different type II keratins expressed in humans. Keratin 6A was the first type II keratin sequence determined. Analysis of the sequence of this keratin together with that of the first type I keratin led to the discovery of the four helical domains in the central rod of keratins. In humans Keratin 6A is encoded by the KRT6A gene.
# Keratins
Keratins are the intermediate filament proteins that form a dense meshwork of filaments throughout the cytoplasm of epithelial cells. Keratins form heteropolymers consisting of a type I and a type II keratin. Keratins are generally expressed in particular pairs of type I and type II keratin proteins in a tissue-specific and cellular differentiation-specific manner.
The keratin proteins of epithelial tissues are commonly known as "keratins" or are sometimes referred to as "epithelial keratins" or "cytokeratins". The specialized keratins of hair and nail are known as "hard keratins" or "trichocyte keratins". Trichocytes are the specialized epithelial cells from which hair and nail are composed. Trichocyte keratins are similar in their gene and protein structure to keratins except that they are especially rich in the sulfur-containing amino acid cysteine, which facilitates chemical cross-linking of the assembled hard keratins to form a more structurally resilient material.
Both epithelial keratins and hard keratins can be further subdivided into type I (acidic) keratins and type II (neutral-basic) keratins. The genes for the type I keratins are located in a gene cluster on human chromosome 17q, whereas the genes for type II keratins are located in a cluster on human chromosome 12q (the exception being K18, a type I keratin located in the type II gene cluster).
# Keratin 6A
Keratin 6A (protein name K6A; gene name KRT6A), is a type II cytokeratin, one of a number of isoforms of keratin 6 encoded by separate genes located within the type II keratin gene cluster on human chromosome 12q. It is found with keratin 16 and/or keratin 17 in the palm and sole epidermis, the epithelial cells of the nail bed, the filiform papillae of the tongue, the epithelial lining of oral mucosa and esophagus, as well as the hair follicles. This keratin 6 isoform is thought to be the most abundant of the K6 isoforms.
The KRT6A gene consists of 9 exons separated by 8 introns and is located in the type II keratin gene cluster on human chromosome 12q. Keratin 6B and keratin 6C are encoded by the neighbouring genes, which are identical in intron-exon organization to KRT6A and are more than 99% identical in their DNA coding sequences.
# Genetic disorders
Mutations in the genes expressing this protein is associated with the PC-K6A subtype of pachyonychia congenita, an inherited disorder of the epithelial tissues in which keratin 6A is expressed, particularly leading to structural abnormalities of the nails, the epidermis of the palms and soles, and oral epithelia. | Keratin 6A
Keratin 6A is one of the 27 different type II keratins expressed in humans. Keratin 6A was the first type II keratin sequence determined.[1] Analysis of the sequence of this keratin together with that of the first type I keratin led to the discovery of the four helical domains in the central rod of keratins.[1] In humans Keratin 6A is encoded by the KRT6A gene.[2][3]
# Keratins
Keratins are the intermediate filament proteins that form a dense meshwork of filaments throughout the cytoplasm of epithelial cells. Keratins form heteropolymers consisting of a type I and a type II keratin. Keratins are generally expressed in particular pairs of type I and type II keratin proteins in a tissue-specific and cellular differentiation-specific manner.
The keratin proteins of epithelial tissues are commonly known as "keratins" or are sometimes referred to as "epithelial keratins" or "cytokeratins". The specialized keratins of hair and nail are known as "hard keratins" or "trichocyte keratins". Trichocytes are the specialized epithelial cells from which hair and nail are composed. Trichocyte keratins are similar in their gene and protein structure to keratins except that they are especially rich in the sulfur-containing amino acid cysteine, which facilitates chemical cross-linking of the assembled hard keratins to form a more structurally resilient material.
Both epithelial keratins and hard keratins can be further subdivided into type I (acidic) keratins and type II (neutral-basic) keratins. The genes for the type I keratins are located in a gene cluster on human chromosome 17q, whereas the genes for type II keratins are located in a cluster on human chromosome 12q (the exception being K18, a type I keratin located in the type II gene cluster).
# Keratin 6A
Keratin 6A (protein name K6A; gene name KRT6A), is a type II cytokeratin, one of a number of isoforms of keratin 6 encoded by separate genes located within the type II keratin gene cluster on human chromosome 12q. It is found with keratin 16 and/or keratin 17 in the palm and sole epidermis, the epithelial cells of the nail bed, the filiform papillae of the tongue, the epithelial lining of oral mucosa and esophagus, as well as the hair follicles. This keratin 6 isoform is thought to be the most abundant of the K6 isoforms.
The KRT6A gene consists of 9 exons separated by 8 introns and is located in the type II keratin gene cluster on human chromosome 12q. Keratin 6B and keratin 6C are encoded by the neighbouring genes, which are identical in intron-exon organization to KRT6A and are more than 99% identical in their DNA coding sequences.
# Genetic disorders
Mutations in the genes expressing this protein is associated with the PC-K6A subtype of pachyonychia congenita, an inherited disorder of the epithelial tissues in which keratin 6A is expressed, particularly leading to structural abnormalities of the nails, the epidermis of the palms and soles, and oral epithelia.[4][5][6]
# External links
- GeneReviews/NCBI/NIH/UW entry on Pachyonychia Congenita | https://www.wikidoc.org/index.php/Keratin_6 | |
e1ba6c746f1bf423abb0c681f63933702610af74 | wikidoc | Keratin 6C | Keratin 6C
Keratin 6C (protein name K6C; gene name KRT6C), is a type II cytokeratin, one of a number of isoforms of keratin 6 encoded by separate genes located within the type II keratin gene cluster on human chromosome 12q. This gene was uncovered recently by the Human Genome Project and its expression patterns in humans remains unknown.
# Keratins
Keratins are the intermediate filament proteins that form a dense meshwork of filaments throughout the cytoplasm of epithelial cells. Keratins form heteropolymers consisting of a type I and a type II keratin. Keratins are generally expressed in particular pairs of type I and type II keratin proteins in a tissue-specific and cellular differentiation-specific manner.
The keratin proteins of epithelial tissues are commonly known as "keratins" or are sometimes referred to as "epithelial keratins" or "cytokeratins". The specialized keratins of hair and nail are known as "hard keratins" or "trichocyte keratins". Trichocytes are the specialized epithelial cells from which hair and nail are composed. Trichocyte keratins are similar in their gene and protein structure to keratins except that they are especially rich in the sulfur-containing amino acid cysteine, which facilitates chemical cross-linking of the assembled hard keratins to form a more structurally resilient material.
Both epithelial keratins and hard keratins can be further subdivided into type I (acidic) keratins and type II (neutral-basic) keratins. The genes for the type I keratins are located in a gene cluster on human chromosome 17q, whereas the genes for type II keratins are located in a cluster on human chromosome 12q (the exception being K18, a type I keratin located in the type II gene cluster).
Like the closely related KRT6A and KRT6B genes, the KRT6C gene consists of 9 exons separated by 8 introns and is located in the type II keratin gene cluster on human chromosome 12q. Keratin 6A and keratin 6B are encoded by the neighbouring genes, which are identical in intron-exon organization to KRT6C and are more than 99% identical in their DNA coding sequences.
# Genetic disorders
Mutations in K6C have been identified as being able to cause diffuse and focal palmoplantar keratodermas. This has been identified as a form of Pachyonychia congenita. | Keratin 6C
Keratin 6C (protein name K6C; gene name KRT6C), is a type II cytokeratin, one of a number of isoforms of keratin 6 encoded by separate genes located within the type II keratin gene cluster on human chromosome 12q. This gene was uncovered recently by the Human Genome Project and its expression patterns in humans remains unknown.
# Keratins
Keratins are the intermediate filament proteins that form a dense meshwork of filaments throughout the cytoplasm of epithelial cells.[1] Keratins form heteropolymers consisting of a type I and a type II keratin. Keratins are generally expressed in particular pairs of type I and type II keratin proteins in a tissue-specific and cellular differentiation-specific manner.
The keratin proteins of epithelial tissues are commonly known as "keratins" or are sometimes referred to as "epithelial keratins" or "cytokeratins". The specialized keratins of hair and nail are known as "hard keratins" or "trichocyte keratins". Trichocytes are the specialized epithelial cells from which hair and nail are composed. Trichocyte keratins are similar in their gene and protein structure to keratins except that they are especially rich in the sulfur-containing amino acid cysteine, which facilitates chemical cross-linking of the assembled hard keratins to form a more structurally resilient material.
Both epithelial keratins and hard keratins can be further subdivided into type I (acidic) keratins and type II (neutral-basic) keratins. The genes for the type I keratins are located in a gene cluster on human chromosome 17q, whereas the genes for type II keratins are located in a cluster on human chromosome 12q (the exception being K18, a type I keratin located in the type II gene cluster).
Like the closely related KRT6A and KRT6B genes, the KRT6C gene consists of 9 exons separated by 8 introns and is located in the type II keratin gene cluster on human chromosome 12q. Keratin 6A and keratin 6B are encoded by the neighbouring genes, which are identical in intron-exon organization to KRT6C and are more than 99% identical in their DNA coding sequences.
# Genetic disorders
Mutations in K6C have been identified as being able to cause diffuse and focal palmoplantar keratodermas.[2][3][4] This has been identified as a form of Pachyonychia congenita.[5][6] | https://www.wikidoc.org/index.php/Keratin_6C | |
8f8da2eb347787af3b91b5ac99db2584d66782de | wikidoc | Ketanserin | Ketanserin
# Overview
Ketanserin (R41468) is a drug with affinity for multiple G protein-coupled receptors (GPCR). It is a highly selective antagonist for serotonin 5-HT2A receptors, but also has moderate selectivity for 5-HT2C receptors and for alpha-1 adrenergic receptors, and very high affinity for histamine H1
receptors. Therefore, ketanserin can not be used to reliably discriminate between the effects of 5-HT2A and 5-HT2C receptors when both are present in an experimental system. Furthermore, when alpha-1 and H1 receptors are present, the effects of ketanserin can potentially represent a complex interaction of serotonin, adrenergic, and histamine receptor systems. Complicating the matter further is the fact that ketanserin has moderate affinity for delta-1t adrenergic receptor (~200 nM) and 5-HT6 (~300 nM) receptors as well as weak affinity for dopamine D1 and D2 receptors (~300 nM and ~500 nM respectively). Ketanserin at levels of 500 nM or greater are thus potentially affecting at least 8 different GPCRs from 4 different families. (All affinity levels taken from the NIMH Psychoactive Drug Screening Program database )
Receptors for which ketanserin has high affinity binding:
- 5-HT2A = 2-3 nM (rat and human)
- 5-HT2C = 50 nM (rat), 100 nM (human)
- alpha-1 adrenergic = ~40 nM
- Histamine H1 = 2 nM
Solubility:
- 6 mg/mL 0.1 M HCl
- 10 mM H20
- 3.3 mg/mL ethanol
- 52 mg/mL DMSO
Ketanserin was discovered at Janssen Pharmaceutica in 1980.
# Uses
## Antihypertensive
It is classified as an antihypertensive by the World Health Organization and the National Institute of Health.
It has been used to reverse hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).
The reduction in hypertension is not associated with reflex tachycardia.
It has been used in cardiac surgery.
## As a Radioligand
With tritium (3H) radioactively labeled ketanserin is used as a radioligand for the serotonin 5-HT2A receptor, e.g. in receptor binding assays and autoradiography.
This radiolabeling enables the study of the serotonin-2A receptor distribution in the human brain.
An autoradiography study of the human cerebellum has found an increasing binding of H-3-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years og age to over 100 above 75 years).
The same research team found no significant correlation with age in their homogenate binding study.
## As a Blocker with Another Radioligand
Ketanserin has also been used with carbon (11C) radioactively labeled NNC112 in order to image cortical D1 receptors without contamination by 5-HT2A receptors.
# See Also
- Ritanserin | Ketanserin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ketanserin (R41468) is a drug with affinity for multiple G protein-coupled receptors (GPCR). It is a highly selective antagonist for serotonin 5-HT2A receptors, but also has moderate selectivity for 5-HT2C receptors and for alpha-1 adrenergic receptors, and very high affinity for histamine H1
receptors. Therefore, ketanserin can not be used to reliably discriminate between the effects of 5-HT2A and 5-HT2C receptors when both are present in an experimental system. Furthermore, when alpha-1 and H1 receptors are present, the effects of ketanserin can potentially represent a complex interaction of serotonin, adrenergic, and histamine receptor systems. Complicating the matter further is the fact that ketanserin has moderate affinity for delta-1t adrenergic receptor (~200 nM) and 5-HT6 (~300 nM) receptors as well as weak affinity for dopamine D1 and D2 receptors (~300 nM and ~500 nM respectively). Ketanserin at levels of 500 nM or greater are thus potentially affecting at least 8 different GPCRs from 4 different families. (All affinity levels taken from the NIMH Psychoactive Drug Screening Program database [1])
Receptors for which ketanserin has high affinity binding:
- 5-HT2A = 2-3 nM (rat and human)
- 5-HT2C = 50 nM (rat), 100 nM (human)
- alpha-1 adrenergic = ~40 nM
- Histamine H1 = 2 nM
Solubility:
- 6 mg/mL 0.1 M HCl
- 10 mM H20
- 3.3 mg/mL ethanol
- 52 mg/mL DMSO
Ketanserin was discovered at Janssen Pharmaceutica in 1980.
# Uses
## Antihypertensive
It is classified as an antihypertensive by the World Health Organization[2] and the National Institute of Health.[3]
It has been used to reverse hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).[4]
The reduction in hypertension is not associated with reflex tachycardia.[5]
It has been used in cardiac surgery.[6]
## As a Radioligand
With tritium (3H) radioactively labeled ketanserin is used as a radioligand for the serotonin 5-HT2A receptor, e.g. in receptor binding assays and autoradiography.[7]
This radiolabeling enables the study of the serotonin-2A receptor distribution in the human brain.[8]
An autoradiography study of the human cerebellum has found an increasing binding of H-3-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years og age to over 100 above 75 years).[9]
The same research team found no significant correlation with age in their homogenate binding study.
## As a Blocker with Another Radioligand
Ketanserin has also been used with carbon (11C) radioactively labeled NNC112 in order to image cortical D1 receptors without contamination by 5-HT2A receptors.[10]
# See Also
- Ritanserin | https://www.wikidoc.org/index.php/Ketanserin | |
bafb800e376f33953b39288704984258707b22a9 | wikidoc | Ketazocine | Ketazocine
Ketazocine (INN) (Ketocyclazocine) is a cyclazocine derivative used in opioid receptor research.
Ketocyclazocine is an exogenous (not naturally produced by the body) opioid that binds to the kappa opioid receptor.
Activation of this receptor causes a decrease in pain sensations and increased sleepiness but can also cause psychological symptoms such as feelings of unease, paranoia, and hallucinations. It also causes an increase in urine production because it inhibits the release of vasopressin. (Vasopressin is an endogenous (produced by the body) substance that assists in regulating fluid and electrolyte balance in the body and decreases the amount of water released into the urine.)
Unlike other opioids, substances that only bind to the kappa receptor theoretically do not impair the normal drive to breathe. | Ketazocine
Template:Chembox new
Ketazocine (INN) (Ketocyclazocine) is a cyclazocine derivative used in opioid receptor research.
Ketocyclazocine is an exogenous (not naturally produced by the body) opioid that binds to the kappa opioid receptor.
Activation of this receptor causes a decrease in pain sensations and increased sleepiness but can also cause psychological symptoms such as feelings of unease, paranoia, and hallucinations. It also causes an increase in urine production because it inhibits the release of vasopressin. (Vasopressin is an endogenous (produced by the body) substance that assists in regulating fluid and electrolyte balance in the body and decreases the amount of water released into the urine.)
Unlike other opioids, substances that only bind to the kappa receptor theoretically do not impair the normal drive to breathe.
Template:Chem-stub
Template:Opioids
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ketazocine | |
0250bf27b10ea3146a16ff06b38fc0f9dc194b9a | wikidoc | Kick chart | Kick chart
# Overview
A kick chart is a form or graph used by a pregnant woman in the later stages to record the activity of her foetus. If too few kicks are felt within a specified time (usually 12 hours) this could indicate a problem. Once routine, use of these charts has declined, since women often forgot to complete them and foetal movement patterns are very varied, leading to unnecessary concern.
A more recent trend has been to use a pregnancy bracelet; a wearable form of kick counter.
# Fetal Kick Counters
A recent idea in the United Kingdom has been the replacement of the kick chart with jewelry based counters.
A frequent question posed by midwives is how "many times has the baby kicked in the last twelve hours ?", in the UK this is regarded as best indication of the health of the baby from the second trimester and the unborn foetus should kick ten times in any twelve hour period.
The bracelets available work on similar principles, the baby kicks, the mother moves a marker. The idea being that this is more practical than using a pen and paper.
The two most widely advertised bracelets are currently undergoing the patent application process. | Kick chart
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A kick chart is a form or graph used by a pregnant woman in the later stages to record the activity of her foetus. If too few kicks are felt within a specified time (usually 12 hours) this could indicate a problem. Once routine, use of these charts has declined, since women often forgot to complete them and foetal movement patterns are very varied, leading to unnecessary concern.
A more recent trend has been to use a pregnancy bracelet; a wearable form of kick counter.
# Fetal Kick Counters
A recent idea in the United Kingdom has been the replacement of the kick chart with jewelry based counters.
A frequent question posed by midwives is how "many times has the baby kicked in the last twelve hours ?", in the UK this is regarded as best indication of the health of the baby from the second trimester and the unborn foetus should kick ten times in any twelve hour period.
The bracelets available work on similar principles, the baby kicks, the mother moves a marker. The idea being that this is more practical than using a pen and paper.
The two most widely advertised bracelets are currently undergoing the patent application process.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Kick_chart | |
098e6588c63b81f4625ad03ee63e33a867d64769 | wikidoc | Nephrology | Nephrology
Nephrology is the branch of internal medicine dealing with the study of the function and diseases of the kidney. The word nephrology is derived from the Greek word nephros, which means "kidney," and the suffix -ology, signifying "study of."
# Scope of the specialty
Nephrology concerns itself with the diagnosis and treatment of kidney diseases including electrolyte disturbances and hypertension, and the care of those requiring renal replacement therapy, including dialysis and renal transplant patients. Many diseases affecting the kidney are not limited to the organ itself, but are systemic disorders, and may require not only a whole patient approach, but also special treatment, such as systemic vasculitides or other autoimmune diseases, such as lupus.
# Who sees a nephrologist?
Patients are referred to nephrology specialists for various reasons, such as:
- Acute renal failure, a sudden loss of renal function
- Chronic kidney disease, declining renal function, usually with an inexorable rise in creatinine.
- Hematuria, blood loss in the urine
- Proteinuria, the loss of protein especially albumin in the urine
- Kidney stones, usually only recurrent stone formers.
- Chronic or recurrent urinary tract infections
- Hypertension that has failed to respond to multiple forms of anti-hypertensive medication or could have a secondary cause
- Electrolyte disorders or acid/base imbalance
Urologists are surgical specialists of the urinary tract - see Urology. They are involved in renal diseases that might be amenable to surgery:
- Diseases of the Bladder and prostate such as malignancy, stones, or obstruction of the urinary tract.
# Diagnosis
As with the rest of medicine, important clues as to the cause of any symptom are gained in the history and physical examination. For example, pink and white nails are associated with kidney disease.
Laboratory tests are almost always aimed at: urea, creatinine, electrolytes, and urinalysis-- which is frequently the key test in suggesting a diagnosis.
More specialized tests can be ordered to discover or link certain systemic diseases to kidney failure such as hepatitis B or hepatitis C, lupus serologies, paraproteinemias such as amyloidosis or multiple myeloma or various other systemic diseases that lead to kidney failure. Collection of a 24-hour sample of urine can give valuable information on the filtering capacity of the kidney and the amount of protein loss in some forms of kidney disease. However, 24-hour urine samples have recently, in the setting of chronic renal disease, been replaced by spot urine ratio of protein and creatinine.
Other tests often performed by nephrologists are:
- Renal biopsy, to obtain a tissue diagnosis of a disorder when the exact nature or stage remains uncertain.;
- Ultrasound scanning of the urinary tract and occasionally examining the renal blood vessels;
- CT scanning when mass lesions are suspected or to help diagnosis nephrolithiasis;
- Scintigraphy (nuclear medicine) for accurate measurement of renal function (rarely done), diagnosis of renal artery disease, or 'split function' of each kidney;
- Angiography or Magnetic resonance imaging angiography when the blood vessels might be affected
# Therapy
Many kidney diseases are treated with medication, such as steroids, DMARDs (disease-modifying antirheumatic drugs), antihypertensives (many kidney diseases feature hypertension). Often erythropoietin and vitamin D treatment is required to replace these two hormones, the production of which stagnates in chronic renal disease.
When symptoms of renal failure become too severe, dialysis might be required. Please refer to dialysis for a comprehensive account of this treatment.
If patients proceed to renal transplant, nephrologists often monitor the immunosuppressive regimen and the infections that can occur at this stage.
# See Also
- Abderhalden-Kaufmann-Lignac syndrome
- Acute renal failure
- Alport syndrome
- Aminoaciduria
- Analgesic nephropathy
- Azotemia
- Balkan nephropathy
- Bright's disease
- Chronic kidney disease
- Chronic renal failure
- Danubian endemic familial nephropathy
- Dent's disease
- Diabetic nephropathy
- Fanconi syndrome
- Fibromuscular dysplasia
- Focal segmental glomerulosclerosis
- Galloway Mowat syndrome
- Glomerulonephritis
- Glycosuria
- Goodpasture's syndrome
- HIV associated nephropathy
- Horseshoe kidney
- Hypercalcemia
- Hypertensive nephropathy
- Hyponephrosis
- Hypophosphatemia
- IgA nephropathy
- Interstitial nephritis
- Kidney stone
- Lupus nephritis
- Medullary cystic kidney disease
- Minimal change disease
- Multicystic dysplastic kidney
- Nephritis
- Nephropathy
- Nephroptosis
- Nephrotic syndrome
- Nutcracker syndrome
- Papillorenal syndrome
- Phosphate nephropathy
- Polycystic kidney disease
- Post-streptococcal glomerulonephritis
- Pyonephrosis
- Rapidly progressive glomerulonephritis
- Rebound diuresis
- Renal agenesis
- Renal artery stenosis
- Renal cell carcinoma
- Renal osteodystrophy
- Renal papillary necrosis
- Renal tubular acidosis
- Secondary hypertension
- Tetracapsuloides bryosalmonae
- Thin basement membrane disease
- Uremia
- Wilms' tumor
# Pioneers in Nephrology
- Dr. Joseph W. Eschbach, nephrologist whose research lead to the treatment of anemia.
- Dr. Georg Haas, preformed the first human hemodialysis treatment.
- Dr. Willem Johan Kolff, is a pioneer in the development of the hemodialysis machine as well as in the field of other artificial organs.
- Dr. Arthur Arnold Osman, was the first nephrologist.
- Dr. Belding H. Scribner, one of the pioneers of kidney dialysis. | Nephrology
Editors-In-Chief: C. Michael Gibson, M.S., M.D. [1], Vijay Lapsia, M.D. Assistant professor of Medicine/Nephrology, Medical Director, Mount Sinai Kidney Center. [2], and Stephanie Fernandez, M.D. [3]
Nephrology is the branch of internal medicine dealing with the study of the function and diseases of the kidney. The word nephrology is derived from the Greek word nephros, which means "kidney," and the suffix -ology, signifying "study of."
# Scope of the specialty
Nephrology concerns itself with the diagnosis and treatment of kidney diseases including electrolyte disturbances and hypertension, and the care of those requiring renal replacement therapy, including dialysis and renal transplant patients. Many diseases affecting the kidney are not limited to the organ itself, but are systemic disorders, and may require not only a whole patient approach, but also special treatment, such as systemic vasculitides or other autoimmune diseases, such as lupus.
# Who sees a nephrologist?
Patients are referred to nephrology specialists for various reasons, such as:
- Acute renal failure, a sudden loss of renal function
- Chronic kidney disease, declining renal function, usually with an inexorable rise in creatinine.
- Hematuria, blood loss in the urine
- Proteinuria, the loss of protein especially albumin in the urine
- Kidney stones, usually only recurrent stone formers.
- Chronic or recurrent urinary tract infections
- Hypertension that has failed to respond to multiple forms of anti-hypertensive medication or could have a secondary cause
- Electrolyte disorders or acid/base imbalance
Urologists are surgical specialists of the urinary tract - see Urology. They are involved in renal diseases that might be amenable to surgery:
- Diseases of the Bladder and prostate such as malignancy, stones, or obstruction of the urinary tract.
# Diagnosis
As with the rest of medicine, important clues as to the cause of any symptom are gained in the history and physical examination. For example, pink and white nails are associated with kidney disease.
Laboratory tests are almost always aimed at: urea, creatinine, electrolytes, and urinalysis-- which is frequently the key test in suggesting a diagnosis.
More specialized tests can be ordered to discover or link certain systemic diseases to kidney failure such as hepatitis B or hepatitis C, lupus serologies, paraproteinemias such as amyloidosis or multiple myeloma or various other systemic diseases that lead to kidney failure. Collection of a 24-hour sample of urine can give valuable information on the filtering capacity of the kidney and the amount of protein loss in some forms of kidney disease. However, 24-hour urine samples have recently, in the setting of chronic renal disease, been replaced by spot urine ratio of protein and creatinine.
Other tests often performed by nephrologists are:
- Renal biopsy, to obtain a tissue diagnosis of a disorder when the exact nature or stage remains uncertain.;
- Ultrasound scanning of the urinary tract and occasionally examining the renal blood vessels;
- CT scanning when mass lesions are suspected or to help diagnosis nephrolithiasis;
- Scintigraphy (nuclear medicine) for accurate measurement of renal function (rarely done), diagnosis of renal artery disease, or 'split function' of each kidney;
- Angiography or Magnetic resonance imaging angiography when the blood vessels might be affected
# Therapy
Many kidney diseases are treated with medication, such as steroids, DMARDs (disease-modifying antirheumatic drugs), antihypertensives (many kidney diseases feature hypertension). Often erythropoietin and vitamin D treatment is required to replace these two hormones, the production of which stagnates in chronic renal disease.
When symptoms of renal failure become too severe, dialysis might be required. Please refer to dialysis for a comprehensive account of this treatment.
If patients proceed to renal transplant, nephrologists often monitor the immunosuppressive regimen and the infections that can occur at this stage.
# See Also
- Abderhalden-Kaufmann-Lignac syndrome
- Acute renal failure
- Alport syndrome
- Aminoaciduria
- Analgesic nephropathy
- Azotemia
- Balkan nephropathy
- Bright's disease
- Chronic kidney disease
- Chronic renal failure
- Danubian endemic familial nephropathy
- Dent's disease
- Diabetic nephropathy
- Fanconi syndrome
- Fibromuscular dysplasia
- Focal segmental glomerulosclerosis
- Galloway Mowat syndrome
- Glomerulonephritis
- Glycosuria
- Goodpasture's syndrome
- HIV associated nephropathy
- Horseshoe kidney
- Hypercalcemia
- Hypertensive nephropathy
- Hyponephrosis
- Hypophosphatemia
- IgA nephropathy
- Interstitial nephritis
- Kidney stone
- Lupus nephritis
- Medullary cystic kidney disease
- Minimal change disease
- Multicystic dysplastic kidney
- Nephritis
- Nephropathy
- Nephroptosis
- Nephrotic syndrome
- Nutcracker syndrome
- Papillorenal syndrome
- Phosphate nephropathy
- Polycystic kidney disease
- Post-streptococcal glomerulonephritis
- Pyonephrosis
- Rapidly progressive glomerulonephritis
- Rebound diuresis
- Renal agenesis
- Renal artery stenosis
- Renal cell carcinoma
- Renal osteodystrophy
- Renal papillary necrosis
- Renal tubular acidosis
- Secondary hypertension
- Tetracapsuloides bryosalmonae
- Thin basement membrane disease
- Uremia
- Wilms' tumor
# Pioneers in Nephrology
- Dr. Joseph W. Eschbach, nephrologist whose research lead to the treatment of anemia.
- Dr. Georg Haas, preformed the first human hemodialysis treatment.
- Dr. Willem Johan Kolff, is a pioneer in the development of the hemodialysis machine as well as in the field of other artificial organs.
- Dr. Arthur Arnold Osman, was the first nephrologist.
- Dr. Belding H. Scribner, one of the pioneers of kidney dialysis.
# External links
- On-line Nephrology Journal Club (via JournalReview.org)
- British Journal of Renal Medicine
- Nature Clinical Practice Nephrology
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Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Kidney_Disease | |
cdc5af16b500ac29d464c6833e1c3d017d8413d5 | wikidoc | Kimberlite | Kimberlite
Kimberlite is a type of igneous rock best known for sometimes containing diamonds. It is named after the town of Kimberley in South Africa, where the discovery of an 83.5 carat diamond in 1871 spawned a diamond rush, eventually creating the Big Hole.
Kimberlite occurs in the Earth's crust in vertical structures known as kimberlite pipes. Kimberlite pipes are the most important source of mined diamonds today. The general consensus reached on kimberlites is that they are formed deep within the mantle, at between 150 and 450 kilometres depth, from anomalously enriched exotic mantle compositions, and are erupted rapidly and violently, often with considerable carbon dioxide and other volatile components. It is this depth of melting and generation which makes kimberlites prone to hosting diamond xenocrysts.
Kimberlite has in many ways attracted more attention than its relative volume might suggest that it deserves. This is largely because it serves as a carrier of diamonds and garnet peridotite mantle xenoliths to the Earth's surface. Furthermore, its probable derivation from depths greater than any other igneous rock type, and the extreme magma composition that it reflects in terms of low silica content and high levels of incompatible trace element enrichment, make an understanding of kimberlite petrogenesis important. In this regard, the study of kimberlite has the potential to provide valuable information on the composition of the deep mantle, and melting processes occurring at or near the interface between the cratonic continental lithosphere and the underlying convecting asthenospheric mantle.
# Morphology and volcanology
Kimberlites occur as carrot shaped, vertical intrusions termed dykes or diatremes. This classic carrot shape is due to a large proportion of both CO2 and H2O in the system which produces a deep explosive boiling stage and produces a significant amount of vertical flaring (Bergman, 1987). Kimberlite classification is based on the recognition of differing rock facies. These differing facies are associated with a particular style of magmatic activity, namely crater, diatreme and hypabyssal rocks (Clement and Skinner 1985, and Clement, 1982).
The morphology of kimberlite pipes, and the classical carrot shape, is the result of explosive diatreme volcanism from very deep mantle derived sources. These volcanic explosions produce vertical columns of rock that rise from deep magma reservoirs. The morphology of kimberlite pipes is varied but generally includes a sheeted dyke complex of tabular, vertically dipping feeder dykes in the root of the pipe which extends down to the mantle. Within 1.5-2 km of the surface the highly pressured magma explodes upwards and expands to form a conical to cylindrical diatreme, which erupts to the surface. The surface expression is rarely preserved but is usually similar to a maar volcano. The diameter of a kimberlite pipe at the surface is typically a few hundred meters to a kilometer.
Two Jurassic kimberlite dikes exist in Pennsylvania. One, the Gates-Adah Dike, outcrops on the Monongahela River on the border of Fayette and Greene Counties. The other, the Dixonville-Tanoma Dike in central Indiana County, does not outcrop at the surface and was discovered by miners.
# Petrology
Both the location and origin of kimberlitic magmas are areas of contention. Their extreme enrichment and geochemistry has led to a large amount of speculation about their origin, with models placing their source within the sub-continental lithospheric mantle (SCLM) or even as deep as the transition zone. The mechanism of enrichment has also been the topic of interest with models including partial melting, assimilation of subducted sediment or derivation from a primary magma source.
Historically, kimberlites have been subdivided into two distinct varieties termed 'basaltic' and 'micaceous' based primarily on petrographic observations (Wagner, 1914). This was later revised by Smith (1983) who re-named these divisions Group I and Group II based on the isotopic affinities of these rocks using the Nd, Sr and Pb systems. Mitchell (1995) later proposed that these group I and II kimberlites display such distinct differences, that they may not be as closely related as once thought. He showed that Group II kimberlites actually show closer affinities to lamproites than they do to Group I kimberlites. Hence, he reclassified Group II kimberlites as orangeites to prevent confusion.
## Group I kimberlites
Group I kimberlites are of CO2-rich ultramafic potassic igneous rocks dominated by a primary mineral assemblage of forsteritic olivine, magnesian ilmenite, chromian pyrope, almandine-pyrope, chromian diopside (in some cases subcalcic), phlogopite, enstatite and of Ti-poor chromite. Group I kimberlites exhibit a distinctive inequigranular texture cause by macrocrystic (0.5-10 mm) to megacrystic (10-200 mm) phenocrysts of olivine, pyrope, chromian diopside, magnesian ilmenite and phlogopite in a fine to medium grained groundmass.
The groundmass mineralogy, which more closely resembles a true composition of the igneous rock, contains forsteritic olivine, pyrope garnet, Cr-diopside, magnesian ilmenite and spinel.
## Group II kimberlites
Group-II kimberlites (or orangeites) are ultrapotassic, peralkaline rocks rich in volatiles (dominantly H2O). The distinctive characteristic of orangeites is phlogopite macrocrysts and microphenocrysts, together with groundmass micas that vary in composition from phlogopite to "tetraferriphlogopite" (anomalously Fe-rich phlogopite). Resorbed olivine macrocrysts and euhedral primary crystals of groundmass olivine are common but not essential constituents.
Characteristic primary phases in the groundmass include: zoned pyroxenes (cores of diopside rimmed by Ti-aegirine); spinel-group minerals (magnesian chromite to titaniferous magnetite); Sr- and REE-rich perovskite; Sr-rich apatite; REE-rich phosphates (monazite, daqingshanite); potassian barian hollandite group minerals; Nb-bearing rutile and Mn-bearing ilmenite.
## Kimberlitic indicator minerals
Kimberlites are peculiar igneous rocks because they contain a variety of mineral species with peculiar chemical compositions. These minerals such as potassic richterite, chromian diopside (a pyroxene), chromium spinels, magnesian ilmenite, and garnets rich in pyrope plus chromium are generally absent from most other igneous rocks, making them particularly useful as indicators for kimberlites.
These indicator minerals are generally sought in stream sediments in modern alluvial material. Their presence, when found, may be indicative of the presence of a kimberlite within the erosional watershed which has produced the alluvium.
# Geochemistry
The geochemistry of Kimberlites is defined by the following parameters;
- Ultramafic; MgO >12% and generally >15%
- Ultrapotassic; Molar K2O/Al2O3 >3
- Near-primitive Ni (>400 ppm), Cr (>1000 ppm), Co (>150 ppm)
- REE-enrichment
- Moderate to high LILE enrichment; ΣLILE = >1,000 ppm
- High H2O and CO2
# Economic importance
Kimberlites are the most important source of primary diamonds. Many kimberlite pipes also produce rich alluvial or eluvial diamond placer deposits. However, only about 1 in 200 kimberlite pipes contain gem-quality diamonds.
The deposits occurring at Kimberley, South Africa were the first recognized and the source of the name. The Kimberley diamonds were originally found in weathered kimberlite which was colored yellow by limonite, and so was called yellow ground. Deeper workings encountered less altered rock, serpentinized kimberlite, which miners call blue ground.
See also Udachnaya pipe.
# Related rock types
- Lamproite
- Lamprophyre
- Nepheline syenite
- Ultrapotassic igneous rocks
- Kalsititic rocks | Kimberlite
Kimberlite is a type of igneous rock best known for sometimes containing diamonds. It is named after the town of Kimberley in South Africa, where the discovery of an 83.5 carat diamond in 1871 spawned a diamond rush, eventually creating the Big Hole.
Kimberlite occurs in the Earth's crust in vertical structures known as kimberlite pipes. Kimberlite pipes are the most important source of mined diamonds today. The general consensus reached on kimberlites is that they are formed deep within the mantle, at between 150 and 450 kilometres depth, from anomalously enriched exotic mantle compositions, and are erupted rapidly and violently, often with considerable carbon dioxide and other volatile components. It is this depth of melting and generation which makes kimberlites prone to hosting diamond xenocrysts.
Kimberlite has in many ways attracted more attention than its relative volume might suggest that it deserves. This is largely because it serves as a carrier of diamonds and garnet peridotite mantle xenoliths to the Earth's surface. Furthermore, its probable derivation from depths greater than any other igneous rock type, and the extreme magma composition that it reflects in terms of low silica content and high levels of incompatible trace element enrichment, make an understanding of kimberlite petrogenesis important. In this regard, the study of kimberlite has the potential to provide valuable information on the composition of the deep mantle, and melting processes occurring at or near the interface between the cratonic continental lithosphere and the underlying convecting asthenospheric mantle.
# Morphology and volcanology
Kimberlites occur as carrot shaped, vertical intrusions termed dykes or diatremes. This classic carrot shape is due to a large proportion of both CO2 and H2O in the system which produces a deep explosive boiling stage and produces a significant amount of vertical flaring (Bergman, 1987). Kimberlite classification is based on the recognition of differing rock facies. These differing facies are associated with a particular style of magmatic activity, namely crater, diatreme and hypabyssal rocks (Clement and Skinner 1985, and Clement, 1982).
The morphology of kimberlite pipes, and the classical carrot shape, is the result of explosive diatreme volcanism from very deep mantle derived sources. These volcanic explosions produce vertical columns of rock that rise from deep magma reservoirs. The morphology of kimberlite pipes is varied but generally includes a sheeted dyke complex of tabular, vertically dipping feeder dykes in the root of the pipe which extends down to the mantle. Within 1.5-2 km of the surface the highly pressured magma explodes upwards and expands to form a conical to cylindrical diatreme, which erupts to the surface. The surface expression is rarely preserved but is usually similar to a maar volcano. The diameter of a kimberlite pipe at the surface is typically a few hundred meters to a kilometer.
Two Jurassic kimberlite dikes exist in Pennsylvania. One, the Gates-Adah Dike, outcrops on the Monongahela River on the border of Fayette and Greene Counties. The other, the Dixonville-Tanoma Dike in central Indiana County, does not outcrop at the surface and was discovered by miners.[1]
# Petrology
Both the location and origin of kimberlitic magmas are areas of contention. Their extreme enrichment and geochemistry has led to a large amount of speculation about their origin, with models placing their source within the sub-continental lithospheric mantle (SCLM) or even as deep as the transition zone. The mechanism of enrichment has also been the topic of interest with models including partial melting, assimilation of subducted sediment or derivation from a primary magma source.
Historically, kimberlites have been subdivided into two distinct varieties termed 'basaltic' and 'micaceous' based primarily on petrographic observations (Wagner, 1914). This was later revised by Smith (1983) who re-named these divisions Group I and Group II based on the isotopic affinities of these rocks using the Nd, Sr and Pb systems. Mitchell (1995) later proposed that these group I and II kimberlites display such distinct differences, that they may not be as closely related as once thought. He showed that Group II kimberlites actually show closer affinities to lamproites than they do to Group I kimberlites. Hence, he reclassified Group II kimberlites as orangeites to prevent confusion.
## Group I kimberlites
Group I kimberlites are of CO2-rich ultramafic potassic igneous rocks dominated by a primary mineral assemblage of forsteritic olivine, magnesian ilmenite, chromian pyrope, almandine-pyrope, chromian diopside (in some cases subcalcic), phlogopite, enstatite and of Ti-poor chromite. Group I kimberlites exhibit a distinctive inequigranular texture cause by macrocrystic (0.5-10 mm) to megacrystic (10-200 mm) phenocrysts of olivine, pyrope, chromian diopside, magnesian ilmenite and phlogopite in a fine to medium grained groundmass.
The groundmass mineralogy, which more closely resembles a true composition of the igneous rock, contains forsteritic olivine, pyrope garnet, Cr-diopside, magnesian ilmenite and spinel.
## Group II kimberlites
Group-II kimberlites (or orangeites) are ultrapotassic, peralkaline rocks rich in volatiles (dominantly H2O). The distinctive characteristic of orangeites is phlogopite macrocrysts and microphenocrysts, together with groundmass micas that vary in composition from phlogopite to "tetraferriphlogopite" (anomalously Fe-rich phlogopite). Resorbed olivine macrocrysts and euhedral primary crystals of groundmass olivine are common but not essential constituents.
Characteristic primary phases in the groundmass include: zoned pyroxenes (cores of diopside rimmed by Ti-aegirine); spinel-group minerals (magnesian chromite to titaniferous magnetite); Sr- and REE-rich perovskite; Sr-rich apatite; REE-rich phosphates (monazite, daqingshanite); potassian barian hollandite group minerals; Nb-bearing rutile and Mn-bearing ilmenite.
## Kimberlitic indicator minerals
Kimberlites are peculiar igneous rocks because they contain a variety of mineral species with peculiar chemical compositions. These minerals such as potassic richterite, chromian diopside (a pyroxene), chromium spinels, magnesian ilmenite, and garnets rich in pyrope plus chromium are generally absent from most other igneous rocks, making them particularly useful as indicators for kimberlites.
These indicator minerals are generally sought in stream sediments in modern alluvial material. Their presence, when found, may be indicative of the presence of a kimberlite within the erosional watershed which has produced the alluvium.
# Geochemistry
The geochemistry of Kimberlites is defined by the following parameters;
- Ultramafic; MgO >12% and generally >15%
- Ultrapotassic; Molar K2O/Al2O3 >3
- Near-primitive Ni (>400 ppm), Cr (>1000 ppm), Co (>150 ppm)
- REE-enrichment
- Moderate to high LILE enrichment; ΣLILE = >1,000 ppm
- High H2O and CO2
# Economic importance
Kimberlites are the most important source of primary diamonds. Many kimberlite pipes also produce rich alluvial or eluvial diamond placer deposits. However, only about 1 in 200 kimberlite pipes contain gem-quality diamonds.
The deposits occurring at Kimberley, South Africa were the first recognized and the source of the name. The Kimberley diamonds were originally found in weathered kimberlite which was colored yellow by limonite, and so was called yellow ground. Deeper workings encountered less altered rock, serpentinized kimberlite, which miners call blue ground.
See also Udachnaya pipe.
# Related rock types
- Lamproite
- Lamprophyre
- Nepheline syenite
- Ultrapotassic igneous rocks
- Kalsititic rocks | https://www.wikidoc.org/index.php/Kimberlite | |
f4ba38c11093211ed638323dfa551373856b1926 | wikidoc | Kisspeptin | Kisspeptin
Kisspeptin (formerly known as metastin) is a protein that is encoded by the KISS1 gene in humans. Kisspeptin is a G-protein coupled receptor ligand for GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.
# History
In 1996, Dr. Danny Welch's lab in Hershey, Pennsylvania isolated a cDNA from a cancer cell that was not able to undergo metastasis after the human chromosome 6 was added to the cell. This gene was named KISS1 because of the location of where it was discovered (Hershey, Pennsylvania, home of Hershey's Kisses). Introduction of this chromosome into the once active cancer cell inhibited it from spreading and the cDNA responsible was taken from that cell. The fact that KISS1 was responsible for this was proved when it was transfected into melanoma cells and yet again, metastasis was suppressed. Later, a breakthrough would occur not involving Kisspeptin, but with its receptor.
Three years later in 1999, a G protein coupled receptor was identified in rat, cloned, and termed GPR54. Additionally, two years later, this receptor’s ortholog in humans would be isolated. Using the identified receptors, endogenous ligands were isolated from cells (HEK293, B16-BL6, and CHO-K1 cells) that had these receptors inserted into them. The next step in the history of Kisspeptin involved revealing more of its pathways and the mechanism involved.
Kisspeptin was found to play a role in hypogonadotropic hypogonadism in 2003, which was supported by several independent lab groups. A mutation in GPR54 was considered responsible for this abnormality because those who held this mutation, or were missing GPR54 altogether, had problems in gonadal development during puberty. Several other phenotypes related to this mutation included a smaller sex steroid and gonadotropin concentration in the circulating blood and even sterility. These observations prompted the research on how kisspeptin is involved during the beginning of puberty. This research led to the discovery that kisspeptin stimulates the neurons that were involved in the release of gonadotropin-releasing hormone (GnRH) and possibly may have some impact on the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
Today, much effort is being made to characterize the regulation of kisspeptin and its gene expression, as well as to more specifically determine the mechanism behind kisspeptin's action on GnRH and LH release.
# Sources
## Hippocampal dentate gyrus
Kisspeptin is most notably expressed in the hypothalamus, but is also found in other areas of the brain including the hippocampal dentate gyrus. The hippocampus is known to integrate information on a person's spatial environment and memory. KISS1 is known to be expressed in the hippocampus. However, the levels of KISS1 mRNA expressed are decidedly lower than in the hypothalamus and amygdala. Studies have shown that the levels of KISS1 mRNA expressed in the hippocampus are proportional to less than half of the levels found in the hypothalamus. Despite this, it is suggested that expression of KISS1 is influenced by the gonad hormones similar to the hypothalamus.
There is a high degree of expression of GPR54 in the hippocampus. The density of GPR54 is not discernable in pyramidal cells, but has high levels of expression in the granule cell layer. It is known to be found in specific nuclei and neurons.
## Adrenal gland
The neuropeptide kisspeptin plays an important role in reproduction, but also stimulates aldosterone secretion from the adrenal cortex. Kisspeptin is distributed from the adrenal cortex and it is transcribed in the neocortex. The exact nature of the expression of kisspeptins in human adrenal glands unfortunately has not been fully clarified yet and remains a large topic of research among many scientists.
# Genomics
Kisspeptin is a product of the KISS1 gene which is cleaved from an initial 145 amino acid peptide to a 54 amino acid long protein. This gene is located on the long arm of chromosome 1 (1q32) and has four exons of which the 5' and 3' exons only partly undergo translation. The KISS1 gene was first isolated as a tumor spreading gene by investigators and named metastin. Metastin is derived from the protein kisspeptin and is a natural ligand of the receptor known as GPR54 Kisspeptin expression in the brain: Catalyst for the initiation of puberty. Different types made up of 14 and 13 amino acids have been isolated and they each share a common C-terminal sequence. These N-terminally truncated peptides are known as the kisspeptins and belong to a larger family of peptides known as RFamides which all share a common arginine-phenylalanine-NH2 motif at their C-terminus. Among these conserved amino acids are arginine and phenylalanine residues, which are paired in this family of peptides. Also within this conserved family is a C-terminus that has an amide added to it. This family which kisspeptin includes prolactin releasing peptide and gonadotropin releasing inhibiting hormone.
A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues.
# Structure
## Kisspeptin
The gene for kisspeptin codes for a peptide that can be cleaved into several pieces. In humans, one of these pieces is made up of 54 amino acids, while in mice it is made up of 52 amino acids. This fragment is then proteolytically processed into several smaller fragments that have been isolated in humans composed of 13 and 14 amino acids (kisspeptin-13 and kisspeptin-14 respectively). Each of these fragments has a similar conserved region at the C-terminal sequence consisting of ten amino acids. Specifically, positions 2, 4, 6, 7, 8, and 9 in this region are completely conserved where any variation seen is due to random mutations. The sequence on the carboxy terminal side of the conserved region is a well-known site for cleavage in neuropeptides.
## GPR54
The structure for GPR54 is very similar throughout many different vertebrates. It is composed of 398 amino acids that form seven transmembrane domains, like most G-protein coupled receptors. Sequences found in transmembrane spanning regions one, four, and seven are all very highly conserved throughout species. Variation appears in the around the amino and C-terminal domains, which accounts for the different types of Kisspeptin receptors seen in various species.
# Pathway
## GnRH release
Kisspeptin-54 interacts with G protein-coupled receptors, specifically GPR54 (Kiss1R). Other versions of kisspeptin are also able to interact with Kiss1R. Research in both rats and humans has provided evidence that the binding of kisspeptin stimulates PIP2 hydrolysis, Ca2+ mobilization, arachidonic acid release, extracellular signal-regulated protein kinase 1 (ERK1), ERK2, and p38 MAP kinase phosphorylation. Although GnRH is located in many areas such as the pituitary gland and the GnRH neurons, research proves that GnRH is highly dependent upon GnRH neuron activation and less dependent on the pituitary gonadotropes. Many studies show that kisspeptin has the ability to not only cause depolarization, but also excite many GnRH neurons, leading to high expression of kisspeptin in these genes. But, it is hypothesized that there are two different types of GFP-GnRH neurons due to expression in some neurons but not others, only one of which responds to kisspeptin. The neurons response to kisspeptin is also hypothesized to be related to age and puberty. The binding of kisspeptin to the GnRH receptor can have effects on puberty, tumor suppression and reproduction.
# Biological function
Kisspeptin can stimulate secretion of aldosterone and the release of insulin.
Kisspeptin appears to directly activate GnRH neurons. Evidence for this involves the persistence of a neural response to kisspeptin levels even in the presence of TTX, a neurotoxin that blocks nerve signals.
- Gramicidin-perforated patch recordings: about 30% of GnRH neurons respond to kisspeptin administration in prepubertal males, whereas 60% of GnRH neurons in adult mice responded.
- Because only adult mice respond to low doses of kisspeptin, it appears that GnRH neurons become developmentally activated by kisspeptin over the course of puberty.
- Kisspeptin induces production of LH and FSH, which are required for female's menstruation. Athletes may not undergo menstruation due to low fat levels; fat produces the hormone leptin, which induces production of kisspeptin.
## Role in puberty
The onset of puberty is marked by an increase in gonadotropin secretion, which leads to sexual maturity and the ability to reproduce. Puberty can also be affected by a range of environmental factors, and is known to be affected by a person's metabolic capacity. Gonadotropin secretion is brought about and regulated by gonadotropin releasing hormone (GnRH). GnRH leads to the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which primarily target the gonads to trigger puberty and reproduction. The primary event that leads to the beginning of puberty is the activation of GnRH neurons. This event is thought to involve kisspeptin/GPR54 signaling, which leads to the eventual activation of GnRH neurons.
Several studies have confirmed that addition of kisspeptin to biological systems including rat, mouse, and sheep are able to bring about the release of LH and FSH. In addition to this, the release of these gonadotropins has proven to be dose dependent. A greater addition of kisspeptin peptide resulted in greater release of LH and FSH. Kisspeptin was found to evoke one of the strongest effects on the gonadotropin system.
Kisspeptin's ability to stimulate the release of GnRH and gonadotropins is the result of its effect on GnRH release at the hypothalamus. In rat hypothalamus, it was found that over three-fourths of GnRH neurons coexpress the receptor for kisspeptin, GPR54, in their RNA. Kisspeptin was also able to bring about the release of GnRH both ex vivo and in vivo in rat and sheep. It can be concluded that by activating GnRH neurons in the hypothalamus, kisspeptin causes GnRH release which leads to the release of FSH and LH. The major role kisspeptin/GPR54 plays in sexual development was initially found in sexually immature humans and mice who had mutations that blocked the expression of the GPR54 gene. In rats, the initiation of puberty accompanied a greater presence of KISS1 and GPR54 in mRNA. The same events were later observed in mammals, where KISS1 and GPR54 mRNA increased more than twofold in the hypothalamus. This suggests that there is greater expression of KISS1 and potentially even GPR54 at the onset of puberty leading to an increase in kisspeptin/GPR54 signaling that results in the activation of the gonadotropin pathway. The addition of kisspeptin to female rats who had yet to mature led to the initiation of gonadotropin pathway. In humans, it was shown that females at the beginning stages of puberty had much higher kisspeptin levels than those females of the same age who had yet to begin puberty. It has been concluded that the activation of the GPR54/kisspeptin pathway is a catalyst that leads to puberty onset.
## Role in tumor suppression
Kisspeptin plays a role in tumor suppression. In a study where malignant tumor cells were injected into a model system, the system was then tested for genes involved in the injected chromosome 6. KISS1 was discovered to be the only gene expressed in non-metastatic cells and absent in metastatic, metastatic meaning the ability for cancer to spread to unconnected areas. This suggested that there Kisspeptin is an essential regulation factor in whether or not a cell will be metastatic or not. Additional experimentation identified CRSP3 as the exact gene responsible for KISS1 regulation within chromosome 6. In clinical evidence studies, KISS1 and Kisspeptin were found in primary, metastatic tumors, and growing tumors showing decreased levels of KISS1 and Kisspeptin. In conclusion, kisspeptin plays a large role in tumor suppression. When it is active in cells the tumor stays consolidated and does not spread or grow.
## Role in reproduction
Kisspeptin is highly expressed during pregnancy. In early-term placentas, GPR54 was expressed at a higher rate than placentas at-term. The expression of kisspeptin, however, remains unchanged in the placenta throughout pregnancy. The increased expression of GPR54 in early-term placentas is due to the increased presence of intrusive trophoblasts during the beginning of pregnancy. Term cells, by comparison are less invasive. When measuring kisspeptin-54 during pregnancy, a 1000x increase was observed in early pregnancy with a 10 000x increase seen by the third trimester. Following birth, kisspeptin-54 levels returned to normal, showing the placenta as the source of these increased kisspeptin levels.
## Role in kidney function
Kisspeptin and its receptor was found in various sites in the kidney, including in the collecting duct, vascular smooth muscle, and in the renal tubule cells. Much of the impact on the kidney deals with the increased production of aldosterone in the adrenals glands stimulated by kisspeptin. Kisspeptin directly increases release of aldosterone by several means, the first being through these receptors leading to a direct route to aldosterone release. Secondly, the H295R adrenal cells stimulated by kisspeptin can synthesize aldosterone by breaking down pregnenolone more efficiently. Lastly, the kisspeptin-angiotensin II pathway of producing aldosterone is increased. Aldosterone that comes from the neighboring adrenal glands causes reabsorption of filtrate in order to retain water, leading to an increased blood pressure.
# Kisspeptin neurons
Kisspeptin expressing neurons are located in:
- Anteroventral periventricular nucleus (AVPV)
- Periventricular nucleus (PeN)
- Anterodorsal preoptic nucleus (ADP)
- The arcuate nucleus (Arc)
Kisspeptin-expressing neurons reside in the anteroventral periventricular nucleus and the arcuate nucleus, among others, and send projections into the MPOA, where there is an abundance of GnRH cell bodies. This anatomical evidence suggests that Kisspeptin fibers appear in close anatomical relationship to GnRH (parvicellular) neurons. In fact, Kisspeptin appears to act directly on GnRH neurons (via GPR54) to stimulate the secretion of GnRH.
However, for kisspeptin to be involved in the regulation of GnRH release, it must also be sensitive to circulating sex steroid levels, as it is established that steroids produced by the gonads exert regulatory effects on FSH and LH levels through GnRH mediation. Thus, there are at least two possible scenarios: that either kisspeptin neurons express sex steroid receptors themselves, or they receive input about circulating sex steroid levels from a different mechanism .
Coexpression imaging of KISS1 mRNA (using vector red) and steroid receptors determined that neurons that express KISS1 mRNA are targets for the action of sex steroids in both male and female mice. | Kisspeptin
Kisspeptin (formerly known as metastin) is a protein that is encoded by the KISS1 gene in humans. Kisspeptin is a G-protein coupled receptor ligand for GPR54.[1] Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis.[2] Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research.[3] Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.
# History
In 1996, Dr. Danny Welch's lab in Hershey, Pennsylvania isolated a cDNA from a cancer cell that was not able to undergo metastasis after the human chromosome 6 was added to the cell. This gene was named KISS1 because of the location of where it was discovered (Hershey, Pennsylvania, home of Hershey's Kisses). Introduction of this chromosome into the once active cancer cell inhibited it from spreading and the cDNA responsible was taken from that cell. The fact that KISS1 was responsible for this was proved when it was transfected into melanoma cells and yet again, metastasis was suppressed.[4] Later, a breakthrough would occur not involving Kisspeptin, but with its receptor.
Three years later in 1999, a G protein coupled receptor was identified in rat, cloned, and termed GPR54.[4] Additionally, two years later, this receptor’s ortholog in humans would be isolated.[4] Using the identified receptors, endogenous ligands were isolated from cells (HEK293, B16-BL6, and CHO-K1 cells) that had these receptors inserted into them.[4] The next step in the history of Kisspeptin involved revealing more of its pathways and the mechanism involved.
Kisspeptin was found to play a role in hypogonadotropic hypogonadism in 2003, which was supported by several independent lab groups.[4] A mutation in GPR54 was considered responsible for this abnormality because those who held this mutation, or were missing GPR54 altogether, had problems in gonadal development during puberty.[4] Several other phenotypes related to this mutation included a smaller sex steroid and gonadotropin concentration in the circulating blood and even sterility.[4] These observations prompted the research on how kisspeptin is involved during the beginning of puberty. This research led to the discovery that kisspeptin stimulates the neurons that were involved in the release of gonadotropin-releasing hormone (GnRH) and possibly may have some impact on the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).[4]
Today, much effort is being made to characterize the regulation of kisspeptin and its gene expression, as well as to more specifically determine the mechanism behind kisspeptin's action on GnRH and LH release.[5]
# Sources
## Hippocampal dentate gyrus
Kisspeptin is most notably expressed in the hypothalamus, but is also found in other areas of the brain including the hippocampal dentate gyrus. The hippocampus is known to integrate information on a person's spatial environment and memory. KISS1 is known to be expressed in the hippocampus. However, the levels of KISS1 mRNA expressed are decidedly lower than in the hypothalamus and amygdala. Studies have shown that the levels of KISS1 mRNA expressed in the hippocampus are proportional to less than half of the levels found in the hypothalamus. Despite this, it is suggested that expression of KISS1 is influenced by the gonad hormones similar to the hypothalamus.
There is a high degree of expression of GPR54 in the hippocampus. The density of GPR54 is not discernable in pyramidal cells, but has high levels of expression in the granule cell layer. It is known to be found in specific nuclei and neurons.[6]
## Adrenal gland
The neuropeptide kisspeptin plays an important role in reproduction, but also stimulates aldosterone secretion from the adrenal cortex. Kisspeptin is distributed from the adrenal cortex and it is transcribed in the neocortex. The exact nature of the expression of kisspeptins in human adrenal glands unfortunately has not been fully clarified yet and remains a large topic of research among many scientists.[7]
# Genomics
Kisspeptin is a product of the KISS1 gene which is cleaved from an initial 145 amino acid peptide to a 54 amino acid long protein.[8] This gene is located on the long arm of chromosome 1 (1q32) and has four exons of which the 5' and 3' exons only partly undergo translation. The KISS1 gene was first isolated as a tumor spreading gene by investigators and named metastin. Metastin is derived from the protein kisspeptin and is a natural ligand of the receptor known as GPR54 Kisspeptin expression in the brain: Catalyst for the initiation of puberty.[9] Different types made up of 14 and 13 amino acids have been isolated and they each share a common C-terminal sequence. These N-terminally truncated peptides are known as the kisspeptins and belong to a larger family of peptides known as RFamides which all share a common arginine-phenylalanine-NH2 motif at their C-terminus. Among these conserved amino acids are arginine and phenylalanine residues, which are paired in this family of peptides. Also within this conserved family is a C-terminus that has an amide added to it. This family which kisspeptin includes prolactin releasing peptide and gonadotropin releasing inhibiting hormone.[9]
A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues.[10]
# Structure
## Kisspeptin
The gene for kisspeptin codes for a peptide that can be cleaved into several pieces.[5] In humans, one of these pieces is made up of 54 amino acids, while in mice it is made up of 52 amino acids.[11] This fragment is then proteolytically processed into several smaller fragments that have been isolated in humans composed of 13 and 14 amino acids (kisspeptin-13 and kisspeptin-14 respectively). Each of these fragments has a similar conserved region at the C-terminal sequence consisting of ten amino acids.[4] Specifically, positions 2, 4, 6, 7, 8, and 9 in this region are completely conserved where any variation seen is due to random mutations. The sequence on the carboxy terminal side of the conserved region is a well-known site for cleavage in neuropeptides.[4]
## GPR54
The structure for GPR54 is very similar throughout many different vertebrates.[4] It is composed of 398 amino acids that form seven transmembrane domains, like most G-protein coupled receptors. Sequences found in transmembrane spanning regions one, four, and seven are all very highly conserved throughout species. Variation appears in the around the amino and C-terminal domains, which accounts for the different types of Kisspeptin receptors seen in various species.[4]
# Pathway
## GnRH release
Kisspeptin-54 interacts with G protein-coupled receptors, specifically GPR54 (Kiss1R). Other versions of kisspeptin are also able to interact with Kiss1R.[5] Research in both rats and humans has provided evidence that the binding of kisspeptin stimulates PIP2 hydrolysis, Ca2+ mobilization, arachidonic acid release, extracellular signal-regulated protein kinase 1 (ERK1), ERK2, and p38 MAP kinase phosphorylation.[5] Although GnRH is located in many areas such as the pituitary gland and the GnRH neurons, research proves that GnRH is highly dependent upon GnRH neuron activation and less dependent on the pituitary gonadotropes.[5] Many studies show that kisspeptin has the ability to not only cause depolarization, but also excite many GnRH neurons, leading to high expression of kisspeptin in these genes.[5] But, it is hypothesized that there are two different types of GFP-GnRH neurons due to expression in some neurons but not others, only one of which responds to kisspeptin.[5] The neurons response to kisspeptin is also hypothesized to be related to age and puberty.[5] The binding of kisspeptin to the GnRH receptor can have effects on puberty, tumor suppression and reproduction.
# Biological function
Kisspeptin can stimulate secretion of aldosterone and the release of insulin.
Kisspeptin appears to directly activate GnRH neurons. Evidence for this involves the persistence of a neural response to kisspeptin levels even in the presence of TTX, a neurotoxin that blocks nerve signals.
- Gramicidin-perforated patch recordings: about 30% of GnRH neurons respond to kisspeptin administration in prepubertal males, whereas 60% of GnRH neurons in adult mice responded.
- Because only adult mice respond to low doses of kisspeptin, it appears that GnRH neurons become developmentally activated by kisspeptin over the course of puberty.
- Kisspeptin induces production of LH and FSH, which are required for female's menstruation. Athletes may not undergo menstruation due to low fat levels; fat produces the hormone leptin, which induces production of kisspeptin.
## Role in puberty
The onset of puberty is marked by an increase in gonadotropin secretion, which leads to sexual maturity and the ability to reproduce. Puberty can also be affected by a range of environmental factors, and is known to be affected by a person's metabolic capacity.[12] Gonadotropin secretion is brought about and regulated by gonadotropin releasing hormone (GnRH). GnRH leads to the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which primarily target the gonads to trigger puberty and reproduction. The primary event that leads to the beginning of puberty is the activation of GnRH neurons. This event is thought to involve kisspeptin/GPR54 signaling, which leads to the eventual activation of GnRH neurons.[9]
Several studies have confirmed that addition of kisspeptin to biological systems including rat, mouse, and sheep are able to bring about the release of LH and FSH. In addition to this, the release of these gonadotropins has proven to be dose dependent. A greater addition of kisspeptin peptide resulted in greater release of LH and FSH. Kisspeptin was found to evoke one of the strongest effects on the gonadotropin system.[12]
Kisspeptin's ability to stimulate the release of GnRH and gonadotropins is the result of its effect on GnRH release at the hypothalamus. In rat hypothalamus, it was found that over three-fourths of GnRH neurons coexpress the receptor for kisspeptin, GPR54, in their RNA. Kisspeptin was also able to bring about the release of GnRH both ex vivo and in vivo in rat and sheep. It can be concluded that by activating GnRH neurons in the hypothalamus, kisspeptin causes GnRH release which leads to the release of FSH and LH.[12] The major role kisspeptin/GPR54 plays in sexual development was initially found in sexually immature humans and mice who had mutations that blocked the expression of the GPR54 gene. In rats, the initiation of puberty accompanied a greater presence of KISS1 and GPR54 in mRNA. The same events were later observed in mammals, where KISS1 and GPR54 mRNA increased more than twofold in the hypothalamus. This suggests that there is greater expression of KISS1 and potentially even GPR54 at the onset of puberty leading to an increase in kisspeptin/GPR54 signaling that results in the activation of the gonadotropin pathway.[12] The addition of kisspeptin to female rats who had yet to mature led to the initiation of gonadotropin pathway. In humans, it was shown that females at the beginning stages of puberty had much higher kisspeptin levels than those females of the same age who had yet to begin puberty. It has been concluded that the activation of the GPR54/kisspeptin pathway is a catalyst that leads to puberty onset.[12]
## Role in tumor suppression
Kisspeptin plays a role in tumor suppression. In a study where malignant tumor cells were injected into a model system, the system was then tested for genes involved in the injected chromosome 6. KISS1 was discovered to be the only gene expressed in non-metastatic cells and absent in metastatic, metastatic meaning the ability for cancer to spread to unconnected areas. This suggested that there Kisspeptin is an essential regulation factor in whether or not a cell will be metastatic or not. Additional experimentation identified CRSP3 as the exact gene responsible for KISS1 regulation within chromosome 6. In clinical evidence studies, KISS1 and Kisspeptin were found in primary, metastatic tumors, and growing tumors showing decreased levels of KISS1 and Kisspeptin.[8] In conclusion, kisspeptin plays a large role in tumor suppression. When it is active in cells the tumor stays consolidated and does not spread or grow.
## Role in reproduction
Kisspeptin is highly expressed during pregnancy. In early-term placentas, GPR54 was expressed at a higher rate than placentas at-term. The expression of kisspeptin, however, remains unchanged in the placenta throughout pregnancy. The increased expression of GPR54 in early-term placentas is due to the increased presence of intrusive trophoblasts during the beginning of pregnancy. Term cells, by comparison are less invasive. When measuring kisspeptin-54 during pregnancy, a 1000x increase was observed in early pregnancy with a 10 000x increase seen by the third trimester. Following birth, kisspeptin-54 levels returned to normal, showing the placenta as the source of these increased kisspeptin levels.[8]
## Role in kidney function
Kisspeptin and its receptor was found in various sites in the kidney, including in the collecting duct, vascular smooth muscle, and in the renal tubule cells.[13] Much of the impact on the kidney deals with the increased production of aldosterone in the adrenals glands stimulated by kisspeptin.[14] Kisspeptin directly increases release of aldosterone by several means, the first being through these receptors leading to a direct route to aldosterone release.[14] Secondly, the H295R adrenal cells stimulated by kisspeptin can synthesize aldosterone by breaking down pregnenolone more efficiently.[14] Lastly, the kisspeptin-angiotensin II pathway of producing aldosterone is increased.[14] Aldosterone that comes from the neighboring adrenal glands causes reabsorption of filtrate in order to retain water, leading to an increased blood pressure.[15]
# Kisspeptin neurons
Kisspeptin expressing neurons are located in:
- Anteroventral periventricular nucleus (AVPV)
- Periventricular nucleus (PeN)
- Anterodorsal preoptic nucleus (ADP)
- The arcuate nucleus (Arc)
Kisspeptin-expressing neurons reside in the anteroventral periventricular nucleus and the arcuate nucleus, among others, and send projections into the MPOA, where there is an abundance of GnRH cell bodies. This anatomical evidence suggests that Kisspeptin fibers appear in close anatomical relationship to GnRH (parvicellular) neurons. In fact, Kisspeptin appears to act directly on GnRH neurons (via GPR54) to stimulate the secretion of GnRH.
However, for kisspeptin to be involved in the regulation of GnRH release, it must also be sensitive to circulating sex steroid levels, as it is established that steroids produced by the gonads exert regulatory effects on FSH and LH levels through GnRH mediation. Thus, there are at least two possible scenarios: that either kisspeptin neurons express sex steroid receptors themselves, or they receive input about circulating sex steroid levels from a different mechanism .
Coexpression imaging of KISS1 mRNA (using vector red) and steroid receptors determined that neurons that express KISS1 mRNA are targets for the action of sex steroids in both male and female mice. | https://www.wikidoc.org/index.php/Kisspeptin | |
87d89023ceac6c14c532d431a4834e6a2214a52d | wikidoc | Kyotorphin | Kyotorphin
Kyotorphin (L-tyrosyl-L-arginine) is a neuroactive dipeptide which plays a role in pain regulation in the brain. It was first isolated from bovine brain by Japanese scientists in 1979. Kyotorphin was named for the site of its discovery, Kyoto, Japan and because of its morphine- (or endorphin-) like analgesic activity. Kyotorphin has an analgesic effect, but it does not interact with the opioid receptors. Instead, it acts by releasing an Met-enkephalin and stabilizing it from degradation. It may also possess properties of neuromediator/neuromodulator. It has been shown that kyotorphin is present in the human cerebrospinal fluid and that it is lower in patients with persistent pain.
# Notes
- ↑ Takagi H, Shiomi H, Ueda and Amano H (1979) A novel analgesic dipeptide from bovine brain is a possible met-enkephalin releaser. Nature (Lond) 282: 410-412.
- ↑ K, Kaya K, Hazato T, Ueda H, Satoh M, Takagi H. (1991) Kyotorphin like substance in human cerebrospinal fluid of patients with persistent pain Masui. Nov;40(11):1686-90. | Kyotorphin
Kyotorphin (L-tyrosyl-L-arginine) is a neuroactive dipeptide which plays a role in pain regulation in the brain. It was first isolated from bovine brain by Japanese scientists in 1979[1]. Kyotorphin was named for the site of its discovery, Kyoto, Japan and because of its morphine- (or endorphin-) like analgesic activity. Kyotorphin has an analgesic effect, but it does not interact with the opioid receptors. Instead, it acts by releasing an Met-enkephalin and stabilizing it from degradation. It may also possess properties of neuromediator/neuromodulator. It has been shown that kyotorphin is present in the human cerebrospinal fluid and that it is lower in patients with persistent pain[2].
# Notes
- ↑ Takagi H, Shiomi H, Ueda and Amano H (1979) A novel analgesic dipeptide from bovine brain is a possible met-enkephalin releaser. Nature (Lond) 282: 410-412.
- ↑ K, Kaya K, Hazato T, Ueda H, Satoh M, Takagi H. (1991) Kyotorphin like substance in human cerebrospinal fluid of patients with persistent pain Masui. Nov;40(11):1686-90.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Kyotorphin | |
c8fd52948ef3ed8b26b15350da81cf2676c1ece5 | wikidoc | Tryptophan | Tryptophan
Tryptophan (abbreviated as Trp or W) is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in genetic code as the codon TGG. Only the L-stereoisomer of tryptophan is used in structural or enzyme proteins, but the D-stereoisomer is occasionally found in naturally produced peptides (for example, the marine venom peptide contryphan). The distinguishing structural characteristic of tryptophan is that it contains an indole functional group.
# Isolation
The isolation of tryptophan was first reported by Sir Frederick Hopkins in 1901 through hydrolysis of casein. From 600 grams of crude casein one obtains 4-8 grams of tryptophan.
# Biosynthesis and industrial production
Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate. The latter condenses with phosphoribosylpyrophosphate (PRPP), generating pyrophosphate as a by-product. After ring opening of the ribose moiety and following reductive decarboxylation, indole-3-glycerinephosphate is produced, which in turn is transformed into indole. In the last step, tryptophan synthase catalyzes the formation of tryptophan from indole and the amino acid, serine.
The industrial production of tryptophan is also biosynthetic and is based on the fermentation of serine and indole using either wild-type or genetically modified E. coli. The conversion is catalyzed by the enzyme tryptophan synthase.
# Function
For many organisms (including humans), tryptophan is an essential amino acid. This means that it cannot be synthesized by the organism and therefore must be part of its diet. The principal function of amino acids including tryptophan are as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for the following compounds (see also figure to the right):
- Serotonin (a neurotransmitter), synthesized via tryptophan hydroxylase. Serotonin, in turn, can be converted to melatonin (a neurohormone), via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase activities.
- Niacin is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates.
The disorder Fructose Malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood and depression.
In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. Binding of this repressor to the tryptophan operon prevents transcription of downstream DNA that codes for the enzymes involved in the biosynthesis of tryptophan. So high levels of tryptophan prevent tryptophan synthesis through a negative feedback loop and, when the cell's tryptophan levels are reduced, transcription from the trp operon resumes. The genetic organisation of the trp operon thus permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.
# Dietary sources
Tryptophan is a routine constituent of most protein-based foods or dietary proteins. It is particularly plentiful in chocolate, oats, bananas, mangoes, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, sunflower seeds, pumpkin seeds, spirulina, and peanuts. It is also found in turkey at a level typical of poultry in general.
## Use as a dietary supplement
For some time, tryptophan was available in health food stores as a dietary supplement, although it is common in dietary protein. Many people found tryptophan to be a safe and reasonably effective sleep aid, probably due to its ability to increase brain levels of serotonin (a calming neurotransmitter when present in moderate levels) and/or melatonin (a sleep-inducing hormone secreted by the pineal gland in response to darkness or low light levels).
Clinical research tends to confirm tryptophan's effectiveness as a sleep aid and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain such as premenstrual dysphoric disorder
and seasonal affective disorder. In particular, tryptophan has been showing considerable promise as an antidepressant alone, and as an "augmenter" of antidepressant drugs. However, the reliability of these clinical trials has been questioned.
## Metabolites
5-Hydroxytryptophan (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for epilepsy and depression, although clinical trials are regarded inconclusive and lacking.
5-HTP readily crosses the blood-brain barrier and in addition is rapidly decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) and therefore may be useful for the treatment of depression. However serotonin has a relatively short half-life since it is rapidly metabolized by monoamine oxidase, and therefore is likely to have limited efficacy. It is marketed in Europe for depression and other indications under the brand names Cincofarm and Tript-OH.
In the United States, 5-HTP does not require a prescription, as it is covered under the Dietary Supplement Act. However, since the quality of dietary supplements is not regulated by the FDA, the quality of dietary and nutritional supplements tends to vary, and there is no guarantee that the label accurately depicts what the bottle contains.
## Tryptophan supplements and EMS
Although currently available for purchase, in 1989 a large outbreak (1500 cases of permanent disability including at least 37 deaths) of a disabling autoimmune illness called eosinophilia-myalgia syndrome (EMS) was traced by some epidemiological studies to L-tryptophan supplied by a Japanese manufacturer, Showa Denko KK. It was further hypothesized that one or more trace impurities produced during the manufacture of tryptophan may have been responsible for the EMS outbreak. However, many people who consumed Showa Denko L-tryptophan did not develop EMS and cases of EMS have occurred prior to and after the 1989 epidemic. Furthermore the methodology used in the initial epidemiological studies has been criticized. An alternative explanation for the 1989 EMS outbreak is that large doses of tryptophan produce metabolites which inhibit the normal degradation of histamine and excess histamine in turn has been proposed to cause EMS.
Most tryptophan was banned from sale in the US in 1991, and other countries followed suit. Tryptophan from one manufacturer, of six, continued to be sold for manufacture of baby formulas. A Rutgers Law Journal article observed, "Political pressures have played a role in the FDA's decision to ban L-tryptophan as well as its desire to increase its regulatory power over dietary supplements."
At the time of the ban, the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch, and yet, even when the contamination was discovered and the purification process fixed, the FDA maintained that L-tryptophan was unsafe. In February 2001, the FDA loosened the restrictions on marketing (though not on importation), but still expressed the following concern:
Since 2002, L-tryptophan has been sold in the U.S. in its original form. Several high-quality sources of L-tryptophan do exist, and are sold in many of the largest health food stores nationwide. Indeed, tryptophan has continued to be used in clinical and experimental studies employing human patients and subjects.
In recent years in the U.S., compounding pharmacies and some mail-order supplement retailers have begun selling tryptophan to the general public. Tryptophan has also remained on the market as a prescription drug (Tryptan), which some psychiatrists continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs.
## Turkey meat and drowsiness
One widely-held belief is that heavy consumption of turkey meat (as for example in a Thanksgiving feast) results in drowsiness, which has been attributed to high levels of tryptophan contained in turkey. While turkey does contain high levels of tryptophan, the amount is comparable to that contained in most other meats. Furthermore, postprandial Thanksgiving sedation may have more to do with what is consumed along with the turkey, in particular carbohydrates, rather than the turkey itself.
It has been demonstrated in both animal models and in humans that ingestion of a meal rich in carbohydrates triggers release of insulin. Insulin in turn stimulates the uptake of large neutral branched-chain amino acids (LNAA) but not tryptophan (trp) into muscle, increasing the ratio of trp to LNAA in the blood stream. The resulting increased ratio of tryptophan to large neutral amino acids in the blood reduces competition with other amino acids for the large neutral amino acid transporter protein for uptake of tryptophan across the blood-brain barrier into the central nervous system (CNS). Once inside the CNS, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway. The resultant serotonin is further metabolised into melatonin by the pineal gland. Hence, these data suggest that "feast-induced drowsiness," and in particular, the common American post-Thanksgiving dinner drowsiness, may be the result of a heavy meal rich in carbohydrates which, via an indirect mechanism, increases the production of sleep-promoting serotonin and melatonin in the brain.
# Fluorescence
The fluorescence of a folded protein is a mixture of the fluorescence from individual aromatic residues. Most of the intrinsic fluorescence emissions of a folded protein are due to excitation of tryptophan residues, with some emissions due to tyrosine and phenylalanine. Typically, tryptophan has a wavelength of maximum absorption of 280 nm and an emission peak that is solvatochromic, ranging from ca. 300 to 350 nm depending in the polarity of the local environment Hence, protein fluorescence may be used as a diagnostic of the conformational state of a protein. Furthermore, tryptophan fluorescence is strongly influenced by the proximity of other residues (i.e., nearby protonated acidic groups such as Asp or Glu can cause quenching of Trp fluorescence). Also, energy transfer between tryptophan and the other fluorescent amino acids is possible, which would affect the analysis, especially in cases where the Förster approach is taken. In addition, tryptophan is a relatively rare amino acid; many proteins contain only one or a few tryptophan residues. Therefore, tryptophan fluorescence can be a very sensitive measurement of the conformational state of individual tryptophan residues. The advantage compared to extrinsic probes is that the protein itself is not changed. The use of intrinsic fluorescence for the study of protein conformation is in practice limited to cases with few (or perhaps only one) tryptophan residues, since each experiences a different local environment, which gives rise to different emission spectra. This could be avoided by the use of time-resolved fluorescence, but would not really make the analysis much easier. | Tryptophan
Template:NatOrganicBox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Tryptophan (abbreviated as Trp or W)[1] is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in genetic code as the codon TGG. Only the L-stereoisomer of tryptophan is used in structural or enzyme proteins, but the D-stereoisomer is occasionally found in naturally produced peptides (for example, the marine venom peptide contryphan).[2] The distinguishing structural characteristic of tryptophan is that it contains an indole functional group.
# Isolation
The isolation of tryptophan was first reported by Sir Frederick Hopkins in 1901 [3] through hydrolysis of casein. From 600 grams of crude casein one obtains 4-8 grams of tryptophan.[4]
# Biosynthesis and industrial production
Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate.[5] The latter condenses with phosphoribosylpyrophosphate (PRPP), generating pyrophosphate as a by-product. After ring opening of the ribose moiety and following reductive decarboxylation, indole-3-glycerinephosphate is produced, which in turn is transformed into indole. In the last step, tryptophan synthase catalyzes the formation of tryptophan from indole and the amino acid, serine.
The industrial production of tryptophan is also biosynthetic and is based on the fermentation of serine and indole using either wild-type or genetically modified E. coli. The conversion is catalyzed by the enzyme tryptophan synthase.[6]
# Function
For many organisms (including humans), tryptophan is an essential amino acid. This means that it cannot be synthesized by the organism and therefore must be part of its diet. The principal function of amino acids including tryptophan are as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for the following compounds (see also figure to the right):
- Serotonin (a neurotransmitter), synthesized via tryptophan hydroxylase.[7][8] Serotonin, in turn, can be converted to melatonin (a neurohormone), via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase activities.[9]
- Niacin is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates.[10]
The disorder Fructose Malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood[11] and depression.[12]
In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. Binding of this repressor to the tryptophan operon prevents transcription of downstream DNA that codes for the enzymes involved in the biosynthesis of tryptophan. So high levels of tryptophan prevent tryptophan synthesis through a negative feedback loop and, when the cell's tryptophan levels are reduced, transcription from the trp operon resumes. The genetic organisation of the trp operon thus permits tightly regulated and rapid responses to changes in the cell's internal and external tryptophan levels.
# Dietary sources
Tryptophan is a routine constituent of most protein-based foods or dietary proteins. It is particularly plentiful in chocolate, oats, bananas, mangoes, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, sunflower seeds, pumpkin seeds, spirulina, and peanuts.[13] It is also found in turkey at a level typical of poultry in general.[14]
## Use as a dietary supplement
For some time, tryptophan was available in health food stores as a dietary supplement, although it is common in dietary protein. Many people found tryptophan to be a safe and reasonably effective sleep aid, probably due to its ability to increase brain levels of serotonin (a calming neurotransmitter when present in moderate levels)[16] and/or melatonin (a sleep-inducing hormone secreted by the pineal gland in response to darkness or low light levels).[17][18]
Clinical research tends to confirm tryptophan's effectiveness as a sleep aid[19][20][21] and for a growing variety of other conditions typically associated with low serotonin levels or activity in the brain[22] such as premenstrual dysphoric disorder
[23] and seasonal affective disorder.[24][25] In particular, tryptophan has been showing considerable promise as an antidepressant alone,[26] and as an "augmenter" of antidepressant drugs.[26][27] However, the reliability of these clinical trials has been questioned.[28][29]
## Metabolites
5-Hydroxytryptophan (5-HTP), a metabolite of tryptophan, has been suggested as a treatment for epilepsy[30] and depression, although clinical trials are regarded inconclusive and lacking.[31]
5-HTP readily crosses the blood-brain barrier and in addition is rapidly decarboxylated to serotonin (5-hydroxytryptamine or 5-HT)[32] and therefore may be useful for the treatment of depression. However serotonin has a relatively short half-life since it is rapidly metabolized by monoamine oxidase, and therefore is likely to have limited efficacy. It is marketed in Europe for depression and other indications under the brand names Cincofarm and Tript-OH.
In the United States, 5-HTP does not require a prescription, as it is covered under the Dietary Supplement Act. However, since the quality of dietary supplements is not regulated by the FDA, the quality of dietary and nutritional supplements tends to vary, and there is no guarantee that the label accurately depicts what the bottle contains.
## Tryptophan supplements and EMS
Although currently available for purchase, in 1989 a large outbreak (1500 cases of permanent disability including at least 37 deaths) of a disabling autoimmune illness called eosinophilia-myalgia syndrome (EMS) was traced by some epidemiological studies[33][34][35] to L-tryptophan supplied by a Japanese manufacturer, Showa Denko KK.[36] It was further hypothesized that one or more trace impurities produced during the manufacture of tryptophan may have been responsible for the EMS outbreak.[37][38] However, many people who consumed Showa Denko L-tryptophan did not develop EMS and cases of EMS have occurred prior to and after the 1989 epidemic. Furthermore the methodology used in the initial epidemiological studies has been criticized.[39][40] An alternative explanation for the 1989 EMS outbreak is that large doses of tryptophan produce metabolites which inhibit the normal degradation of histamine and excess histamine in turn has been proposed to cause EMS.[41]
Most tryptophan was banned from sale in the US in 1991, and other countries followed suit. Tryptophan from one manufacturer, of six, continued to be sold for manufacture of baby formulas. A Rutgers Law Journal article observed, "Political pressures have played a role in the FDA's decision to ban L-tryptophan as well as its desire to increase its regulatory power over dietary supplements."[42]
At the time of the ban, the FDA did not know, or did not indicate, that EMS was caused by a contaminated batch,[43][44] and yet, even when the contamination was discovered and the purification process fixed, the FDA maintained that L-tryptophan was unsafe. In February 2001, the FDA loosened the restrictions on marketing (though not on importation), but still expressed the following concern:
Since 2002, L-tryptophan has been sold in the U.S. in its original form. Several high-quality sources of L-tryptophan do exist, and are sold in many of the largest health food stores nationwide. Indeed, tryptophan has continued to be used in clinical and experimental studies employing human patients and subjects.
In recent years in the U.S., compounding pharmacies and some mail-order supplement retailers have begun selling tryptophan to the general public. Tryptophan has also remained on the market as a prescription drug (Tryptan), which some psychiatrists continue to prescribe, particularly as an augmenting agent for people who are unresponsive to antidepressant drugs.
## Turkey meat and drowsiness
One widely-held belief is that heavy consumption of turkey meat (as for example in a Thanksgiving feast) results in drowsiness, which has been attributed to high levels of tryptophan contained in turkey.[45][46][47] While turkey does contain high levels of tryptophan, the amount is comparable to that contained in most other meats.[14] Furthermore, postprandial Thanksgiving sedation may have more to do with what is consumed along with the turkey, in particular carbohydrates, rather than the turkey itself.
It has been demonstrated in both animal models[48] and in humans[49][50][51] that ingestion of a meal rich in carbohydrates triggers release of insulin. Insulin in turn stimulates the uptake of large neutral branched-chain amino acids (LNAA) but not tryptophan (trp) into muscle, increasing the ratio of trp to LNAA in the blood stream. The resulting increased ratio of tryptophan to large neutral amino acids in the blood reduces competition with other amino acids for the large neutral amino acid transporter protein for uptake of tryptophan across the blood-brain barrier into the central nervous system (CNS).[52][53] Once inside the CNS, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway.[48][50] The resultant serotonin is further metabolised into melatonin by the pineal gland.[9] Hence, these data suggest that "feast-induced drowsiness," and in particular, the common American post-Thanksgiving dinner drowsiness, may be the result of a heavy meal rich in carbohydrates which, via an indirect mechanism, increases the production of sleep-promoting serotonin and melatonin in the brain.[48][49][50][51]
# Fluorescence
The fluorescence of a folded protein is a mixture of the fluorescence from individual aromatic residues. Most of the intrinsic fluorescence emissions of a folded protein are due to excitation of tryptophan residues, with some emissions due to tyrosine and phenylalanine. Typically, tryptophan has a wavelength of maximum absorption of 280 nm and an emission peak that is solvatochromic, ranging from ca. 300 to 350 nm depending in the polarity of the local environment [54] Hence, protein fluorescence may be used as a diagnostic of the conformational state of a protein.[55] Furthermore, tryptophan fluorescence is strongly influenced by the proximity of other residues (i.e., nearby protonated acidic groups such as Asp or Glu can cause quenching of Trp fluorescence). Also, energy transfer between tryptophan and the other fluorescent amino acids is possible, which would affect the analysis, especially in cases where the Förster approach is taken. In addition, tryptophan is a relatively rare amino acid; many proteins contain only one or a few tryptophan residues. Therefore, tryptophan fluorescence can be a very sensitive measurement of the conformational state of individual tryptophan residues. The advantage compared to extrinsic probes is that the protein itself is not changed. The use of intrinsic fluorescence for the study of protein conformation is in practice limited to cases with few (or perhaps only one) tryptophan residues, since each experiences a different local environment, which gives rise to different emission spectra. This could be avoided by the use of time-resolved fluorescence, but would not really make the analysis much easier. | https://www.wikidoc.org/index.php/L-Tryptophan_use | |
b36a3b4b30f0ee5a145e5cfb9cf64755977d8673 | wikidoc | L-selectin | L-selectin
L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups. It is cleaved by ADAM17.
SELL is a cell surface component that is a member of a family of adhesion/homing receptors that play important roles in lymphocyte-endothelial cell interactions. The molecule is composed of multiple domains: one homologous to lectins, one to epidermal growth factor, and two to the consensus repeat units found in C3/C4-binding proteins.
# Ligands
- GlyCAM-1, found in the high endothelial venules of the lymph nodes.
- CD34, found on endothelial cells.
- MadCAM-1, found on endothelial cells of gut-associated lymphoid tissue.
- PSGL-1, binds with low affinity.
# Function
L-selectin acts as a "homing receptor" for lymphocytes to enter secondary lymphoid tissues via high endothelial venules. Ligands present on endothelial cells will bind to lymphocytes expressing L-selectin, slowing lymphocyte trafficking through the blood, and facilitating entry into a secondary lymphoid organ at that point. The receptor is commonly found on the cell surfaces of T cells. Naive T-lymphocytes, which have not yet encountered their specific antigen, need to enter secondary lymph nodes to encounter their antigen. Central memory T-lymphocytes, which have encountered antigen, express L-selectin to localize in secondary lymphoid organs. Here they reside ready to proliferate upon re-encountering antigen. Effector memory T-lymphocytes do not express L-selectin, as they circulate in the periphery and have immediate effector functions upon encountering antigen.
High expression of L-selectin on human bone marrow progenitor cells is an early sign of cells becoming committed to lymphoid differentiation.
L-selectin is also present on the surface of human embryo trophoblasts prior to implantation into the uterus. Similar to its function in lymphocytes, L-selectin acts as a receptor to facilitate adhesion of the embryo to the site of invasion on the surface epithelium of the uterine endometrium. The embryo secretes human chorionic gonadotropin (hCG), which downregulates anti-adhesion factor, MUC-1, located on the uterine epithelium at the site of invasion. Removal of MUC-1 exposes the oligosaccharide ligands of the uterine epithelium, thus allowing binding by the L-selectin receptor of the trophopblast cell, followed by embryo adhesion and invasion. | L-selectin
L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups. It is cleaved by ADAM17.
SELL is a cell surface component that is a member of a family of adhesion/homing receptors that play important roles in lymphocyte-endothelial cell interactions. The molecule is composed of multiple domains: one homologous to lectins, one to epidermal growth factor, and two to the consensus repeat units found in C3/C4-binding proteins.[1]
# Ligands
- GlyCAM-1, found in the high endothelial venules of the lymph nodes.
- CD34, found on endothelial cells.
- MadCAM-1, found on endothelial cells of gut-associated lymphoid tissue.
- PSGL-1, binds with low affinity.
# Function
L-selectin acts as a "homing receptor" for lymphocytes to enter secondary lymphoid tissues via high endothelial venules. Ligands present on endothelial cells will bind to lymphocytes expressing L-selectin, slowing lymphocyte trafficking through the blood, and facilitating entry into a secondary lymphoid organ at that point.[2] The receptor is commonly found on the cell surfaces of T cells. Naive T-lymphocytes, which have not yet encountered their specific antigen, need to enter secondary lymph nodes to encounter their antigen. Central memory T-lymphocytes, which have encountered antigen, express L-selectin to localize in secondary lymphoid organs. Here they reside ready to proliferate upon re-encountering antigen. Effector memory T-lymphocytes do not express L-selectin, as they circulate in the periphery and have immediate effector functions upon encountering antigen.
High expression of L-selectin on human bone marrow progenitor cells is an early sign of cells becoming committed to lymphoid differentiation.[3]
L-selectin is also present on the surface of human embryo trophoblasts prior to implantation into the uterus. Similar to its function in lymphocytes, L-selectin acts as a receptor to facilitate adhesion of the embryo to the site of invasion on the surface epithelium of the uterine endometrium. The embryo secretes human chorionic gonadotropin (hCG), which downregulates anti-adhesion factor, MUC-1, located on the uterine epithelium at the site of invasion. Removal of MUC-1 exposes the oligosaccharide ligands of the uterine epithelium, thus allowing binding by the L-selectin receptor of the trophopblast cell, followed by embryo adhesion and invasion.[4] | https://www.wikidoc.org/index.php/L-selectin | |
7f2397589d04bc7f5de645290abd89bde578837a | wikidoc | LCP theory | LCP theory
In chemistry, ligand close packing theory (LCP theory), sometimes called the ligand close packing model describes how ligand – ligand repulsions affect the geometry around a central atom. It has been developed by R.J Gillespie and others from 1997 onwards and is said to sit alongside VSEPR which was originally developed by R.J Gillespie and R Nyholm. The inter-ligand distances in a wide range of molecules have been determined. The example below shows a series of related molecules:
The consistency of the interligand distances (F-F and O-F) in the above molecules is striking and this phenomenon is repeated across a wide range of molecules and forms the basis for LCP theory.
# Ligand radius
From a study of known structural data a series of inter-ligand distances has been determined and it has been found that there is a constant inter-ligand radius for a given central atom. The table below shows the inter-ligand radius (pm) for some of the period 2 elements:
The ligand radius should not be confused with the ionic radius.
# Treatment of lone pairs
In LCP theory a lone pair is treated as a ligand. Gillespie terms the lone pair a lone pair domain and states that these lone pair domains push the ligands together until they reach the interligand distance predicted by the relevant inter-ligand radii. An example demonstrating this is shown below, where the F-F distance is the same in the AF3 and AF4+ species :
# LCP and VSEPR
LCP and VSEPR make very similar predictions as to geometry but LCP theory has the advantage that predictions are more quantitative particularly for the second period elements, Be, B, C, N, O, F. Ligand -ligand repulsions are important when
- the central atom is small e.g. period 2, (Be, B, C, N, O)
- the ligands are only weakly electronegative compared to the central atom
- the ligands are large compared to the central atom
- there are 5 or more ligands around the central atom | LCP theory
In chemistry, ligand close packing theory (LCP theory), sometimes called the ligand close packing model describes how ligand – ligand repulsions affect the geometry around a central atom[1]. It has been developed by R.J Gillespie and others from 1997 onwards [2] and is said to sit alongside VSEPR[1] which was originally developed by R.J Gillespie and R Nyholm[3]. The inter-ligand distances in a wide range of molecules have been determined. The example below shows a series of related molecules[4]:
The consistency of the interligand distances (F-F and O-F) in the above molecules is striking and this phenomenon is repeated across a wide range of molecules and forms the basis for LCP theory.
## Ligand radius
From a study of known structural data a series of inter-ligand distances has been determined[1] and it has been found that there is a constant inter-ligand radius for a given central atom. The table below shows the inter-ligand radius (pm) for some of the period 2 elements:
The ligand radius should not be confused with the ionic radius.
## Treatment of lone pairs
In LCP theory a lone pair is treated as a ligand. Gillespie terms the lone pair a lone pair domain and states that these lone pair domains push the ligands together until they reach the interligand distance predicted by the relevant inter-ligand radii[1]. An example demonstrating this is shown below, where the F-F distance is the same in the AF3 and AF4+ species :
## LCP and VSEPR
LCP and VSEPR make very similar predictions as to geometry but LCP theory has the advantage that predictions are more quantitative particularly for the second period elements, Be, B, C, N, O, F. Ligand -ligand repulsions are important when[1]
- the central atom is small e.g. period 2, (Be, B, C, N, O)
- the ligands are only weakly electronegative compared to the central atom
- the ligands are large compared to the central atom
- there are 5 or more ligands around the central atom | https://www.wikidoc.org/index.php/LCP_theory | |
f1bd1329c9a49aade70670b5e43ef38b01b71c59 | wikidoc | White coat | White coat
A white coat or laboratory coat (abbreviated lab coat) is a knee-length overcoat/smock worn by professionals in the medical field or by those involved in laboratory work to protect their street clothes. The garment is made from white cotton or linen to allow it to be washed at high temperature and make it easy to see if it is clean. Similar coats are a symbol of learning in Argentina, where they are worn by students.
When used in the laboratory, they protect against accidental spills, e.g. acids. In this case they have to have long sleeves and be made of an absorbent material, such as cotton, so that the user can be protected from the chemical. Some lab coats have buttons at the end of the sleeves, to secure them around the wrist so that they do not hang into beakers of chemicals.
Like the word "suit", the phrase, "white coat", is sometimes used to denote the wearer, i.e. the scientific personnel in a biotechnology or chemical company.
# White coats in medicine
White coats are sometimes seen as the distinctive dress of physicians, who have worn them for over 100 years. Recently, white coat ceremonies have become popular amongst those starting medical school.
The white coat was introduced to medicine in Canada by Dr. George Armstrong (1855-1933) who was a surgeon at the Montreal General Hospital and President of the Canadian Medical Association.
Some doctors in institutions such as the Mayo Clinic are instructed to wear business attire, to convey professionalism, as the clinic dislikes the message that white coats represent to the patient.
## Patient preference
A systematic review found "patients often prefer formal physician attire, perceptions of attire are influenced by age, locale, setting and context of care".
A subsequent study found similar results (see chart and photos).
An earlier study found that the majority of patients prefer their doctors to wear white coats, but the majority of doctors prefer other clothing, such as scrubs The study found that psychiatrists were among the least likely to wear white coats, perhaps in part due to the stereotyping that the pop culture phrase suggests. Some medical doctors view the coats as hot and uncomfortable, and many feel that they spread infection.
Ties may have higher bacterial counts. However, the clinical consequences are uncertain.
Other studies of physician appearance suggest that physicians should display open posture.
## White coat hypertension
Some patients who have their blood pressure measured in a clinical setting have higher readings than they do when measured in a home setting. This is sometimes called "white coat hypertension", in reference to the traditional white coats worn in a clinical setting, though the coats themselves may have nothing to do with the elevated readings.
## In psychiatry
The term is also used as verbal shorthand for psychiatric orderlies or other personnel and may be used, in a usually jocular manner, to imply someone's lunacy. In the 1966 song, They're Coming to Take Me Away Ha-Haaa!, Napoleon XIV fictionalized the public's view of the symbolic relationship between such institutions and white coats in the following lyrics:
They're coming to take me away ho ho hee hee ha haaa!
To the funny farm,
Where life is beautiful all the time.
And I'll be happy to see those nice young men
In their clean white coats,
And they're coming to take me away ha haaa!
## White versus black
Until the mid 1920's, students who were examining cadavers would wear black lab coats to show respect for the dead. Black lab coats were used in early biomedical and microbiology laboratories because any dust (i.e. contamination) that settled on them was easily visible.
## White coat ceremony
A white coat ceremony (WCC) is a relatively new ritual that marks one's entrance into medical school and, more recently, into a number of related health-related schools and professions. It originated in Columbia University's College of Physicians and Surgeons in 1993 and involves a formal "robing" or "cloaking" in white lab coats.
# Biology
In industries and institutions related to biology, white and green coats are used. Typically, white coats are used in laboratory work.
# Argentina
In Argentina white coats which resemble lab coats are worn by students and teachers of most public primary schools as a daily uniform. | White coat
A white coat or laboratory coat (abbreviated lab coat) is a knee-length overcoat/smock worn by professionals in the medical field or by those involved in laboratory work to protect their street clothes. The garment is made from white cotton or linen to allow it to be washed at high temperature and make it easy to see if it is clean. Similar coats are a symbol of learning in Argentina, where they are worn by students.
When used in the laboratory, they protect against accidental spills, e.g. acids. In this case they have to have long sleeves and be made of an absorbent material, such as cotton, so that the user can be protected from the chemical. Some lab coats have buttons at the end of the sleeves, to secure them around the wrist so that they do not hang into beakers of chemicals.
Like the word "suit", the phrase, "white coat", is sometimes used to denote the wearer, i.e. the scientific personnel in a biotechnology or chemical company.
# White coats in medicine
White coats are sometimes seen as the distinctive dress of physicians, who have worn them for over 100 years.[1] Recently, white coat ceremonies have become popular amongst those starting medical school.
The white coat was introduced to medicine in Canada by Dr. George Armstrong (1855-1933) who was a surgeon at the Montreal General Hospital and President of the Canadian Medical Association.
Some doctors in institutions such as the Mayo Clinic are instructed to wear business attire, to convey professionalism, as the clinic dislikes the message that white coats represent to the patient.[2]
## Patient preference
A systematic review found "patients often prefer formal physician attire, perceptions of attire are influenced by age, locale, setting and context of care"[3].
A subsequent study found similar results (see chart and photos)[4].
An earlier study found that the majority of patients prefer their doctors to wear white coats, but the majority of doctors prefer other clothing, such as scrubs[5] The study found that psychiatrists were among the least likely to wear white coats, perhaps in part due to the stereotyping that the pop culture phrase suggests. Some medical doctors view the coats as hot and uncomfortable, and many feel that they spread infection.[5]
Ties may have higher bacterial counts[6]. However, the clinical consequences are uncertain[7].
Other studies of physician appearance suggest that physicians should display open posture[8].
## White coat hypertension
Some patients who have their blood pressure measured in a clinical setting have higher readings than they do when measured in a home setting. This is sometimes called "white coat hypertension", in reference to the traditional white coats worn in a clinical setting, though the coats themselves may have nothing to do with the elevated readings.[9]
## In psychiatry
The term is also used as verbal shorthand for psychiatric orderlies or other personnel and may be used, in a usually jocular manner, to imply someone's lunacy. In the 1966 song, They're Coming to Take Me Away Ha-Haaa!, Napoleon XIV fictionalized the public's view of the symbolic relationship between such institutions and white coats in the following lyrics:
They're coming to take me away ho ho hee hee ha haaa!
To the funny farm,
Where life is beautiful all the time.
And I'll be happy to see those nice young men
In their clean white coats,
And they're coming to take me away ha haaa!
## White versus black
Until the mid 1920's, students who were examining cadavers would wear black lab coats to show respect for the dead. Black lab coats were used in early biomedical and microbiology laboratories because any dust (i.e. contamination) that settled on them was easily visible.
## White coat ceremony
A white coat ceremony (WCC) is a relatively new ritual that marks one's entrance into medical school and, more recently, into a number of related health-related schools and professions. It originated in Columbia University's College of Physicians and Surgeons in 1993[10] and involves a formal "robing" or "cloaking" in white lab coats.
# Biology
In industries and institutions related to biology, white and green coats are used. Typically, white coats are used in laboratory work.[citation needed]
# Argentina
In Argentina white coats which resemble lab coats are worn by students and teachers of most public primary schools as a daily uniform. | https://www.wikidoc.org/index.php/Lab_coat | |
4f74bf338a61a450c23642cf3aba7e478c7dc0bf | wikidoc | Laboratory | Laboratory
A laboratory is a construct you create so as to produce reproducible measurements.
# Theoretical laboratory
Def. "a room, building or institution equipped for scientific research, experimentation or analysis" is called a laboratory.
# Conditions
Laboratory conditions are often expressed in terms of standard temperature and pressure.
Standard condition for temperature and pressure are standard sets of conditions for experimental measurements established to allow comparisons to be made between different sets of data. The most used standards are those of the International Union of Pure and Applied Chemistry (IUPAC) and the National Institute of Standards and Technology (NIST), although these are not universally accepted standards. Other organizations have established a variety of alternative definitions for their standard reference conditions.
In chemistry, IUPAC established standard temperature and pressure (informally abbreviated as STP) as a temperature of 273.15 K (0 °C, 32 °F) and an absolute pressure of 100 kPa (14.504 psi, 0.986 atm, 1 bar), An unofficial, but commonly used standard is standard ambient temperature and pressure (SATP) as a temperature of 298.15 K (25 °C, 77 °F) and an absolute pressure of 100 kPa (14.504 psi, 0.986 atm). The STP and the SATP should not be confused with the standard state commonly used in thermodynamic evaluations of the Gibbs free energy of a reaction.
"Standard conditions for gases: Temperature, 273.15 K and pressure of 105 pascals. The previous standard absolute pressure of 1 atm (equivalent to 1.01325 × 105 Pa) was changed to 100 kPa in 1982. IUPAC recommends that the former pressure should be discontinued."
NIST uses a temperature of 20 °C (293.15 K, 68 °F) and an absolute pressure of 101.325 kPa (14.696 psi, 1 atm). The International Standard Metric Conditions for natural gas and similar fluids are 288.15 K (59.00 °F, 15.00 °C) and 101.325 kPa.
# Measurements
Def. any act of quantifying relative to a standard is called a measurement.
# Machine shops
"Our objective is to design, build, and maintain the highest quality research and teaching instruments, while always keeping finished cost to a minimum and safety to a maximum."
"I asked him where he had it made, he said he made it himself, & when I asked him where he got his tools said he made them himself & laughing added if I had staid for other people to make my tools & things for me... I had never made any thing..."
# Hypotheses
- A laboratory can be set up in virtual space to test reality for reproducibility. | Laboratory
Editor-In-Chief: Henry A. Hoff
A laboratory is a construct you create so as to produce reproducible measurements.
# Theoretical laboratory
Def. "a room, building or institution equipped for scientific research, experimentation or analysis"[1] is called a laboratory.
# Conditions
Laboratory conditions are often expressed in terms of standard temperature and pressure.
Standard condition for temperature and pressure are standard sets of conditions for experimental measurements established to allow comparisons to be made between different sets of data. The most used standards are those of the International Union of Pure and Applied Chemistry (IUPAC) and the National Institute of Standards and Technology (NIST), although these are not universally accepted standards. Other organizations have established a variety of alternative definitions for their standard reference conditions.
In chemistry, IUPAC established standard temperature and pressure (informally abbreviated as STP) as a temperature of 273.15 K (0 °C, 32 °F) and an absolute pressure of 100 kPa (14.504 psi, 0.986 atm, 1 bar),[2] An unofficial, but commonly used standard is standard ambient temperature and pressure (SATP) as a temperature of 298.15 K (25 °C, 77 °F) and an absolute pressure of 100 kPa (14.504 psi, 0.986 atm). The STP and the SATP should not be confused with the standard state commonly used in thermodynamic evaluations of the Gibbs free energy of a reaction.
"Standard conditions for gases: Temperature, 273.15 K [...] and pressure of 105 pascals. The previous standard absolute pressure of 1 atm (equivalent to 1.01325 × 105 Pa) was changed to 100 kPa in 1982. IUPAC recommends that the former pressure should be discontinued."[2]
NIST uses a temperature of 20 °C (293.15 K, 68 °F) and an absolute pressure of 101.325 kPa (14.696 psi, 1 atm). The International Standard Metric Conditions for natural gas and similar fluids are 288.15 K (59.00 °F, 15.00 °C) and 101.325 kPa.[3]
# Measurements
Def. any act of quantifying relative to a standard is called a measurement.
# Machine shops
"Our objective is to design, build, and maintain the highest quality research and teaching instruments, while always keeping finished cost to a minimum and safety to a maximum."[4]
"I asked him where he had it made, he said he made it himself, & when I asked him where he got his tools said he made them himself & laughing added if I had staid for other people to make my tools & things for me... I had never made any thing..."[5]
# Hypotheses
- A laboratory can be set up in virtual space to test reality for reproducibility. | https://www.wikidoc.org/index.php/Laboratory | |
61af906267cb35de404bf921ed5f5bf5e2c4db5c | wikidoc | Lacosamide | Lacosamide
# 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
Lacosamide is an anticonvulsant that is FDA approved for the treatment of partial-onset seizures. Common adverse reactions include diplopia, headache, dizziness, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Partial seizures
Monotherapy
- Initial: 100 mg twice daily (200 mg per day)
- Every week, dose should be increased by 50 mg twice daily (100 mg per day),up to a recommended maintenance dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day).
- Alternatively, lacosamide may be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by 100 mg twice daily (200 mg per day); this dose regimen should be continued for one week.
- Based on individual response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day), as needed, up to the recommended maintenance dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day).
- The loading dose should be administered with medical supervision because of the increased incidence of CNS adverse reactions.
- For patients who are already on a single antiepileptic and will convert to lacosamide monotherapy, the therapeutic dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day) should be maintained for at least 3 days before initiating withdrawal of the concomitant antiepileptic drug.
- A gradual withdrawal of the concomitant antiepileptic drug over at least 6 weeks is recommended.
- The initial recommended dose is 50 mg twice daily (100 mg per day). Based on individual patient response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day).
- The recommended maintenance dose is 100 mg twice daily to 200 mg twice daily (200 mg to 400 mg per day).
- In clinical trials, the 300 mg twice daily (600 mg per day) dose was not more effective than the 200 mg twice daily dose (400 mg per day), but was associated with a substantially higher rate of adverse reactions.
- Alternatively, lacosamide may be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice daily (200 mg per day); this maintenance dose regimen should be continued for one week.
- Based on individual patient response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day), as needed, up to the maximum recommended maintenance dose of 200 mg twice daily (400 mg per day).
- The loading dose should be administered with medical supervision because of the increased incidence of CNS adverse reactions.
When discontinuing lacosamide, a gradual withdrawal over at least 1 week is recommended.
- Intravenous lacosamide can be administered in the same dosing regimens described for oral dosing, including the loading dose.
- Dosages may be infused intravenously over a period of 15 minutes to 60 minutes.
- Intravenous infusion of 30 to 60 minutes is preferable, and should be used when a 15 minute administration is not required.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lacosamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lacosamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lacosamide 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 Lacosamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lacosamide in pediatric patients.
# Contraindications
- None
# Warnings
### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including lacosamide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
- In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
- There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
- The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
- The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.
- Anyone considering prescribing lacosamide or any other AED must balance this risk with the risk of untreated illness.
- Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
- Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
- Behaviors of concern should be reported immediately to healthcare providers.
### Dizziness and Ataxia
- Lacosamide may cause dizziness and ataxia.
- In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%).
- Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared to 2% of placebo patients).
- The onset of dizziness and ataxia was most commonly observed during titration.
- There was a substantial increase in these adverse events at doses higher than 400 mg/day.
### Cardiac Rhythm and Conduction Abnormalities
- Dose-dependent prolongations in PR interval with lacosamide have been observed in clinical studies in patients and in healthy volunteers.
- In adjunctive clinical trials in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive lacosamide and 0% (0/364) of patients randomized to receive placebo.
- In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving lacosamide and 0% (0/291) of patients receiving placebo.
- Second degree and complete AV block have been reported in patients in pain studies and in patients with seizures.
- When lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.
- Lacosamide should be used with caution in patients with known conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), sodium channelopathies (e.g., Brugada Syndrome), on concomitant medications that prolong PR interval, or with severe cardiac disease such as myocardial ischemia or heart failure, or structural heart disease.
- In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state maintenance dose, is recommended.
- In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route.
- One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg lacosamide.
- There were two postmarketing reports of third degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended.
### Atrial fibrillation and Atrial flutter
- In the short-term investigational trials of lacosamide in epilepsy patients, there were no cases of atrial fibrillation or flutter.
- Both atrial fibrillation and atrial flutter have been reported in open label epilepsy trials and in postmarketing experience.
- In patients with diabetic neuropathy, 0.5% of patients treated with lacosamide experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients.
- Lacosamide administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
### Syncope
- In the short-term controlled trials of lacosamide in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo.
- In the short-term controlled trials of lacosamide in patients with diabetic neuropathy, 1.2% of patients who were treated with lacosamide reported an adverse reaction of syncope or loss of consciousness, compared to 0% of placebo-treated patients with diabetic neuropathy.
- Most of the cases of syncope were observed in patients receiving doses above 400 mg/day.
- The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.
- Cases of syncope have also been observed in open-label clinical epilepsy studies.
- These cases were associated with a history of risk factors for cardiac disease and the use of drugs that slow AV conduction.
### Withdrawal of Antiepileptic Drugs (AEDs)
- As with all AEDs, lacosamide should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.
### Multiorgan Hypersensitivity Reactions
- One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to lacosamide during clinical development.
- The event occurred in a healthy volunteer, 10 days after stopping lacosamide treatment.
- The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out.
- The subject fully recovered within a month, without specific treatment.
- The case is consistent with a delayed multiorgan hypersensitivity reaction. *Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.
- Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS) have been reported with other antiepileptics and typically, although not exclusively, present with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur.
- If this reaction is suspected, lacosamide should be discontinued and alternative treatment started.
### Phenylketonurics
- Lacosamide oral solution contains aspartame, a source of phenylalanine.
- A 200 mg dose of lacosamide oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.
# 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.
- In the premarketing development of adjunctive therapy for partial onset seizures, 1327 patients received lacosamide in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months.
- The monotherapy development program included 425 patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.
### Lacosamide Tablet and Oral solution
- In the monotherapy trial, 16% of patients randomized to receive lacosamide at the recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse event.
- The adverse reaction most commonly (≥1% on lacosamide) leading to discontinuation was dizziness.
- Adverse reactions observed in this study were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies.
- One adverse reaction, insomnia, was observed at a rate of ≥2% and was not reported at a similar rate in previous studies.
- This adverse reaction has also been observed in postmarketing experience. Because this study did not include a placebo control group, causality could not be established.
- Dizziness, headache, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase.
- In adjunctive therapy controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and 17% in patients randomized to receive lacosamide at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo.
- The adverse events most commonly (>1% on lacosamide and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.
Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult patients with partial-onset seizures in the lacosamide total group and for which the incidence was greater than placebo.
- The majority of adverse events in the lacosamide patients were reported with a maximum intensity of 'mild' or 'moderate'.
- The overall adverse event rate was similar in male and female patients. *Although there were few non-Caucasian patients, no differences in the incidences of adverse events compared to Caucasian patients were observed.
### Laboratory Abnormalities
- Abnormalities in liver function tests have been observed in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs.
- Elevations of ALT to ≥3× ULN occurred in 0.7% (7/935) of lacosamide patients and 0% (0/356) of placebo patients.
- One case of hepatitis with transaminases >20× ULN was observed in one healthy subject 10 days after lacosamide treatment completion, along with nephritis (proteinuria and urine casts).
- Serologic studies were negative for viral hepatitis.
- Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirubin was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to lacosamide.
### Other Adverse Reactions
- The following is a list of treatment-emergent adverse reactions reported by patients treated with lacosamide in all clinical trials in patients with partial-onset seizures, including controlled trials and long-term open-label extension trials.
- Events addressed in other tables or sections are not listed here. Events included in this list from the controlled trials occurred more frequently on drug than on placebo and were based on consideration of lacosamide pharmacology, frequency above that expected in the population, seriousness, and likelihood of a relationship to lacosamide. Events are further classified within system organ class.
- Neutropenia
- Anemia
- Palpitations
- Tinnitus
- Constipation
- Dyspepsia
- Dry mouth
- Oral hypoaesthesia
- Irritability
- Pyrexia
- Feeling drunk
- Fall
- Muscle spasms
- Paresthesia
- Cognitive disorder
- Hypoaesthesia
- Dysarthria
- Disturbance in attention
- Cerebellar syndrome
- Confusional state
- Mood altered
- Depressed mood
- Adverse reactions with intravenous administration generally were similar to those observed with the oral formulation, although intravenous administration was associated with local adverse events such as injection site pain or discomfort (2.5%), irritation (1%), and erythema (0.5%).
- One case of profound bradycardia (26 bpm: BP 100/60 mmHg) was observed in a patient during a 15-minute infusion of 150 mg lacosamide.
- This patient was on a beta-blocker.
- Infusion was discontinued and the patient experienced a rapid recovery.
- The safety of a 15-minute loading dose administration of lacosamide Injection 200 mg to 400 mg followed by oral administration of lacosamide given twice daily at the same total daily dose as the initial intravenous infusion was assessed in an open-label study in patients with partial onset seizures. *Patients had to have been maintained on a stable dose regimen of 1 to 2 marketed antiepileptics for at least 28 days prior to treatment assignment. Treatment groups were as follows:
- Single dose of intravenous lacosamide Injection 200 mg followed by oral lacosamide 200 mg/day (100 mg every 12 hours).
- Single dose of intravenous lacosamide Injection 300 mg followed by oral lacosamide 300 mg/day (150 mg every 12 hours)
- Single dose of intravenous lacosamide Injection 400 mg followed by oral lacosamide 400 mg/day (200 mg every 12 hours).
Table 3 gives the incidence of adverse events that occurred in ≥5% of adult patients in any lacosamide dosing group.
- Adverse events observed with infusion of lacosamide 200 mg over 15-minutes followed by lacosamide 100 mg administered orally twice day were similar in frequency to those observed in 3-month adjunctive therapy controlled trials. *Considering the difference in period of observations (1 week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15-minute administration of lacosamide Injection than with administration over a 30-to 60-minute period.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of lacosamide. 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.
- Agranulocytosis
- Aggression
- Agitation
- Hallucination
- Insomnia
- Psychotic disorder
- Angioedema
- Rash
- Urticaria
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
# Drug Interactions
### Pharmacokinetic Interactions
- Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between lacosamide and carbamazepine, valproate, digoxin, metformin, omeprazole, midazolam, oral contraceptives containing ethinylestradiol and levonorgestrel, or warfarin.
- There was no evidence for any relevant drug-drug interaction of lacosamide with the AEDs used most commonly in the placebo-controlled clinical trials in patients with partial-onset seizures.
- The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system.
### Strong CYP3A4 or CYP2C9 Inhibitors
- Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to lacosamide.
- Dose reduction may be necessary in these patients.
### Concomitant Medications that Prolong PR Interval
- Lacosamide should be used with caution in patients on concomitant medications that prolong PR interval, because of a risk of AV block or bradycardia, e.g., beta-blockers and calcium channel blockers.
- In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state, is recommended.
- In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy.
- Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy.
- These effects were observed at doses associated with clinically relevant plasma exposures.
- Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
- Potential related adverse effects on CNS development cannot be ruled out.
- There are no adequate and well-controlled studies in pregnant women. *Lacosamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any teratogenic effects. However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats. These doses were associated with maternal plasma lacosamide exposures ≈2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
- When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights were observed in the offspring at the highest dose. *The no-effect dose for pre- and post-natal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC approximately equal to that in humans at the MRHD.
- Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).
- The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development.
- The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lacosamide in women who are pregnant.
### Labor and Delivery
- The effects of lacosamide on labor and delivery in pregnant women are unknown. *In a pre- and post-natal study in rats, there was a tendency for prolonged gestation in all lacosamide treated groups at plasma exposures (AUC) at or below the plasma AUC in humans at the maximum recommended human dose of 400 mg/day.
### Nursing Mothers
- Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk.
- It is not known whether lacosamide is excreted in human milk. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue lacosamide, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of lacosamide in pediatric patients <17 years have not been established.
- Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
- Potential related adverse effects on CNS development cannot be ruled out. *Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).
- The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg/day.
### Geriatic Use
- There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately assess the effectiveness of lacosamide in this population.
- No lacosamide dose adjustment based on age is necessary.
- In elderly patients, dose titration should be performed with caution
### Gender
There is no FDA guidance on the use of Lacosamide with respect to specific gender populations.
### Race
- There are no clinically relevant differences in the pharmacokinetics of lacosamide between Asian, Black, and Caucasian subjects.
### Renal Impairment
- A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. *Lacosamide is effectively removed from plasma by hemodialysis.
- Dosage supplementation of up to 50% following hemodialysis should be considered.
- In all renally impaired patients, dose titration should be performed with caution.
### Hepatic Impairment
- Patients with mild to moderate hepatic impairment should be observed closely during dose titration.
- A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment.
- Lacosamide use is not recommended in patients with severe hepatic impairment. *Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lacosamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lacosamide in patients who are immunocompromised.
### CYP2C19 Polymorphism
There are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.
- Monitor closely patients with known cardiac conduction problems, on concomitant medications that prolong PR interval, or with severe cardiac disease
- Monitor patients for suicidal behavior and ideation
# IV Compatibility
Lacosamide injection can be administered intravenously without further dilution or may be mixed with diluents listed below. The diluted solution should not be stored for more than 4 hours at room temperature.
Diluents:
- Sodium Chloride Injection 0.9% (w/v)
- Dextrose Injection 5% (w/v)
- Lactated Ringer's Injection
- Product with particulate matter or discoloration should not be used.
- Any unused portion of lacosamide injection should be discarded.
# Overdosage
### Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans
- The types of adverse events experienced by patients exposed to supratherapeutic lacosamide doses during clinical trials were not clinically different from those of patients administered recommended doses of lacosamide.
- The highest reported accidental overdose of lacosamide during clinical development was 1200 mg/day which was non-fatal.
- There has been a single case of intentional overdose in a clinical trial by a patient who self-administered 12,000 mg lacosamide along with large doses of zonisamide, topiramate, and gabapentin.
- The patient presented in a coma with AV block and was hospitalized.
- An EEG revealed epileptic waveforms.
- The patient recovered 2 days later.
- In postmarketing experience, cardiac conduction disorders and fatal cardiac arrest were reported following an acute overdose of 7,000 mg of lacosamide in a patient with cardiovascular risk factors.
### Treatment or Management of Overdose
- There is no specific antidote for overdose with lacosamide.
- Standard decontamination procedures should be followed.
- General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient.
- A Certified Poison Control Center should be contacted for up to date information on the management of overdose with lacosamide.
- Standard hemodialysis procedures result in significant clearance of lacosamide (reduction of systemic exposure by 50% in 4 hours).
- Hemodialysis has not been performed in the few known cases of overdose, but may be indicated based on the patient's clinical state or in patients with significant renal impairment.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which lacosamide exerts its antiepileptic effects in humans remains to be fully elucidated.
- In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.
## Structure
The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC). Lacosamide is a functionalized amino acid. Its molecular formula is C13H18N2O3 and its molecular weight is 250.30. The chemical structure is:
## Pharmacodynamics
- A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. *Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.
### Cardiac Electrophysiology
- Electrocardiographic effects of lacosamide were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects.
- Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin).
- Lacosamide did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration.
- Lacosamide produced a small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax.
- The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximum increase in PR interval for a 400 mg/day lacosamide dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.
## Pharmacokinetics
- The pharmacokinetics of lacosamide have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment.
- Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. *The maximum lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours.
- Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration.
- Pharmacokinetics of lacosamide are dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability.
- Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours).
### Absorption and Bioavailability
- Lacosamide is completely absorbed after oral administration.
- The oral bioavailability of lacosamide tablets is approximately 100%.
- Food does not affect the rate and extent of absorption.
- After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC(0-tz) but not for Cmax.
- The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range.
- In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.
- A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice daily oral administration.
### Distribution
- The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water.
- Lacosamide is less than 15% bound to plasma proteins.
### Metabolism and Elimination
- Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation.
- After oral and intravenous administration of 100 mg -lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces.
- The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%).
- The plasma exposure of the major human metabolite, O-desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.
- The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19.
- The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.
- There is no enantiomeric interconversion of lacosamide.
### Special Populations
- Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.
- The AUC of lacosamide was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected.
- No dose adjustment is considered necessary in mildly and moderately renal impaired subjects.
- A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. *Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore dosage supplementation of up to 50% following hemodialysis should be considered.
- In all renally impaired patients, the dose titration should be performed with caution.
### Hepatic impairment
- Lacosamide undergoes metabolism.
- Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects).
- The dose titration should be performed with caution in patients with hepatic impairment.
- A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.
- Patients with mild to moderate hepatic impairment should be observed closely during dose titration.
- A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment.
- The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment.
- Lacosamide use is not recommended in patients with severe hepatic impairment.
- Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.
### Geriatric
- In the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18-64 years).
- This may be related to body weight and decreased renal function in elderly subjects.
- Dose reduction is not considered to be necessary.
### Pediatric Patients
- Pharmacokinetics of lacosamide have not been studied in pediatric patients.
### Gender
- Lacosamide clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of lacosamide.
### Race
- There are no clinically relevant differences in the pharmacokinetics of lacosamide between Asian, Black, and Caucasian subjects.
### CYP2C19 Polymorphism
- There are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. *Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.
### Drug interactions
- In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4.
- Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.
- In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.
- Lacosamide is a substrate of CYP3A4, CYP2C9, and CYP2C19.
- Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to lacosamide.
- Since <15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.
Effect of lacosamide on concomitant AEDs
- Lacosamide 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.
- The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of lacosamide at any dose.
Effect of concomitant AEDs on lacosamide
- Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of lacosamide in a healthy subject study.
- Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when lacosamide was coadministered with carbamazepine, phenobarbital or phenytoin.
Digoxin
- There was no effect of lacosamide (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.
Metformin
- There were no clinically relevant changes in metformin levels following coadministration of lacosamide (400 mg/day).
- Metformin (500 mg three times a day) had no effect on the pharmacokinetics of lacosamide (400 mg/day).
Omeprazole
- Omeprazole is a CYP2C19 substrate and inhibitor.
- There was no effect of lacosamide (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.
Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of lacosamide (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.
Midazolam
- Midazolam is a 3A4 substrate.
- There was no effect of lacosamide (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.
Oral Contraceptives
- There was no influence of lacosamide (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed.
Warfarin
- Co-administration of lacosamide (400 mg/day) with warfarin (25 mg single dose) did not result in a clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in a study in healthy male subjects.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- There was no evidence of drug related carcinogenicity in mice or rats.
- Mice and rats received lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
- Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay.
- Lacosamide induced a positive response in the in vitro mouse lymphoma assay.
- No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the MRHD.
# Clinical Studies
### Monotherapy in Patients with Partial Onset Seizures
- The efficacy of lacosamide in monotherapy was established in a historical-control, multicenter, randomized trial that included 425 patients, age 16 to 70 years, with partial-onset seizures (Study 1).
- To be included in Study 1, patients were required to be taking stable doses of 1 or 2 marketed antiepileptic drugs.
- This treatment continued into the 8 week baseline period.
- To remain in the study, patients were required to have at least 2 partial onset seizures per 28 days during the 8 week baseline period.
- The baseline period was followed by a 3 week titration period, during which lacosamide was added to the ongoing antiepileptic regimen.
- This was followed by a 16-week maintenance period (i.e., a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period).
- Patients were randomized 3 to 1 to receive lacosamide 400 mg/day or lacosamide 300 mg/day.
- Treatment assignments were blinded.
- Response to treatment was based upon a comparison of the number of patients who met exit criteria during the maintenance phase, compared to historical controls.
- The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug.
- Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving lacosamide remained below the lower 95% prediction limit of 65% derived from the historical control data.
- The exit criteria were one or more of the following:
- (1) Doubling of average monthly seizure frequency during any 28 consecutive days.
- (2) Doubling of highest consecutive 2-day seizure frequency.
- (3) Occurrence of a single generalized tonic-clonic seizure
- (4) Clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation.
- (5) Status epilepticus or new onset of serial/cluster seizures. The study population profile appeared comparable to that of the historical control population.
- For the lacosamide 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30% (95% CI: 25%, 36%).
- The upper limit of the 2-sided 95% CI (36%) was below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy. Lacosamide 300 mg/day also met the pre-specified criteria for efficacy.
### Adjunctive Therapy in Patients with Partial Onset Seizures
- The efficacy of lacosamide as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients (Study 2, Study 3, and Study 4).
- Enrolled patients had partial-onset seizures with or without secondary generalization, and were not adequately controlled with 1 to 3 concomitant AEDs.
- During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.
- Study 2 compared doses of lacosamide 200, 400, and 600 mg/day with placebo. *Study 3 compared doses of lacosamide 400 and 600 mg/day with placebo.
- Study 4 compared doses of lacosamide 200 and 400 mg/day with placebo.
- In all three trials, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of lacosamide 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the titration phase).
- During the titration phase, in all 3 adjunctive therapy trials, treatment was initiated at 100 mg/day (50 mg twice daily), and increased in weekly increments of 100 mg/day to the target dose.
- The titration phase lasted 6 weeks in Study 2 and Study 3, and 4 weeks in Study 4. In all three trials, the titration phase was followed by a maintenance phase that lasted 12 weeks, during which patients were to remain on a stable dose of lacosamide.
- A reduction in 28 day seizure frequency (baseline to maintenance phase), as compared to the placebo group, was the primary variable in all three adjunctive therapy trials.
- A statistically significant effect was observed with lacosamide treatment (Figure 1) at doses of 200 mg/day (Study 4), 400 mg/day (Studies 2, 3, and 4), and 600 mg/day (Studies 2 and 3).
- Subset evaluations of lacosamide demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).
# How Supplied
### Lacosamide Tablets 50 mg
- Are pink, oval, film-coated tablets debossed with "SP" on one side and "50" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2477-35
- Unit Dose Carton of 60 tablets NDC 0131-2477-60
### Lacosamide Tablets 100 mg
- Are dark yellow, oval, film-coated tablets debossed with "SP" on one side and "100" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2478-35
- Unit Dose Carton of 60 tablets NDC 0131-2478-60
### Lacosamide Tablets 150 mg
- Are salmon, oval, film-coated tablets debossed with "SP" on one side and "150" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2479-35
- Unit Dose Carton of 60 tablets NDC 0131-2479-60
### Lacosamide Tablets 200 mg
- Are blue, oval, film-coated tablets debossed with "SP" on one side and "200" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2480-35
- Unit Dose Carton of 60 tablets NDC 0131-2480-60
### Lacosamide injection 200 mg/20 m
- Is a clear, colorless sterile solution supplied in 20 mL colorless single-use glass vials.
- 200 mg/20 mL vial in cartons of 10 vials NDC 0131-1810-67
### Lacosamide oral solution 10 mg/mL
- Is a clear, colorless to yellow or yellow-brown, strawberry-flavored liquid. It is supplied in PET bottles as follows:
- 200 mL bottles NDC 0131-5410-71
- 465 mL bottles NDC 0131-5410-70
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
- Do not freeze lacosamide injection or oral solution. Discard any unused lacosamide oral solution remaining after seven (7) weeks of first opening the bottle.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
### Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be counseled that AEDs, including lacosamide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. *Behaviors of concern should be reported immediately to healthcare providers.
### Dizziness and Ataxia
- Patients should be counseled that lacosamide use may cause dizziness, double vision, abnormal coordination and balance, and somnolence. *Patients taking lacosamide should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with lacosamide.
### Cardiac Rhythm and Conduction Abnormalities
- Patients should be counseled that lacosamide is associated with electrocardiographic changes that may predispose to irregular beat and syncope, particularly in patients with underlying cardiovascular disease, with heart conduction problems or who are taking other medications that affect the heart.
- Patients who develop syncope should lay down with raised legs and contact their health care provider.
### Multiorgan Hypersensitivity Reactions
- Patients should be aware that lacosamide may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney. Lacosamide should be discontinued if a serious hypersensitivity reaction is suspected. *Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g. fatigue, jaundice, dark urine).
### Pregnancy Registry
- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during lacosamide therapy.
- Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant.
- This registry is collecting information about the safety of AEDs during pregnancy.
# Precautions with Alcohol
Alcohol-Lacosamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VIMPAT
# Look-Alike Drug Names
There is limited information regarding Lacosamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Lacosamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
# Disclaimer
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# Overview
Lacosamide is an anticonvulsant that is FDA approved for the treatment of partial-onset seizures. Common adverse reactions include diplopia, headache, dizziness, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Partial seizures
Monotherapy
- Initial: 100 mg twice daily (200 mg per day)
- Every week, dose should be increased by 50 mg twice daily (100 mg per day),up to a recommended maintenance dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day).
- Alternatively, lacosamide may be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by 100 mg twice daily (200 mg per day); this dose regimen should be continued for one week.
- Based on individual response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day), as needed, up to the recommended maintenance dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day).
- The loading dose should be administered with medical supervision because of the increased incidence of CNS adverse reactions.
- For patients who are already on a single antiepileptic and will convert to lacosamide monotherapy, the therapeutic dose of 150 mg twice daily to 200 mg twice daily (300 mg to 400 mg per day) should be maintained for at least 3 days before initiating withdrawal of the concomitant antiepileptic drug.
- A gradual withdrawal of the concomitant antiepileptic drug over at least 6 weeks is recommended.
- The initial recommended dose is 50 mg twice daily (100 mg per day). Based on individual patient response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day).
- The recommended maintenance dose is 100 mg twice daily to 200 mg twice daily (200 mg to 400 mg per day).
- In clinical trials, the 300 mg twice daily (600 mg per day) dose was not more effective than the 200 mg twice daily dose (400 mg per day), but was associated with a substantially higher rate of adverse reactions.
- Alternatively, lacosamide may be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice daily (200 mg per day); this maintenance dose regimen should be continued for one week.
- Based on individual patient response and tolerability, the dose can be increased at weekly intervals by 50 mg twice daily (100 mg per day), as needed, up to the maximum recommended maintenance dose of 200 mg twice daily (400 mg per day).
- The loading dose should be administered with medical supervision because of the increased incidence of CNS adverse reactions.
When discontinuing lacosamide, a gradual withdrawal over at least 1 week is recommended.
- Intravenous lacosamide can be administered in the same dosing regimens described for oral dosing, including the loading dose.
- Dosages may be infused intravenously over a period of 15 minutes to 60 minutes.
- Intravenous infusion of 30 to 60 minutes is preferable, and should be used when a 15 minute administration is not required.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lacosamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lacosamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lacosamide 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 Lacosamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lacosamide in pediatric patients.
# Contraindications
- None
# Warnings
### Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including lacosamide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
- In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
- There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
- The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
- The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar.
- Anyone considering prescribing lacosamide or any other AED must balance this risk with the risk of untreated illness.
- Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
- Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
- Behaviors of concern should be reported immediately to healthcare providers.
### Dizziness and Ataxia
- Lacosamide may cause dizziness and ataxia.
- In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%).
- Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of lacosamide (compared to 2% of placebo patients).
- The onset of dizziness and ataxia was most commonly observed during titration.
- There was a substantial increase in these adverse events at doses higher than 400 mg/day.
### Cardiac Rhythm and Conduction Abnormalities
- Dose-dependent prolongations in PR interval with lacosamide have been observed in clinical studies in patients and in healthy volunteers.
- In adjunctive clinical trials in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive lacosamide and 0% (0/364) of patients randomized to receive placebo.
- In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving lacosamide and 0% (0/291) of patients receiving placebo.
- Second degree and complete AV block have been reported in patients in pain studies and in patients with seizures.
- When lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.
- Lacosamide should be used with caution in patients with known conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), sodium channelopathies (e.g., Brugada Syndrome), on concomitant medications that prolong PR interval, or with severe cardiac disease such as myocardial ischemia or heart failure, or structural heart disease.
- In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state maintenance dose, is recommended.
- In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route.
- One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg lacosamide.
- There were two postmarketing reports of third degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended.
### Atrial fibrillation and Atrial flutter
- In the short-term investigational trials of lacosamide in epilepsy patients, there were no cases of atrial fibrillation or flutter.
- Both atrial fibrillation and atrial flutter have been reported in open label epilepsy trials and in postmarketing experience.
- In patients with diabetic neuropathy, 0.5% of patients treated with lacosamide experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients.
- Lacosamide administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
### Syncope
- In the short-term controlled trials of lacosamide in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo.
- In the short-term controlled trials of lacosamide in patients with diabetic neuropathy, 1.2% of patients who were treated with lacosamide reported an adverse reaction of syncope or loss of consciousness, compared to 0% of placebo-treated patients with diabetic neuropathy.
- Most of the cases of syncope were observed in patients receiving doses above 400 mg/day.
- The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.
- Cases of syncope have also been observed in open-label clinical epilepsy studies.
- These cases were associated with a history of risk factors for cardiac disease and the use of drugs that slow AV conduction.
### Withdrawal of Antiepileptic Drugs (AEDs)
- As with all AEDs, lacosamide should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.
### Multiorgan Hypersensitivity Reactions
- One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to lacosamide during clinical development.
- The event occurred in a healthy volunteer, 10 days after stopping lacosamide treatment.
- The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out.
- The subject fully recovered within a month, without specific treatment.
- The case is consistent with a delayed multiorgan hypersensitivity reaction. *Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.
- Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS) have been reported with other antiepileptics and typically, although not exclusively, present with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur.
- If this reaction is suspected, lacosamide should be discontinued and alternative treatment started.
### Phenylketonurics
- Lacosamide oral solution contains aspartame, a source of phenylalanine.
- A 200 mg dose of lacosamide oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.
# 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.
- In the premarketing development of adjunctive therapy for partial onset seizures, 1327 patients received lacosamide in controlled and uncontrolled trials, of whom 1000 were treated for longer than 6 months, and 852 for longer than 12 months.
- The monotherapy development program included 425 patients, 310 of whom were treated for longer than 6 months, and 254 for longer than 12 months.
### Lacosamide Tablet and Oral solution
- In the monotherapy trial, 16% of patients randomized to receive lacosamide at the recommended doses of 300 and 400 mg/day discontinued from the trial as a result of an adverse event.
- The adverse reaction most commonly (≥1% on lacosamide) leading to discontinuation was dizziness.
- Adverse reactions observed in this study were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies.
- One adverse reaction, insomnia, was observed at a rate of ≥2% and was not reported at a similar rate in previous studies.
- This adverse reaction has also been observed in postmarketing experience. Because this study did not include a placebo control group, causality could not be established.
- Dizziness, headache, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase, compared with the Titration Phase.
- In adjunctive therapy controlled clinical trials, the rate of discontinuation as a result of an adverse event was 8% and 17% in patients randomized to receive lacosamide at the recommended doses of 200 and 400 mg/day, respectively, 29% at 600 mg/day, and 5% in patients randomized to receive placebo.
- The adverse events most commonly (>1% on lacosamide and greater than placebo) leading to discontinuation were dizziness, ataxia, vomiting, diplopia, nausea, vertigo, and vision blurred.
Table 2 gives the incidence of treatment-emergent adverse events that occurred in ≥2% of adult patients with partial-onset seizures in the lacosamide total group and for which the incidence was greater than placebo.
- The majority of adverse events in the lacosamide patients were reported with a maximum intensity of 'mild' or 'moderate'.
- The overall adverse event rate was similar in male and female patients. *Although there were few non-Caucasian patients, no differences in the incidences of adverse events compared to Caucasian patients were observed.
### Laboratory Abnormalities
- Abnormalities in liver function tests have been observed in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs.
- Elevations of ALT to ≥3× ULN occurred in 0.7% (7/935) of lacosamide patients and 0% (0/356) of placebo patients.
- One case of hepatitis with transaminases >20× ULN was observed in one healthy subject 10 days after lacosamide treatment completion, along with nephritis (proteinuria and urine casts).
- Serologic studies were negative for viral hepatitis.
- Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirubin was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to lacosamide.
### Other Adverse Reactions
- The following is a list of treatment-emergent adverse reactions reported by patients treated with lacosamide in all clinical trials in patients with partial-onset seizures, including controlled trials and long-term open-label extension trials.
- Events addressed in other tables or sections are not listed here. Events included in this list from the controlled trials occurred more frequently on drug than on placebo and were based on consideration of lacosamide pharmacology, frequency above that expected in the population, seriousness, and likelihood of a relationship to lacosamide. Events are further classified within system organ class.
- Neutropenia
- Anemia
- Palpitations
- Tinnitus
- Constipation
- Dyspepsia
- Dry mouth
- Oral hypoaesthesia
- Irritability
- Pyrexia
- Feeling drunk
- Fall
- Muscle spasms
- Paresthesia
- Cognitive disorder
- Hypoaesthesia
- Dysarthria
- Disturbance in attention
- Cerebellar syndrome
- Confusional state
- Mood altered
- Depressed mood
- Adverse reactions with intravenous administration generally were similar to those observed with the oral formulation, although intravenous administration was associated with local adverse events such as injection site pain or discomfort (2.5%), irritation (1%), and erythema (0.5%).
- One case of profound bradycardia (26 bpm: BP 100/60 mmHg) was observed in a patient during a 15-minute infusion of 150 mg lacosamide.
- This patient was on a beta-blocker.
- Infusion was discontinued and the patient experienced a rapid recovery.
- The safety of a 15-minute loading dose administration of lacosamide Injection 200 mg to 400 mg followed by oral administration of lacosamide given twice daily at the same total daily dose as the initial intravenous infusion was assessed in an open-label study in patients with partial onset seizures. *Patients had to have been maintained on a stable dose regimen of 1 to 2 marketed antiepileptics for at least 28 days prior to treatment assignment. Treatment groups were as follows:
- Single dose of intravenous lacosamide Injection 200 mg followed by oral lacosamide 200 mg/day (100 mg every 12 hours).
- Single dose of intravenous lacosamide Injection 300 mg followed by oral lacosamide 300 mg/day (150 mg every 12 hours)
- Single dose of intravenous lacosamide Injection 400 mg followed by oral lacosamide 400 mg/day (200 mg every 12 hours).
Table 3 gives the incidence of adverse events that occurred in ≥5% of adult patients in any lacosamide dosing group.
- Adverse events observed with infusion of lacosamide 200 mg over 15-minutes followed by lacosamide 100 mg administered orally twice day were similar in frequency to those observed in 3-month adjunctive therapy controlled trials. *Considering the difference in period of observations (1 week vs. 3 months), the incidence of CNS adverse reactions, such as dizziness, somnolence, and paresthesia may be higher with 15-minute administration of lacosamide Injection than with administration over a 30-to 60-minute period.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of lacosamide. 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.
- Agranulocytosis
- Aggression
- Agitation
- Hallucination
- Insomnia
- Psychotic disorder
- Angioedema
- Rash
- Urticaria
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
# Drug Interactions
### Pharmacokinetic Interactions
- Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between lacosamide and carbamazepine, valproate, digoxin, metformin, omeprazole, midazolam, oral contraceptives containing ethinylestradiol and levonorgestrel, or warfarin.
- There was no evidence for any relevant drug-drug interaction of lacosamide with the AEDs used most commonly in the placebo-controlled clinical trials in patients with partial-onset seizures.
- The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system.
### Strong CYP3A4 or CYP2C9 Inhibitors
- Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to lacosamide.
- Dose reduction may be necessary in these patients.
### Concomitant Medications that Prolong PR Interval
- Lacosamide should be used with caution in patients on concomitant medications that prolong PR interval, because of a risk of AV block or bradycardia, e.g., beta-blockers and calcium channel blockers.
- In such patients, obtaining an ECG before beginning lacosamide, and after lacosamide is titrated to steady-state, is recommended.
- In addition, these patients should be closely monitored if they are administered lacosamide through the intravenous route.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy.
- Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy.
- These effects were observed at doses associated with clinically relevant plasma exposures.
- Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
- Potential related adverse effects on CNS development cannot be ruled out.
- There are no adequate and well-controlled studies in pregnant women. *Lacosamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any teratogenic effects. However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats. These doses were associated with maternal plasma lacosamide exposures [area under the plasma-time concentration curve; (AUC)] ≈2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
- When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights were observed in the offspring at the highest dose. *The no-effect dose for pre- and post-natal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC approximately equal to that in humans at the MRHD.
- Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).
- The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development.
- The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lacosamide in women who are pregnant.
### Labor and Delivery
- The effects of lacosamide on labor and delivery in pregnant women are unknown. *In a pre- and post-natal study in rats, there was a tendency for prolonged gestation in all lacosamide treated groups at plasma exposures (AUC) at or below the plasma AUC in humans at the maximum recommended human dose of 400 mg/day.
### Nursing Mothers
- Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk.
- It is not known whether lacosamide is excreted in human milk. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue lacosamide, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of lacosamide in pediatric patients <17 years have not been established.
- Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
- Potential related adverse effects on CNS development cannot be ruled out. *Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).
- The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg/day.
### Geriatic Use
- There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately assess the effectiveness of lacosamide in this population.
- No lacosamide dose adjustment based on age is necessary.
- In elderly patients, dose titration should be performed with caution
### Gender
There is no FDA guidance on the use of Lacosamide with respect to specific gender populations.
### Race
- There are no clinically relevant differences in the pharmacokinetics of lacosamide between Asian, Black, and Caucasian subjects.
### Renal Impairment
- A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. *Lacosamide is effectively removed from plasma by hemodialysis.
- Dosage supplementation of up to 50% following hemodialysis should be considered.
- In all renally impaired patients, dose titration should be performed with caution.
### Hepatic Impairment
- Patients with mild to moderate hepatic impairment should be observed closely during dose titration.
- A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment.
- Lacosamide use is not recommended in patients with severe hepatic impairment. *Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lacosamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lacosamide in patients who are immunocompromised.
### CYP2C19 Polymorphism
There are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.
- Monitor closely patients with known cardiac conduction problems, on concomitant medications that prolong PR interval, or with severe cardiac disease
- Monitor patients for suicidal behavior and ideation
# IV Compatibility
Lacosamide injection can be administered intravenously without further dilution or may be mixed with diluents listed below. The diluted solution should not be stored for more than 4 hours at room temperature.
Diluents:
- Sodium Chloride Injection 0.9% (w/v)
- Dextrose Injection 5% (w/v)
- Lactated Ringer's Injection
- Product with particulate matter or discoloration should not be used.
- Any unused portion of lacosamide injection should be discarded.
# Overdosage
### Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans
- The types of adverse events experienced by patients exposed to supratherapeutic lacosamide doses during clinical trials were not clinically different from those of patients administered recommended doses of lacosamide.
- The highest reported accidental overdose of lacosamide during clinical development was 1200 mg/day which was non-fatal.
- There has been a single case of intentional overdose in a clinical trial by a patient who self-administered 12,000 mg lacosamide along with large doses of zonisamide, topiramate, and gabapentin.
- The patient presented in a coma with AV block and was hospitalized.
- An EEG revealed epileptic waveforms.
- The patient recovered 2 days later.
- In postmarketing experience, cardiac conduction disorders and fatal cardiac arrest were reported following an acute overdose of 7,000 mg of lacosamide in a patient with cardiovascular risk factors.
### Treatment or Management of Overdose
- There is no specific antidote for overdose with lacosamide.
- Standard decontamination procedures should be followed.
- General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient.
- A Certified Poison Control Center should be contacted for up to date information on the management of overdose with lacosamide.
- Standard hemodialysis procedures result in significant clearance of lacosamide (reduction of systemic exposure by 50% in 4 hours).
- Hemodialysis has not been performed in the few known cases of overdose, but may be indicated based on the patient's clinical state or in patients with significant renal impairment.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which lacosamide exerts its antiepileptic effects in humans remains to be fully elucidated.
- In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.
## Structure
The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC). Lacosamide is a functionalized amino acid. Its molecular formula is C13H18N2O3 and its molecular weight is 250.30. The chemical structure is:
## Pharmacodynamics
- A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. *Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.
### Cardiac Electrophysiology
- Electrocardiographic effects of lacosamide were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects.
- Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin).
- Lacosamide did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration.
- Lacosamide produced a small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax.
- The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximum increase in PR interval for a 400 mg/day lacosamide dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.
## Pharmacokinetics
- The pharmacokinetics of lacosamide have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment.
- Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. *The maximum lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours.
- Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration.
- Pharmacokinetics of lacosamide are dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability.
- Compared to lacosamide the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours).
### Absorption and Bioavailability
- Lacosamide is completely absorbed after oral administration.
- The oral bioavailability of lacosamide tablets is approximately 100%.
- Food does not affect the rate and extent of absorption.
- After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC(0-tz) but not for Cmax.
- The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range.
- In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.
- A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice daily oral administration.
### Distribution
- The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water.
- Lacosamide is less than 15% bound to plasma proteins.
### Metabolism and Elimination
- Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation.
- After oral and intravenous administration of 100 mg [14C]-lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces.
- The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%).
- The plasma exposure of the major human metabolite, O-desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.
- The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19.
- The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.
- There is no enantiomeric interconversion of lacosamide.
### Special Populations
- Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.
- The AUC of lacosamide was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected.
- No dose adjustment is considered necessary in mildly and moderately renal impaired subjects.
- A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30 mL/min) and in patients with endstage renal disease. *Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore dosage supplementation of up to 50% following hemodialysis should be considered.
- In all renally impaired patients, the dose titration should be performed with caution.
### Hepatic impairment
- Lacosamide undergoes metabolism.
- Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects).
- The dose titration should be performed with caution in patients with hepatic impairment.
- A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.
- Patients with mild to moderate hepatic impairment should be observed closely during dose titration.
- A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment.
- The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment.
- Lacosamide use is not recommended in patients with severe hepatic impairment.
- Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.
### Geriatric
- In the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18-64 years).
- This may be related to body weight and decreased renal function in elderly subjects.
- Dose reduction is not considered to be necessary.
### Pediatric Patients
- Pharmacokinetics of lacosamide have not been studied in pediatric patients.
### Gender
- Lacosamide clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of lacosamide.
### Race
- There are no clinically relevant differences in the pharmacokinetics of lacosamide between Asian, Black, and Caucasian subjects.
### CYP2C19 Polymorphism
- There are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. *Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.
### Drug interactions
- In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4.
- Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.
- In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.
- Lacosamide is a substrate of CYP3A4, CYP2C9, and CYP2C19.
- Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to lacosamide.
- Since <15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.
Effect of lacosamide on concomitant AEDs
- Lacosamide 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.
- The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of lacosamide at any dose.
Effect of concomitant AEDs on lacosamide
- Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of lacosamide in a healthy subject study.
- Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when lacosamide was coadministered with carbamazepine, phenobarbital or phenytoin.
Digoxin
- There was no effect of lacosamide (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.
Metformin
- There were no clinically relevant changes in metformin levels following coadministration of lacosamide (400 mg/day).
- Metformin (500 mg three times a day) had no effect on the pharmacokinetics of lacosamide (400 mg/day).
Omeprazole
- Omeprazole is a CYP2C19 substrate and inhibitor.
- There was no effect of lacosamide (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.
Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of lacosamide (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.
Midazolam
- Midazolam is a 3A4 substrate.
- There was no effect of lacosamide (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.
Oral Contraceptives
- There was no influence of lacosamide (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed.
Warfarin
- Co-administration of lacosamide (400 mg/day) with warfarin (25 mg single dose) did not result in a clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in a study in healthy male subjects.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- There was no evidence of drug related carcinogenicity in mice or rats.
- Mice and rats received lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
- Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay.
- Lacosamide induced a positive response in the in vitro mouse lymphoma assay.
- No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the MRHD.
# Clinical Studies
### Monotherapy in Patients with Partial Onset Seizures
- The efficacy of lacosamide in monotherapy was established in a historical-control, multicenter, randomized trial that included 425 patients, age 16 to 70 years, with partial-onset seizures (Study 1).
- To be included in Study 1, patients were required to be taking stable doses of 1 or 2 marketed antiepileptic drugs.
- This treatment continued into the 8 week baseline period.
- To remain in the study, patients were required to have at least 2 partial onset seizures per 28 days during the 8 week baseline period.
- The baseline period was followed by a 3 week titration period, during which lacosamide was added to the ongoing antiepileptic regimen.
- This was followed by a 16-week maintenance period (i.e., a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period).
- Patients were randomized 3 to 1 to receive lacosamide 400 mg/day or lacosamide 300 mg/day.
- Treatment assignments were blinded.
- Response to treatment was based upon a comparison of the number of patients who met exit criteria during the maintenance phase, compared to historical controls.
- The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug.
- Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving lacosamide remained below the lower 95% prediction limit of 65% derived from the historical control data.
- The exit criteria were one or more of the following:
- (1) Doubling of average monthly seizure frequency during any 28 consecutive days.
- (2) Doubling of highest consecutive 2-day seizure frequency.
- (3) Occurrence of a single generalized tonic-clonic seizure
- (4) Clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation.
- (5) Status epilepticus or new onset of serial/cluster seizures. The study population profile appeared comparable to that of the historical control population.
- For the lacosamide 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30% (95% CI: 25%, 36%).
- The upper limit of the 2-sided 95% CI (36%) was below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy. Lacosamide 300 mg/day also met the pre-specified criteria for efficacy.
### Adjunctive Therapy in Patients with Partial Onset Seizures
- The efficacy of lacosamide as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients (Study 2, Study 3, and Study 4).
- Enrolled patients had partial-onset seizures with or without secondary generalization, and were not adequately controlled with 1 to 3 concomitant AEDs.
- During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.
- Study 2 compared doses of lacosamide 200, 400, and 600 mg/day with placebo. *Study 3 compared doses of lacosamide 400 and 600 mg/day with placebo.
- Study 4 compared doses of lacosamide 200 and 400 mg/day with placebo.
- In all three trials, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of lacosamide 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the titration phase).
- During the titration phase, in all 3 adjunctive therapy trials, treatment was initiated at 100 mg/day (50 mg twice daily), and increased in weekly increments of 100 mg/day to the target dose.
- The titration phase lasted 6 weeks in Study 2 and Study 3, and 4 weeks in Study 4. In all three trials, the titration phase was followed by a maintenance phase that lasted 12 weeks, during which patients were to remain on a stable dose of lacosamide.
- A reduction in 28 day seizure frequency (baseline to maintenance phase), as compared to the placebo group, was the primary variable in all three adjunctive therapy trials.
- A statistically significant effect was observed with lacosamide treatment (Figure 1) at doses of 200 mg/day (Study 4), 400 mg/day (Studies 2, 3, and 4), and 600 mg/day (Studies 2 and 3).
- Subset evaluations of lacosamide demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).
# How Supplied
### Lacosamide Tablets 50 mg
- Are pink, oval, film-coated tablets debossed with "SP" on one side and "50" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2477-35
- Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2477-60
### Lacosamide Tablets 100 mg
- Are dark yellow, oval, film-coated tablets debossed with "SP" on one side and "100" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2478-35
- Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2478-60
### Lacosamide Tablets 150 mg
- Are salmon, oval, film-coated tablets debossed with "SP" on one side and "150" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2479-35
- Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2479-60
### Lacosamide Tablets 200 mg
- Are blue, oval, film-coated tablets debossed with "SP" on one side and "200" on the other. They are supplied as follows:
- Bottles of 60 NDC 0131-2480-35
- Unit Dose Carton of 60 tablets [6 cards, each card contains 10 tablets] NDC 0131-2480-60
### Lacosamide injection 200 mg/20 m
- Is a clear, colorless sterile solution supplied in 20 mL colorless single-use glass vials.
- 200 mg/20 mL vial in cartons of 10 vials NDC 0131-1810-67
### Lacosamide oral solution 10 mg/mL
- Is a clear, colorless to yellow or yellow-brown, strawberry-flavored liquid. It is supplied in PET bottles as follows:
- 200 mL bottles NDC 0131-5410-71
- 465 mL bottles NDC 0131-5410-70
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
- Do not freeze lacosamide injection or oral solution. Discard any unused lacosamide oral solution remaining after seven (7) weeks of first opening the bottle.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
### Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be counseled that AEDs, including lacosamide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. *Behaviors of concern should be reported immediately to healthcare providers.
### Dizziness and Ataxia
- Patients should be counseled that lacosamide use may cause dizziness, double vision, abnormal coordination and balance, and somnolence. *Patients taking lacosamide should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with lacosamide.
### Cardiac Rhythm and Conduction Abnormalities
- Patients should be counseled that lacosamide is associated with electrocardiographic changes that may predispose to irregular beat and syncope, particularly in patients with underlying cardiovascular disease, with heart conduction problems or who are taking other medications that affect the heart.
- Patients who develop syncope should lay down with raised legs and contact their health care provider.
### Multiorgan Hypersensitivity Reactions
- Patients should be aware that lacosamide may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney. Lacosamide should be discontinued if a serious hypersensitivity reaction is suspected. *Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g. fatigue, jaundice, dark urine).
### Pregnancy Registry
- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during lacosamide therapy.
- Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant.
- This registry is collecting information about the safety of AEDs during pregnancy.
# Precautions with Alcohol
Alcohol-Lacosamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VIMPAT[1]
# Look-Alike Drug Names
There is limited information regarding Lacosamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lacosamide | |
6d4ae22ec051a39cfaa034b733807068845e1995 | wikidoc | Lafutidine | Lafutidine
# Overview
Lafutidine (INN) is a second generation histamine H2 receptor antagonist having multimodal mechanism of action and used to treat gastrointestinal disorders. It is marketed in Japan and India.
# Medical use
Lafutidine is used to treat gastric ulcers, duodenal ulcers, stomal ulcers, wounds in the lining of the stomach associated with acute gastritis and with acute exacerbation of chronic gastritis.
# Adverse effects
Adverse events observed during clinical trials included constipation, diarrhea, drug rash, nausea or vomiting and dizziness.
# Mechanisms of action
Like other H2 receptor antagonists it prevents the secretion of gastric acid. It also activates calcitonin gene related peptide, resulting in the stimulation of nitric oxide (NO) and regulation of gastric mucosal blood flow, increases somatostatin levels also resulting in less gastric acid secretion, causes the stomach lining to generate more mucin, inhibits neutrophil activation thus preventing injury from inflammation, and blocks the attachment of H. pylori to gastric cells.
# History
It is marketed in Japan as Stogar by UCB and in India as Lafaxid by Zuventus Healthcare. | Lafutidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lafutidine (INN) is a second generation histamine H2 receptor antagonist having multimodal mechanism of action and used to treat gastrointestinal disorders. It is marketed in Japan and India.
# Medical use
Lafutidine is used to treat gastric ulcers, duodenal ulcers, stomal ulcers, wounds in the lining of the stomach associated with acute gastritis and with acute exacerbation of chronic gastritis.[1][2]
# Adverse effects
Adverse events observed during clinical trials included constipation, diarrhea, drug rash, nausea or vomiting and dizziness.[2]
# Mechanisms of action
Like other H2 receptor antagonists it prevents the secretion of gastric acid.[2] It also activates calcitonin gene related peptide, resulting in the stimulation of nitric oxide (NO) and regulation of gastric mucosal blood flow, increases somatostatin levels also resulting in less gastric acid secretion, causes the stomach lining to generate more mucin, inhibits neutrophil activation thus preventing injury from inflammation, and blocks the attachment of H. pylori to gastric cells.[2]
# History
It is marketed in Japan as Stogar by UCB[1] and in India as Lafaxid by Zuventus Healthcare.[2] | https://www.wikidoc.org/index.php/Lafutidine | |
eef13411fd45c40e87f36951d8095379f3b70549 | wikidoc | Lamarckism | Lamarckism
Lamarckism or Lamarckian evolution refers to the once widely accepted idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as based on heritability of acquired characteristics or "soft inheritance"). It is named for the French biologist Jean-Baptiste Lamarck, who incorporated the action of soft inheritance into his evolutionary theories and is often incorrectly cited as the founder of soft inheritance. It proposed that individual efforts during the lifetime of the organisms were the main mechanism driving species to adaptation, as they supposedly would acquire adaptive changes and pass them on to offspring.
After publication of Charles Darwin's theory of natural selection, the importance of individual efforts in the generation of adaptation was considerably diminished. Later, Mendelian genetics supplanted the notion of inheritance of acquired traits, eventually leading to the development of the modern evolutionary synthesis, and the general abandonment of the Lamarckian theory of evolution in biology. In a wider context, soft inheritance is of use when examining the evolution of cultures and ideas, and is related to the theory of Memetics.
While enormously popular during the early 19th century as an explanation for the complexity observed in living systems, the relevance of soft inheritance within the scientific community dwindled following the theories of August Weismann and the formation of the modern evolutionary synthesis.
# History
Between 1794 and 1796 Erasmus Darwin wrote Zoönomia suggesting "that all warm-blooded animals have arisen from one living filament... with the power of acquiring new parts" in response to stimuli, with each round of "improvements" being inherited by successive generations. Subsequently Jean-Baptiste Lamarck repeated in his Philosophie Zoologique of 1809 the folk wisdom that characteristics which were "needed" were acquired (or diminished) during the lifetime of an organism then passed on to the offspring. He incorporated this mechanism into his thoughts on evolution, seeing it as resulting in the adaptation of life to local environments.
Lamarck founded a school of French Transformationism which included Étienne Geoffroy Saint-Hilaire, and which corresponded with a radical British school of comparative anatomy based at the University of Edinburgh which included the surgeon Robert Knox and the anatomist Robert Edmund Grant. Professor Robert Jameson wrote an anonymous paper in 1826 praising "Mr. Lamarck" for explaining how the higher animals had "evolved" from the "simplest worms" – this was the first use of the word "evolved" in a modern sense. As a young student, Charles Darwin was tutored by Grant, and worked with him on marine creatures.
The Vestiges of the Natural History of Creation, authored by Robert Chambers and published anonymously in England in 1844, proposed a theory modelled after Lamarckism, causing political controversy for its radicalism and unorthodoxy, but exciting popular interest and paving the way for Darwin.
Darwin's Origin of Species proposed natural selection as the main mechanism for development of species, but did not rule out a variant of Lamarckism as a supplementary mechanism. Darwin called his Lamarckian hypothesis Pangenesis, and explained it in the final chapter of his book Variation in Plants and Animals under Domestication, after describing numerous examples to demonstrate what he considered to be the inheritance of acquired characteristics. Pangenesis, which he emphasised was a hypothesis, was based on the idea that somatic cells would, in response to environmental stimulation (use and disuse), throw off 'gemmules' which travelled around the body (though not in necessarily in the bloodstream). These pangenes were microscopic particles that supposedly contained information about the characteristics of their parent cell, and Darwin believed that they eventually accumulated in the germ cells where they could pass on to the next generation the newly acquired characteristics of the parents. Darwin's half-cousin, Francis Galton carried out experiments on rabbits, with Darwin's cooperation, in which he transfused the blood of one variety of rabbit into another variety in the expectation that its offspring would show some characteristics of the first. They did not, and Galton declared that he had disproved Darwin's hypothesis of Pangenesis, but Darwin objected, in a letter to Nature that he had done nothing of the sort, since he had never mentioned blood in his writings. He pointed out that he regarded pangenesis as occurring in Protozoa and plants, which have no blood. With the development of the modern synthesis of the theory of evolution and a lack of evidence for either a mechanism or even the heritability acquired characteristics, Lamarckism largely fell from favor.
In the 1920s, experiments by Paul Kammerer on amphibians, particularly the midwife toad, appeared to find evidence supporting Lamarckism, but were discredited as having been falsified. In The Case of the Midwife Toad Arthur Koestler surmised that the specimens had been faked by a Nazi sympathiser to discredit Kammerer for his political views.
A form of "Lamarckism" was revived in the Soviet Union of the 1930s when Trofim Lysenko promoted Lysenkoism which suited the ideological opposition of Joseph Stalin to Genetics. This ideologically driven research influenced Soviet agricultural policy which in turn was later blamed for crop failures.
Since 1988 certain scientists have produced work proposing that Lamarckism could apply to single celled organisms. The discredited belief that Lamarckism holds for higher order animals is still clung to in certain branches of new-age pseudoscience under the term racial memory.
Neo-Lamarckism is a theory of inheritance based on a modification and extension of Lamarckism, essentially maintaining the principle that genetic changes can be influenced and directed by environmental factors.
# Lamarck's theory
The identification of "Lamarckism" with the inheritance of acquired characteristics is regarded by some as an artifact of the subsequent history of evolutionary thought, repeated in textbooks without analysis. Stephen Jay Gould wrote that late 19th century evolutionists "re-read Lamarck, cast aside the guts of it ... and elevated one aspect of the mechanics - inheritance of acquired characters - to a central focus it never had for Lamarck himself." He argued that "the restriction of "Lamarckism" to this relatively small and non-distinctive corner of Lamarck's thought must be labelled as more than a misnomer, and truly a discredit to the memory of a man and his much more comprehensive system". Gould advocated defining "Lamarckism" more broadly, in line with Lamarck's overall evolutionary theory.
Lamarck incorporated two ideas into his theory of evolution, in his day considered to be generally true:
- Use and disuse – Individuals lose characteristics they do not require (or use) and develop characteristics that are useful.
- Inheritance of acquired traits – Individuals inherit the traits of their ancestors.
Examples of what is traditionally called "Lamarckism" would include:
- Giraffes stretching their necks to reach leaves high in trees (especially Acacias), strengthen and gradually lengthen their necks. These giraffes have offspring with slightly longer necks (also known as "soft inheritance").
- A blacksmith, through his work, strengthens the muscles in his arms. His sons will have similar muscular development when they mature.
With this in mind, Lamarck has been credited in some textbooks and popular culture with developing two laws:
- In every animal which has not passed the limit of its development, a more frequent and continuous use of any organ gradually strengthens, develops and enlarges that organ, and gives it a power proportional to the length of time it has been so used; while the permanent disuse of any organ imperceptibly weakens and deteriorates it, and progressively diminishes its functional capacity, until it finally disappears.
- All the acquisitions or losses wrought by nature on individuals, through the influence of the environment in which their race has long been placed, and hence through the influence of the predominant use or permanent disuse of any organ; all these are preserved by reproduction to the new individuals which arise, provided that the acquired modifications are common to both sexes, or at least to the individuals which produce the young.
In essence, a change in the environment brings about change in "needs" (besoins), resulting in change in behavior, bringing change in organ usage and development, bringing change in form over time — and thus the gradual transmutation of the species.
However, as scientist historians such as Michael Ghiselin and Stephen Jay Gould have pointed out, none of these views were original to Lamarck. On the contrary, Lamarck's contribution was a systematic theoretical framework for understanding evolution. He saw evolution as comprising two processes;
- Le pouvoir de la vie (a complexifying force) - in which the natural, alchemical movements of fluids would etch out organs from tissues, leading to ever more complex construction regardless of the organ's use or disuse. This would drive organisms from simple to complex forms.
- L'influence des circonstances (an adaptive force) - in which the use and disuse of characters led organisms to become more adapted to their environment. This would take organisms sideways off the path from simple to complex, specialising them for their environment.
# Current views on "Lamarckism"
The argument that instinct in animals is evidence for hereditary knowledge is generally regarded within science as false. Such behaviours are more probably passed on through a mechanism called the Baldwin effect. While such a theory might explain the observed diversity of species and the first law is generally true, the main argument against Lamarckism is that experiments simply do not support the second law — purely "acquired traits" do not appear in any meaningful sense to be inherited. For example, a human child must learn how to catch a ball even though his or her parents learned the same feat when they were children. Lamarck’s theories gained initial acceptance because the mechanisms of inheritance were not elucidated until later in the 19th Century, after Lamarck's death.
Several historians have argued that Lamarck's name is linked somewhat unfairly to the theory that has come to bear his name, and that Lamarck deserves credit for being an influential early proponent of the concept of biological evolution, far more than for the mechanism of evolution, in which he simply followed the accepted wisdom of his time. Lamarck died 30 years before the first publication of Charles Darwin's Origin of Species. As science historian Stephen Jay Gould has noted, if Lamarck had been aware of Darwin's proposed mechanism of natural selection, there is no reason to assume he would not have accepted it as a more likely alternative to his "own" mechanism. Note also that Darwin, like Lamarck, lacked a plausible alternative mechanism of inheritance - the particulate nature of inheritance was only to be observed by Gregor Mendel somewhat later, published in 1866. Its importance, although Darwin cited Mendel's paper, was not recognised until the Modern evolutionary synthesis in the early 1900s. An important point in its favour at the time was that Lamarck's theory contained a mechanism describing how variation is maintained, which Darwin’s own theory lacked.
# Neo-Lamarckism
Unlike neo-Darwinism, the term neo-Lamarckism refers more to a loose grouping of largely heterodox theories and mechanisms that emerged after Lamarck's time, than to any coherent body of theoretical work.
In the 1920s, Harvard University researcher William McDougall studied the abilities of rats to correctly solve mazes. He found that children of rats that had learned the maze were able to run it faster. The first rats would get it wrong 165 times before being able to run it perfectly each time, but after a few generations it was down to 20. McDougall attributed this to some sort of Lamarckian evolutionary process.
At around the same time, Ivan Pavlov, who was also a Lamarckist, claimed to have observed a similar phenomena in animals being subject to conditioned reflex experiments. He claimed that with each generation, the animals became easier to condition.
Neither McDougall or Pavlov suggested a mechanism to explain their observations.
Soma to germ line feedback
In the 1970's the immunologist Ted Steele, formerly of the University of Wollongong, and colleagues, proposed a neo-Lamarckiam mechanism to try and explain why homologous DNA sequences from the VDJ gene regions of parent mice were found in their germ cells and seemed to persist in the offspring for a few generations. The mechanism involved the somatic selection and clonal amplification of newly acquired antibody gene sequences that were generated via somatic hyper-mutation in B-cells. The mRNA products of these somatically novel genes were captured by retroviruses endogenous to the B-cells and were then transported through the blood stream where they could breach the soma-germ barrier and retrofect (reverse transcribe) the newly acquired genes into the cells of the germ line. Although Steele was advocating this theory for the better part of two decades, little more than indirect evidence was ever acquired to support it. An interesting attribute of this idea is that it strongly resembles Darwin's own theory of pangenesis, except in the soma to germ line feedback theory, pangenes are replaced with realistic retroviruses.
Epigenetic inheritance
Forms of 'soft' or epigenetic inheritance within organisms have been suggested as neo-Lamarckian in nature by such scientists as Eva Jablonka and Marion J. Lamb. In addition to 'hard' or genetic inheritance, involving the duplication of genetic material and its segregation during meiosis, there are other hereditary elements that pass into the germ cells also. These include things like methylation patterns in DNA and chromatin marks, both of which regulate the activity of genes. These are considered "Lamarckian" in the sense that they are responsive to environmental stimuli and can differentially effect gene expression adaptively, with phenotypic results that can persist for many generations in certain organisms. Although the reality of epigenetic inheritance is not doubted (as countless experiments have validated it) its significance to the evolutionary process is however uncertain. Most neo-Darwinians consider epigenetic inheritance mechanisms to be little more than a specialized form of phenotypic plasticity, with no potential to introduce evolutionary novelty into a species lineage.
# Lamarckism and single-celled organisms
While Lamarckism has been discredited as an evolutionary influence for larger lifeforms, some scientists controversially argue that it can be observed among microorganisms. Whether such mutations are directed or not also remains a point of contention.
In 1988, John Cairns at the Radcliffe Infirmary in Oxford, England, and a group of other scientists renewed the Lamarckian controversy (which by then had been a dead debate for many years). The group took a mutated strain of E. coli that was unable to consume the sugar lactose and placed it in an environment where lactose was the only food source. They observed over time that mutations occurred within the colony at a rate that suggested the bacteria were overcoming their handicap by altering their own genes. Cairns, among others, dubbed the process adaptive mutagenesis.
If bacteria that had overcome their own inability to consume lactose passed on this "learned" trait to future generations, it could be argued as a form of Lamarckism; though Cairns later chose to distance himself from such a position. More typically, it might be viewed as a form of ontogenic evolution.
There has been some research into Lamarckism and prions. A group of researchers, for example, discovered that in yeast cells containing a specific prion protein Sup35, the yeast were able to gain new genetic material, some of which gave them new abilities such as resistance to a particular herbicide. When the researchers mated the yeast cells with cells not containing the prion, the trait reappeared in some of the resulting offspring, indicating that some information indeed was passed down, though whether or not the information is genetic is debatable: trace prion amounts in the cells may be passed to their offspring, giving the appearance of a new genetic trait where there is none.
Finally, there is growing evidence that cells can activate low-fidelity DNA polymerases in times of stress to induce mutations. While this does not directly confer advantage to the organism on the organismal level, it makes sense at the gene-evolution level. While the acquisition of new genetic traits is random, and selection remains Darwinian, the active process of identifying the necessity to mutate is considered to be Lamarckian.
# Lamarckism and societal change
Jean Molino (2000) has proposed that Lamarckian evolution may be accurately applied to cultural evolution. This was also previously suggested by Peter Medawar (1959) and Conrad Waddington (1961). K. N. Laland and colleagues have recently suggested that Human culture can be looked upon as an ecological niche like phenomena, where the effects of cultural niche construction are transmissible from one generation to the next. One interpretation of the Meme theory is that memes are both Darwinian and Lamarckian in nature, as in addition to being subject to selection pressures based on their ability to differentially influence Human minds, memes can be modified and the effects of that modification passed on. | Lamarckism
Lamarckism or Lamarckian evolution refers to the once widely accepted idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as based on heritability of acquired characteristics or "soft inheritance"). It is named for the French biologist Jean-Baptiste Lamarck, who incorporated the action of soft inheritance into his evolutionary theories and is often incorrectly cited as the founder of soft inheritance. It proposed that individual efforts during the lifetime of the organisms were the main mechanism driving species to adaptation, as they supposedly would acquire adaptive changes and pass them on to offspring.
After publication of Charles Darwin's theory of natural selection, the importance of individual efforts in the generation of adaptation was considerably diminished. Later, Mendelian genetics supplanted the notion of inheritance of acquired traits, eventually leading to the development of the modern evolutionary synthesis, and the general abandonment of the Lamarckian theory of evolution in biology. In a wider context, soft inheritance is of use when examining the evolution of cultures and ideas, and is related to the theory of Memetics.
While enormously popular during the early 19th century as an explanation for the complexity observed in living systems, the relevance of soft inheritance within the scientific community dwindled following the theories of August Weismann and the formation of the modern evolutionary synthesis.
# History
Between 1794 and 1796 Erasmus Darwin wrote Zoönomia suggesting "that all warm-blooded animals have arisen from one living filament... with the power of acquiring new parts" in response to stimuli, with each round of "improvements" being inherited by successive generations. Subsequently Jean-Baptiste Lamarck repeated in his Philosophie Zoologique of 1809 the folk wisdom that characteristics which were "needed" were acquired (or diminished) during the lifetime of an organism then passed on to the offspring. He incorporated this mechanism into his thoughts on evolution, seeing it as resulting in the adaptation of life to local environments.
Lamarck founded a school of French Transformationism which included Étienne Geoffroy Saint-Hilaire, and which corresponded with a radical British school of comparative anatomy based at the University of Edinburgh which included the surgeon Robert Knox and the anatomist Robert Edmund Grant. Professor Robert Jameson wrote an anonymous paper in 1826 praising "Mr. Lamarck" for explaining how the higher animals had "evolved" from the "simplest worms" – this was the first use of the word "evolved" in a modern sense. As a young student, Charles Darwin was tutored by Grant, and worked with him on marine creatures.
The Vestiges of the Natural History of Creation, authored by Robert Chambers and published anonymously in England in 1844, proposed a theory modelled after Lamarckism, causing political controversy for its radicalism and unorthodoxy, but exciting popular interest and paving the way for Darwin.
Darwin's Origin of Species proposed natural selection as the main mechanism for development of species, but did not rule out a variant of Lamarckism as a supplementary mechanism.[1] Darwin called his Lamarckian hypothesis Pangenesis, and explained it in the final chapter of his book Variation in Plants and Animals under Domestication, after describing numerous examples to demonstrate what he considered to be the inheritance of acquired characteristics. Pangenesis, which he emphasised was a hypothesis, was based on the idea that somatic cells would, in response to environmental stimulation (use and disuse), throw off 'gemmules' which travelled around the body (though not in necessarily in the bloodstream). These pangenes were microscopic particles that supposedly contained information about the characteristics of their parent cell, and Darwin believed that they eventually accumulated in the germ cells where they could pass on to the next generation the newly acquired characteristics of the parents. Darwin's half-cousin, Francis Galton carried out experiments on rabbits, with Darwin's cooperation, in which he transfused the blood of one variety of rabbit into another variety in the expectation that its offspring would show some characteristics of the first. They did not, and Galton declared that he had disproved Darwin's hypothesis of Pangenesis, but Darwin objected, in a letter to Nature that he had done nothing of the sort, since he had never mentioned blood in his writings. He pointed out that he regarded pangenesis as occurring in Protozoa and plants, which have no blood.[2] With the development of the modern synthesis of the theory of evolution and a lack of evidence for either a mechanism or even the heritability acquired characteristics, Lamarckism largely fell from favor.
In the 1920s, experiments by Paul Kammerer on amphibians, particularly the midwife toad, appeared to find evidence supporting Lamarckism, but were discredited as having been falsified. In The Case of the Midwife Toad Arthur Koestler surmised that the specimens had been faked by a Nazi sympathiser to discredit Kammerer for his political views.
A form of "Lamarckism" was revived in the Soviet Union of the 1930s when Trofim Lysenko promoted Lysenkoism which suited the ideological opposition of Joseph Stalin to Genetics. This ideologically driven research influenced Soviet agricultural policy which in turn was later blamed for crop failures.
Since 1988 certain scientists have produced work proposing that Lamarckism could apply to single celled organisms. The discredited belief that Lamarckism holds for higher order animals is still clung to in certain branches of new-age pseudoscience under the term racial memory.
Neo-Lamarckism is a theory of inheritance based on a modification and extension of Lamarckism, essentially maintaining the principle that genetic changes can be influenced and directed by environmental factors.
# Lamarck's theory
The identification of "Lamarckism" with the inheritance of acquired characteristics is regarded by some as an artifact of the subsequent history of evolutionary thought, repeated in textbooks without analysis. Stephen Jay Gould wrote that late 19th century evolutionists "re-read Lamarck, cast aside the guts of it ... and elevated one aspect of the mechanics - inheritance of acquired characters - to a central focus it never had for Lamarck himself."[3] He argued that "the restriction of "Lamarckism" to this relatively small and non-distinctive corner of Lamarck's thought must be labelled as more than a misnomer, and truly a discredit to the memory of a man and his much more comprehensive system"[4]. Gould advocated defining "Lamarckism" more broadly, in line with Lamarck's overall evolutionary theory.
Lamarck incorporated two ideas into his theory of evolution, in his day considered to be generally true:
- Use and disuse – Individuals lose characteristics they do not require (or use) and develop characteristics that are useful.
- Inheritance of acquired traits – Individuals inherit the traits of their ancestors.
Examples of what is traditionally called "Lamarckism" would include:
- Giraffes stretching their necks to reach leaves high in trees (especially Acacias), strengthen and gradually lengthen their necks. These giraffes have offspring with slightly longer necks (also known as "soft inheritance").
- A blacksmith, through his work, strengthens the muscles in his arms. His sons will have similar muscular development when they mature.
With this in mind, Lamarck has been credited in some textbooks and popular culture with developing two laws:
- In every animal which has not passed the limit of its development, a more frequent and continuous use of any organ gradually strengthens, develops and enlarges that organ, and gives it a power proportional to the length of time it has been so used; while the permanent disuse of any organ imperceptibly weakens and deteriorates it, and progressively diminishes its functional capacity, until it finally disappears.
- All the acquisitions or losses wrought by nature on individuals, through the influence of the environment in which their race has long been placed, and hence through the influence of the predominant use or permanent disuse of any organ; all these are preserved by reproduction to the new individuals which arise, provided that the acquired modifications are common to both sexes, or at least to the individuals which produce the young.
In essence, a change in the environment brings about change in "needs" (besoins), resulting in change in behavior, bringing change in organ usage and development, bringing change in form over time — and thus the gradual transmutation of the species.
However, as scientist historians such as Michael Ghiselin and Stephen Jay Gould have pointed out, none of these views were original to Lamarck.[5][6] On the contrary, Lamarck's contribution was a systematic theoretical framework for understanding evolution. He saw evolution as comprising two processes;
- Le pouvoir de la vie (a complexifying force) - in which the natural, alchemical movements of fluids would etch out organs from tissues, leading to ever more complex construction regardless of the organ's use or disuse. This would drive organisms from simple to complex forms.
- L'influence des circonstances (an adaptive force) - in which the use and disuse of characters led organisms to become more adapted to their environment. This would take organisms sideways off the path from simple to complex, specialising them for their environment.
# Current views on "Lamarckism"
The argument that instinct in animals is evidence for hereditary knowledge is generally regarded within science as false. Such behaviours are more probably passed on through a mechanism called the Baldwin effect. While such a theory might explain the observed diversity of species and the first law is generally true, the main argument against Lamarckism is that experiments simply do not support the second law — purely "acquired traits" do not appear in any meaningful sense to be inherited. For example, a human child must learn how to catch a ball even though his or her parents learned the same feat when they were children. Lamarck’s theories gained initial acceptance because the mechanisms of inheritance were not elucidated until later in the 19th Century, after Lamarck's death.
Several historians have argued that Lamarck's name is linked somewhat unfairly to the theory that has come to bear his name, and that Lamarck deserves credit for being an influential early proponent of the concept of biological evolution, far more than for the mechanism of evolution, in which he simply followed the accepted wisdom of his time. Lamarck died 30 years before the first publication of Charles Darwin's Origin of Species. As science historian Stephen Jay Gould has noted, if Lamarck had been aware of Darwin's proposed mechanism of natural selection, there is no reason to assume he would not have accepted it as a more likely alternative to his "own" mechanism. Note also that Darwin, like Lamarck, lacked a plausible alternative mechanism of inheritance - the particulate nature of inheritance was only to be observed by Gregor Mendel somewhat later, published in 1866. Its importance, although Darwin cited Mendel's paper, was not recognised until the Modern evolutionary synthesis in the early 1900s. An important point in its favour at the time was that Lamarck's theory contained a mechanism describing how variation is maintained, which Darwin’s own theory lacked.
# Neo-Lamarckism
Unlike neo-Darwinism, the term neo-Lamarckism refers more to a loose grouping of largely heterodox theories and mechanisms that emerged after Lamarck's time, than to any coherent body of theoretical work.
In the 1920s, Harvard University researcher William McDougall studied the abilities of rats to correctly solve mazes. He found that children of rats that had learned the maze were able to run it faster. The first rats would get it wrong 165 times before being able to run it perfectly each time, but after a few generations it was down to 20. McDougall attributed this to some sort of Lamarckian evolutionary process.[citation needed]
At around the same time, Ivan Pavlov, who was also a Lamarckist, claimed to have observed a similar phenomena in animals being subject to conditioned reflex experiments. He claimed that with each generation, the animals became easier to condition.
Neither McDougall or Pavlov suggested a mechanism to explain their observations.
Soma to germ line feedback
In the 1970's the immunologist Ted Steele, formerly of the University of Wollongong, and colleagues, proposed a neo-Lamarckiam mechanism to try and explain why homologous DNA sequences from the VDJ gene regions of parent mice were found in their germ cells and seemed to persist in the offspring for a few generations. The mechanism involved the somatic selection and clonal amplification of newly acquired antibody gene sequences that were generated via somatic hyper-mutation in B-cells. The mRNA products of these somatically novel genes were captured by retroviruses endogenous to the B-cells and were then transported through the blood stream where they could breach the soma-germ barrier and retrofect (reverse transcribe) the newly acquired genes into the cells of the germ line. Although Steele was advocating this theory for the better part of two decades, little more than indirect evidence was ever acquired to support it. An interesting attribute of this idea is that it strongly resembles Darwin's own theory of pangenesis, except in the soma to germ line feedback theory, pangenes are replaced with realistic retroviruses.[7]
Epigenetic inheritance
Forms of 'soft' or epigenetic inheritance within organisms have been suggested as neo-Lamarckian in nature by such scientists as Eva Jablonka and Marion J. Lamb. In addition to 'hard' or genetic inheritance, involving the duplication of genetic material and its segregation during meiosis, there are other hereditary elements that pass into the germ cells also. These include things like methylation patterns in DNA and chromatin marks, both of which regulate the activity of genes. These are considered "Lamarckian" in the sense that they are responsive to environmental stimuli and can differentially effect gene expression adaptively, with phenotypic results that can persist for many generations in certain organisms. Although the reality of epigenetic inheritance is not doubted (as countless experiments have validated it) its significance to the evolutionary process is however uncertain. Most neo-Darwinians consider epigenetic inheritance mechanisms to be little more than a specialized form of phenotypic plasticity, with no potential to introduce evolutionary novelty into a species lineage.[8]
# Lamarckism and single-celled organisms
While Lamarckism has been discredited as an evolutionary influence for larger lifeforms, some scientists controversially argue that it can be observed among microorganisms.[9] Whether such mutations are directed or not also remains a point of contention.
In 1988, John Cairns at the Radcliffe Infirmary in Oxford, England, and a group of other scientists renewed the Lamarckian controversy (which by then had been a dead debate for many years).[10] The group took a mutated strain of E. coli that was unable to consume the sugar lactose and placed it in an environment where lactose was the only food source. They observed over time that mutations occurred within the colony at a rate that suggested the bacteria were overcoming their handicap by altering their own genes. Cairns, among others, dubbed the process adaptive mutagenesis.
If bacteria that had overcome their own inability to consume lactose passed on this "learned" trait to future generations, it could be argued as a form of Lamarckism; though Cairns later chose to distance himself from such a position.[11] More typically, it might be viewed as a form of ontogenic evolution.
There has been some research into Lamarckism and prions. A group of researchers, for example, discovered that in yeast cells containing a specific prion protein Sup35, the yeast were able to gain new genetic material, some of which gave them new abilities such as resistance to a particular herbicide. When the researchers mated the yeast cells with cells not containing the prion, the trait reappeared in some of the resulting offspring, indicating that some information indeed was passed down, though whether or not the information is genetic is debatable: trace prion amounts in the cells may be passed to their offspring, giving the appearance of a new genetic trait where there is none.[12]
Finally, there is growing evidence that cells can activate low-fidelity DNA polymerases in times of stress to induce mutations. While this does not directly confer advantage to the organism on the organismal level, it makes sense at the gene-evolution level. While the acquisition of new genetic traits is random, and selection remains Darwinian, the active process of identifying the necessity to mutate is considered to be Lamarckian.
# Lamarckism and societal change
Jean Molino (2000) has proposed that Lamarckian evolution may be accurately applied to cultural evolution. This was also previously suggested by Peter Medawar (1959) and Conrad Waddington (1961). K. N. Laland and colleagues have recently suggested that Human culture can be looked upon as an ecological niche like phenomena, where the effects of cultural niche construction are transmissible from one generation to the next. One interpretation of the Meme theory is that memes are both Darwinian and Lamarckian in nature, as in addition to being subject to selection pressures based on their ability to differentially influence Human minds, memes can be modified and the effects of that modification passed on. | https://www.wikidoc.org/index.php/Lamarckism | |
0de8c9bd46f97c6b4db11ea945238205615685a7 | wikidoc | Lancetfish | Lancetfish
Lancetfishes are large oceanic predatory fishes in the genus Alepisaurus ("Scaleless lizard"), the only living genus in the family Alepisauridae.
They grow up to two metres long. Very little is known about their biology, even though they are widely distributed in all oceans, except the polar seas. Specimens have been recorded as far north as Greenland. They are often caught as by-catch for vessels long-lining for tuna.
The generic name is from Greek a- meaning "without", lepis meanig "scale", and sauros meaning "lizard".
# Morphology
Lancetfishes possess a long and very high dorsal fin, soft-rayed from end to end, with the presence of an adipose fin behind it. The dorsal fin has 41 to 44 rays, and occupies the greater length of the back, is rounded in outline, about twice as high as the fish is deep, and can be depressed in a groove along the back. The body is slender, laterally flattened, deepest at the gill covers, and tapers back to a slender caudal peduncle. The mouth is wide, gaping to the back of the eye, and each jaw has two or three large fangs, besides smaller teeth. The adipose fin recalls that of the smelt in form and location. The caudal fin is very deeply forked; its upper lobe is prolonged as a long filament, and although most of the specimens seem to lose this when captured. The anal fin originates under the last dorsal ray, and is deeply concave in outline. The ventral fins, are about halfway between the anal and the tip of the snout, while the pectoral fins are considerably longer than the body is deep and are situated very low down on the sides. There are no scales and the fins are exceedingly fragile.
# Species
There are currently two species recognised as valid:
- Longnose lancetfish, Alepisaurus ferox Lowe, 1833
- Shortnose lancetfish, Alepisaurus brevirostris Gibbs 1960.
The main difference is the shape of the snout, which is long and pointed in A. ferox, and slightly shorter in A. brevirostris.
# Ecology
Lancetfish have large mouths and sharp teeth, indicating a predatory mode of life. Their watery muscle is not suited to fast swimming and long pursuit, so it is likely that they are ambush predators, using their narrow body profile and silvery colouration to conceal their presence, then use their large dorsal fin to generate large acceleration, and large mouth and teeth to engulf prey before it can escape. That said, stomach content studies have revealed that they feed mainly upon planktonic crustaceans, squid and salps, as well as other fish. They have also been shown to be cannibalistic. They are preyed upon by opah, sharks, albacore, yellowfin tuna, and fur seals.
There are no commercial fisheries for lancetfishes. Their flesh is watery and gelatinous and, although edible would prove difficult to utilise. They are caught as bycatch by tuna fisheries, and are seen as a pest, taking bait intended for more valuable species. Anecdotal evidence suggesting that they have an aphrodisiac effect is likely to be an urban myth.
The tetraphyllidean tapeworm Pelichnibothrium speciosum is a significant parasite of Longnose lancetfish. It seems that the species is an intermediate or paratenic host for the tapeworm (Scholz et al. 1998).
# Reproduction
The reproductive system of lancetfish is something of a mystery. The gonads of adolescents have been shown to be hermaphroditic, although there is no evidence of functional hermaphroditism in adults. They are oviparous. | Lancetfish
Lancetfishes are large oceanic predatory fishes in the genus Alepisaurus ("Scaleless lizard"), the only living genus in the family Alepisauridae.[2]
They grow up to two metres long. Very little is known about their biology, even though they are widely distributed in all oceans, except the polar seas.[3] Specimens have been recorded as far north as Greenland.[4] They are often caught as by-catch for vessels long-lining for tuna.
The generic name is from Greek a- meaning "without", lepis meanig "scale", and sauros meaning "lizard".
# Morphology
Lancetfishes possess a long and very high dorsal fin, soft-rayed from end to end, with the presence of an adipose fin behind it. The dorsal fin has 41 to 44 rays, and occupies the greater length of the back, is rounded in outline, about twice as high as the fish is deep, and can be depressed in a groove along the back. The body is slender, laterally flattened, deepest at the gill covers, and tapers back to a slender caudal peduncle. The mouth is wide, gaping to the back of the eye, and each jaw has two or three large fangs, besides smaller teeth. The adipose fin recalls that of the smelt in form and location. The caudal fin is very deeply forked; its upper lobe is prolonged as a long filament, and although most of the specimens seem to lose this when captured. The anal fin originates under the last dorsal ray, and is deeply concave in outline. The ventral fins, are about halfway between the anal and the tip of the snout, while the pectoral fins are considerably longer than the body is deep and are situated very low down on the sides. There are no scales and the fins are exceedingly fragile.
# Species
There are currently two species recognised as valid:
- Longnose lancetfish, Alepisaurus ferox Lowe, 1833[5][6]
- Shortnose lancetfish, Alepisaurus brevirostris Gibbs 1960.[7]
The main difference is the shape of the snout, which is long and pointed in A. ferox, and slightly shorter in A. brevirostris.
# Ecology
Lancetfish have large mouths and sharp teeth, indicating a predatory mode of life. Their watery muscle is not suited to fast swimming and long pursuit, so it is likely that they are ambush predators, using their narrow body profile and silvery colouration to conceal their presence, then use their large dorsal fin to generate large acceleration, and large mouth and teeth to engulf prey before it can escape. That said, stomach content studies have revealed that they feed mainly upon planktonic crustaceans, squid and salps, as well as other fish. They have also been shown to be cannibalistic. They are preyed upon by opah, sharks, albacore, yellowfin tuna, and fur seals.
There are no commercial fisheries for lancetfishes. Their flesh is watery and gelatinous and, although edible would prove difficult to utilise. They are caught as bycatch by tuna fisheries, and are seen as a pest, taking bait intended for more valuable species. Anecdotal evidence suggesting that they have an aphrodisiac effect is likely to be an urban myth.
The tetraphyllidean tapeworm Pelichnibothrium speciosum is a significant parasite of Longnose lancetfish. It seems that the species is an intermediate or paratenic host for the tapeworm (Scholz et al. 1998).
# Reproduction
The reproductive system of lancetfish is something of a mystery. The gonads of adolescents have been shown to be hermaphroditic, although there is no evidence of functional hermaphroditism in adults. They are oviparous. | https://www.wikidoc.org/index.php/Lancetfish | |
d66bd2310208be158bd00d11046018a1e035654c | wikidoc | Lanreotide | Lanreotide
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# Overview
Lanreotide is a somatostatin analog that is FDA approved for the treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. Common adverse reactions include diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Somatuline Depot (lanreotide) Injection 60 mg, 90 mg and 120 mg is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.
- The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal.
### Dosage
- Patients should begin treatment with Somatuline Depot 90 mg given via the deep subcutaneous route, at 4 week intervals for 3 months.
- After 3 months dosage may be adjusted as follows:
- Thereafter, the dose should be adjusted according to the response of the patient as judged by a reduction in serum GH and /or IGF-1 levels; and/or changes in symptoms of acromegaly.
- Somatuline Depot should be injected via the deep subcutaneous route in the superior external quadrant of the buttock. The skin should not be folded and the needle should be inserted perpendicular to the skin, rapidly and to its full length. The injection site should alternate between the right and left side.
- The starting dose in patients with moderate and severe renal or moderate and severe hepatic impairment should be 60 mg via the deep subcutaneous route, at 4 week intervals for 3 months followed by dose adjustment as described above
### DOSAGE FORMS AND STRENGTHS
- 60, 90 and 120 mg sterile, single-use, pre-filled syringes. The pre-filled syringes contain a white to pale yellow, semi-solid formulation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lanreotide in adult patients.
### Non–Guideline-Supported Use
- Portal hypertension
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lanreotide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lanreotide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lanreotide in pediatric patients.
# Contraindications
- None
# Warnings
Lanreotide may reduce gallbladder motility and lead to gallstone formation therefore, patients may need to be monitored periodically.
- Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with Somatuline Depot may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.
- Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (<1%). Thyroid function tests are recommended where clinically indicated.
- The most common overall cardiac adverse reactions observed in three pooled Somatuline Depot Cardiac Studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%) and hypertension (12/217, 5.6%).
- In patients without underlying cardiac disease, lanreotide may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to lanreotide treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with lanreotide in patients with bradycardia.
- The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs.
- Lanreotide may decrease the relative bioavailability of cyclosporine. Concomitant administration of Somatuline Depot and cyclosporine may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels.
- Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of 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 practice.
- The data described below reflect exposure to Somatuline Depot in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo controlled run-in period and another had an active control. The population was mainly Caucasian (329/353, 93%) with a median age of 53.0 years of age (range 19-84 years). Fifty-four subjects (13%) were age 66-74 and eighteen subjects (4.3%) were ≥ 75 years of age. Patients were evenly matched for gender (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly severity at baseline (N=265), serum GH levels were < 10 ng/mL for 69% (183/265) of the patients and ≥ 10 ng/mL for 31% (82/265) of the patients.
- The most commonly reported adverse reactions reported by > 5% of patients who received Somatuline Depot (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis and injection site reactions.
- TABLES 1 and 2 present adverse reaction data from clinical studies with Somatuline Depot in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies.
- The incidence of treatment-emergent adverse reactions for Somatuline Depot 60 mg, 90 mg, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 , are provided in TABLE 1.
- In Study 1, the adverse reactions of diarrhea, abdominal pain and flatulence increased in incidence with increasing dose of Somatuline Depot.
- TABLE 2 provides the most common adverse reactions that occurred in 416 acromegalic patients treated with Somatuline Depot in seven studies. The analysis of safety compares adverse reaction rates of patients at baseline from the two efficacy studies, to the overall pooled data from seven studies. Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout
- In addition to the adverse reactions listed in TABLE 2, the following reactions were also seen:
- Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies.
- Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies.
- Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies.
- In the pooled clinical studies of Somatuline Depot therapy, a variety of gastrointestinal reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with Somatuline Depot in the pooled clinical studies discontinued treatment because of gastrointestinal reactions.
- In clinical studies involving 416 acromegalic patients treated with Somatuline Depot, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with Somatuline Depot who underwent routine evaluation with gallbladder ultrasound, 17.4% had gallstones at baseline. New cholelithiasis was reported in 12.0% of patients. Cholelithiasis may be related to dose or duration of exposure.
- In the pooled clinical studies, injection site pain (4.1%) and injection site mass (1.7%) were the most frequently reported local adverse drug reactions that occurred with the administration of Somatuline Depot. In a specific analysis 20 of 413 patients (4.8%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects.
- In the clinical studies in acromegalic patients treated with Somatuline Depot, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients.
- In the pooled clinical studies, sinus bradycardia (3.1%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in < 1% of patients. The relationship of these events to Somatuline Depot could not be established because many of these patients had underlying cardiac disease.
- A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the two treatments over one year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study.
- For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups.
- Laboratory investigations of acromegalic patients treated with Somatuline Depot in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (<1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of Somatuline Depot.
## Postmarketing Experience
- As adverse reactions experienced post approval use 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 profile of reported adverse reactions for Somatuline Depot was consistent with that observed for treatment-related adverse reactions in the clinical studies. Those reported most frequently being gastrointestinal disorders (abdominal pain and diarrhea) and general disorders and administration site conditions (injection site reactions).
# Drug Interactions
- Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.
- Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels.
- The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine.
- Concomitant administration of bradycardia inducing drugs (e.g. beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary.
- Vitamin K absorption was not affected when concomitantly administered with lanreotide.
- The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well controlled studies in pregnant women. Somatuline Depot should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (5-times the human dose based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day, 2-times the human therapeutic exposures at the maximum recommended dose of 120 mg based on comparisons of relative body surface area shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lanreotide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lanreotide during labor and delivery.
### Nursing Mothers
It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions in animals and potential in nursing infants from Somatuline, a decision should be made whether to discontinue nursing or 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
- No overall differences in safety or effectiveness were observed between elderly patients compared with younger patients, and the 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. It is not necessary to alter the starting dose in elderly patients as expected lanreotide serum concentrations in the elderly are well within the range of serum concentrations safely tolerated in healthy young subjects. Similarly, it is not necessary to alter the titration or maintenance doses of Somatuline Depot as dose selection is based on therapeutic response
### Gender
There is no FDA guidance on the use of Lanreotide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lanreotide with respect to specific racial populations.
### Renal Impairment
- Lanreotide has not been studied in patients with mild, moderate and severe renal failure. It is recommended that patients with moderate and severe renal impairment receive a starting dose of lanreotide of 60 mg
### Hepatic Impairment
- It is recommended that patients with moderate and severe hepatic impairment receive a starting dose of lanreotide of 60 mg
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lanreotide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lanreotide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous Injection
### Monitoring
- Lanreotide may reduce gallbladder motility and lead to gallstone formation therefore, patients may need to be monitored periodically
- Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly
- Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment
# IV Compatibility
There is limited information regarding IV Compatibility of Lanreotide in the drug label.
# Overdosage
- If overdose occurs, symptomatic management is indicated.
- There are no confirmed postmarketing cases of overdose with lanreotide that were serious or led to an adverse reaction.
- Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at phone number 1-800-222-1222.
# Pharmacology
## Mechanism of Action
- Lanreotide, the active component of Somatuline Depot is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin.
## Structure
- Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as -3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is:
- Somatuline Depot (lanreotide) Injection 60, 90 and 120 mg is a prolonged-release formulation for deep subcutaneous injection containing the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, and water for injection.
- Somatuline Depot is available as sterile, ready-to-use, pre-filled syringes containing lanreotide supersaturated bulk solution of 24.6% w/w lanreotide base.
## Pharmacodynamics
- Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions.
- The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients . In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Somatuline Depot, plasma GH levels fall rapidly and are maintained for at least 28 days.
- Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits post-prandial secretion of pancreatic polypeptide, gastrin and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in post-prandial insulin secretion, resulting in transient, mild glucose intolerance.
- Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity.
- Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects.
- In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide.
- In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21 day) of lanreotide, serum glucose concentrations were temporarily decreased by 20-30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only.
- Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis.
## Pharmacokinetics
- Somatuline Depot is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the blood stream.
- After a single deep, subcutaneous administration, the mean absolute bioavailability of Somatuline Depot in healthy subjects was 73.4, 69.0 and 78.4%, for the 60, 90 and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Somatuline Depot showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL with 60 mg.
- In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Somatuline Depot between 60 and 120 mg linear pharmacokinetics were observed in acromegalic patients. At steady state mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7 and 7.7 ± 2.5 ng/mL increasing linearly with dose. The mean accumulation ratio index was 2.7 which is in line with the range of values for the half life of Somatuline Depot. The steady-state trough serum lanreotide concentrations in patients receiving Somatuline Depot every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60, 90 and 120 mg doses respectively. A limited initial burst effect and a low peak to trough fluctuation (81% to 108%) of the serum concentration at the plateau was observed.
- For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1 and 4.0 ± 1.4 ng/mL, respectively).
- Somatuline Depot has not been studied in special populations. For completeness, information on studies with an immediate-release formulation (IRF) of lanreotide administered intravenously is provided. A lthough some changes in elimination or distribution have been observed after IRF administration, no changes in the apparent half-life are expected with Somatuline Depot as the terminal phase is controlled by the release of lanreotide from the formulation.
- Subjects with end-stage renal disease requiring dialysis showed an approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC.
- Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects.
- In moderately to severely hepatically-impaired subjects, a 30% reduction in clearance of lanreotide was observed.
- Patients with moderate to severe renal impairment or moderate to severe hepatic impairment should begin treatment with Somatuline Depot 60 mg.
- In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion.
## Nonclinical Toxicology
- Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide acetate at 0.5, 1.5, 5, 10 and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30mg/kg/day resulting in exposures 3-times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide acetate at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant.
- Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay.
- Subcutaneous dosing (30mg/kg/2 wks) before mating and continuing into gestation in rats at doses 5 times the human clinical exposure (120 mg every 4 weeks) based on mg/m2 had reduced fertility. Gestation length was statistically significantly increased suggesting some delay in parturition at 3 times human exposure. The reduction in fertility in non-acromegalic animals is likely related to the pharmacologic activity (decreased growth hormone secretion) of lanreotide acetate.
# Clinical Studies
- The effect of Somatuline Depot on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in two long-term, multiple-dose, randomized multicenter studies.
- This one-year study included a 4-week double-blind, placebo-controlled phase, a 16-week single-blind, fixed-dose phase, and a 32-week open-label dose-titration phase. Patients with active acromegaly based on biochemical tests and medical history entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist.
- Upon entry, patients were randomly allocated to receive a single deep subcutaneous injection of Somatuline Depot 60, 90 or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of Somatuline Depot followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels.
- A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level > 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were to have a mean GH concentration >3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication.
- One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4).
- In the double-blind phase of study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a > 50% decrease in mean GH from baseline to Week 4 including 52%, 44% and 90% of patients in the 60, 90 and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of > 50% including 68% (23/34), 64% (23/36) and 84% (31/37) of patients in the 60, 90 and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see TABLE 3).
- This was a 48-week, open-label, uncontrolled multicenter study which enrolled patients who had an IGF-1 concentration ≥ 1.3 times the upper limit of the age-adjusted normal range. Patients receiving treatment with a somatostatin analog (other than Somatuline Depot) or a dopaminergic agonist had to attain this IGF-1 concentration after a washout period of up to 3 months.
- Patients were initially enrolled in a 4-month fixed-dose phase where they received four deep subcutaneous injections of Somatuline Depot, 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of Somatuline Depot was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again.
- A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48-weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1).
- After 48 weeks of treatment with Somatuline Depot at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline.
- The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations < 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of ≤ 2.5 ng/mL (see TABLE 4) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of <1 ng/mL.
- Examination of age and gender subgroups did not identify differences in response to Somatuline Depot among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of Somatuline Depot in these subgroups.
# How Supplied
- Somatuline Depot is supplied in strengths of 60 mg, 90 mg and 120 mg in a single, sterile, pre-filled, ready-to-use, polypropylene syringe fitted with a 20 mm needle covered by a dry natural rubber sheath. Each pre-filled syringe is sealed in a laminated pouch and packed in a carton.
- NDC 15054-060-01 60-mg, sterile, pre-filled syringe
- NDC 15054-090-01 90-mg, sterile, pre-filled syringe
- NDC 15054-120-02 120-mg, sterile,pre-filled syringe
## Storage
- Somatuline Depot must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light in its original package. Thirty (30) minutes prior to injection, remove sealed pouch of Somatuline Depot from refrigerator and allow it to come to room temperature. Keep pouch sealed until injection.
- Each syringe is intended for single use. Do not use beyond the expiration date on the packaging.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredientd and Appearance
# Patient Counseling Information
- The physician should provide a copy of the FDA-Approved Patient Labeling and review the contents with the patient. Patients should be advised to inform their doctor or pharmacist if they develop any unusual symptoms, or if any known symptom persists or worsens.
- Patients should be advised that response to Somatuline Depot should be monitored by periodic measurements of GH and IGF-1 levels, with a goal of decreasing these levels to the normal range.
### SUPPLEMENTAL PATIENT MATERIAL
- (lanreotide) Injection
- Read the Patient Information that comes with Somatuline® Depot before you receive the first injection and before each monthly injection. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.
- Somatuline® Depot is an injectable medicine used for the long-term treatment of patients with acromegaly:
- Somatuline® Depot contains the medicine lanreotide, which is similar to the hormone somatostatin (which is made in the body). Somatuline® Depot, like somatostatin, lowers the levels of certain hormones in the body such as growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Lowering these hormone levels can help treat patients with acromegaly.
- Somatuline Depot has not been studied in children.
- Tell your doctor about all of your medical conditions, including if you:
- have diabetes.
- have liver or kidney problems.
- have ever had heart problems.
- are allergic to latex or natural dry rubber. The pre-filled syringe needle cover contains rubber.
- are pregnant or can become pregnant. It is not known if Somatuline Depot could harm your unborn baby.
- are breast-feeding or planning to breast-feed. It is not known if Somatuline® Depot passes into your breast milk. Talk to your doctor about the best way to feed your baby if you receive Somatuline® Depot.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Somatuline® Depot and other medicines may affect each other causing side effects. Somatuline® Depot may affect the way other medicines work, and other medicines may affect how Somatuline® Depot works. The dose of Somatuline® Depot or your other medicines may need to be adjusted.
- Especially tell your doctor if you take:
- insulin or other diabetes medicines
- medicines that lower your heart rate such as beta blockers
- Cyclosporine (Gengraf, Neoral, Sandimmune)
- Bromocriptine (Parlodel)
- Know the medicines you take. Keep a list of your medicines and show it to your doctor..
- You will receive a Somatuline® Depot injection every 4 weeks as directed by your doctor. Your doctor will tell you how long you need to receive Somatuline Depot.
- Somatuline® Depot is injected deep under the skin of the upper outer area of your buttock.
- The injection site should change (alternate) between your right and left side each time you receive an injection of Somatuline® Depot.
- After 3 months, your doctor should check your levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), talk to you about your symptoms, and adjust your dose of Somatuline® Depot as needed.
- If you miss an injection, talk with your doctor as soon as possible to advise on another injection.
- Side effects include:
- Stomach and Intestinal problems. Diarrhea, stomach (abdominal) pain, nausea, gas, constipation and loose stools can occur. These side effects tend to diminish with continued treatment.
- Gallbladder problems. Gallstones can develop in the gallbladder. Tell your doctor if you get severe pain in the right upper area of your stomach (abdomen), along with nausea and vomiting. The pain may last for several hours.
- Skin reactions. Pain, itching or a lump may occur at the injection site.
- Heart problems including a low heart rate, high blood pressure, and new or worse heart valve problems.
- Change in blood sugar levels. Somatuline® Depot can cause low blood sugar (hypoglycemia) or high blood sugar (hyperglycemia) levels, especially when you first start receiving the injections or if the dose is changed. If you have diabetes, carefully follow your doctor's instructions for monitoring your blood sugar levels. Your diabetes medicines may need to be changed in order to control your blood sugar while you are receiving Somatuline® Depot.
- Other side effects include: headache, joint pain, anemia (decreased red blood cells), tiredness, and weight loss.
- Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Somatuline® Depot. Ask your doctor for more information.
- Medicines are sometimes prescribed for conditions other than those listed in the patient leaflet. This Patient Information leaflet summarizes the most important information about Somatuline® Depot. If you would like more information about Somatuline® Depot talk with your doctor. You can ask your doctor or healthcare provider for information on Somatuline® Depot that is written for health professionals.
- For more information call TERCICA at 1-866-837-2422 or visit the website at www.somatulinedepot.com.
# Precautions with Alcohol
- Alcohol-Lanreotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Somatuline Depot®
# Look-Alike Drug Names
There is limited information regarding Lanreotide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Lanreotide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Lanreotide is a somatostatin analog that is FDA approved for the treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. Common adverse reactions include diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Somatuline Depot (lanreotide) Injection 60 mg, 90 mg and 120 mg is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.
- The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal.
### Dosage
- Patients should begin treatment with Somatuline Depot 90 mg given via the deep subcutaneous route, at 4 week intervals for 3 months.
- After 3 months dosage may be adjusted as follows:
- Thereafter, the dose should be adjusted according to the response of the patient as judged by a reduction in serum GH and /or IGF-1 levels; and/or changes in symptoms of acromegaly.
- Somatuline Depot should be injected via the deep subcutaneous route in the superior external quadrant of the buttock. The skin should not be folded and the needle should be inserted perpendicular to the skin, rapidly and to its full length. The injection site should alternate between the right and left side.
- The starting dose in patients with moderate and severe renal or moderate and severe hepatic impairment should be 60 mg via the deep subcutaneous route, at 4 week intervals for 3 months followed by dose adjustment as described above
### DOSAGE FORMS AND STRENGTHS
- 60, 90 and 120 mg sterile, single-use, pre-filled syringes. The pre-filled syringes contain a white to pale yellow, semi-solid formulation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lanreotide in adult patients.
### Non–Guideline-Supported Use
- Portal hypertension[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lanreotide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lanreotide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lanreotide in pediatric patients.
# Contraindications
- None
# Warnings
Lanreotide may reduce gallbladder motility and lead to gallstone formation therefore, patients may need to be monitored periodically.
- Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with Somatuline Depot may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.
- Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (<1%). Thyroid function tests are recommended where clinically indicated.
- The most common overall cardiac adverse reactions observed in three pooled Somatuline Depot Cardiac Studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%) and hypertension (12/217, 5.6%).
- In patients without underlying cardiac disease, lanreotide may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to lanreotide treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with lanreotide in patients with bradycardia.
- The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs.
- Lanreotide may decrease the relative bioavailability of cyclosporine. Concomitant administration of Somatuline Depot and cyclosporine may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels.
- Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of 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 practice.
- The data described below reflect exposure to Somatuline Depot in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo controlled run-in period and another had an active control. The population was mainly Caucasian (329/353, 93%) with a median age of 53.0 years of age (range 19-84 years). Fifty-four subjects (13%) were age 66-74 and eighteen subjects (4.3%) were ≥ 75 years of age. Patients were evenly matched for gender (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly severity at baseline (N=265), serum GH levels were < 10 ng/mL for 69% (183/265) of the patients and ≥ 10 ng/mL for 31% (82/265) of the patients.
- The most commonly reported adverse reactions reported by > 5% of patients who received Somatuline Depot (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis and injection site reactions.
- TABLES 1 and 2 present adverse reaction data from clinical studies with Somatuline Depot in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies.
- The incidence of treatment-emergent adverse reactions for Somatuline Depot 60 mg, 90 mg, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 , are provided in TABLE 1.
- In Study 1, the adverse reactions of diarrhea, abdominal pain and flatulence increased in incidence with increasing dose of Somatuline Depot.
- TABLE 2 provides the most common adverse reactions that occurred in 416 acromegalic patients treated with Somatuline Depot in seven studies. The analysis of safety compares adverse reaction rates of patients at baseline from the two efficacy studies, to the overall pooled data from seven studies. Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout
- In addition to the adverse reactions listed in TABLE 2, the following reactions were also seen:
- Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies.
- Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies.
- Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies.
- In the pooled clinical studies of Somatuline Depot therapy, a variety of gastrointestinal reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with Somatuline Depot in the pooled clinical studies discontinued treatment because of gastrointestinal reactions.
- In clinical studies involving 416 acromegalic patients treated with Somatuline Depot, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with Somatuline Depot who underwent routine evaluation with gallbladder ultrasound, 17.4% had gallstones at baseline. New cholelithiasis was reported in 12.0% of patients. Cholelithiasis may be related to dose or duration of exposure.
- In the pooled clinical studies, injection site pain (4.1%) and injection site mass (1.7%) were the most frequently reported local adverse drug reactions that occurred with the administration of Somatuline Depot. In a specific analysis 20 of 413 patients (4.8%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects.
- In the clinical studies in acromegalic patients treated with Somatuline Depot, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients.
- In the pooled clinical studies, sinus bradycardia (3.1%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in < 1% of patients. The relationship of these events to Somatuline Depot could not be established because many of these patients had underlying cardiac disease.
- A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the two treatments over one year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study.
- For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups.
- Laboratory investigations of acromegalic patients treated with Somatuline Depot in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (<1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of Somatuline Depot.
## Postmarketing Experience
- As adverse reactions experienced post approval use 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 profile of reported adverse reactions for Somatuline Depot was consistent with that observed for treatment-related adverse reactions in the clinical studies. Those reported most frequently being gastrointestinal disorders (abdominal pain and diarrhea) and general disorders and administration site conditions (injection site reactions).
# Drug Interactions
- Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.
- Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels.
- The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine.
- Concomitant administration of bradycardia inducing drugs (e.g. beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary.
- Vitamin K absorption was not affected when concomitantly administered with lanreotide.
- The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well controlled studies in pregnant women. Somatuline Depot should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (5-times the human dose based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day, 2-times the human therapeutic exposures at the maximum recommended dose of 120 mg based on comparisons of relative body surface area shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lanreotide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lanreotide during labor and delivery.
### Nursing Mothers
It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions in animals and potential in nursing infants from Somatuline, a decision should be made whether to discontinue nursing or 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
- No overall differences in safety or effectiveness were observed between elderly patients compared with younger patients, and the 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. It is not necessary to alter the starting dose in elderly patients as expected lanreotide serum concentrations in the elderly are well within the range of serum concentrations safely tolerated in healthy young subjects. Similarly, it is not necessary to alter the titration or maintenance doses of Somatuline Depot as dose selection is based on therapeutic response
### Gender
There is no FDA guidance on the use of Lanreotide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lanreotide with respect to specific racial populations.
### Renal Impairment
- Lanreotide has not been studied in patients with mild, moderate and severe renal failure. It is recommended that patients with moderate and severe renal impairment receive a starting dose of lanreotide of 60 mg
### Hepatic Impairment
- It is recommended that patients with moderate and severe hepatic impairment receive a starting dose of lanreotide of 60 mg
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lanreotide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lanreotide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous Injection
### Monitoring
- Lanreotide may reduce gallbladder motility and lead to gallstone formation therefore, patients may need to be monitored periodically
- Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly
- Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment
# IV Compatibility
There is limited information regarding IV Compatibility of Lanreotide in the drug label.
# Overdosage
- If overdose occurs, symptomatic management is indicated.
- There are no confirmed postmarketing cases of overdose with lanreotide that were serious or led to an adverse reaction.
- Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at phone number 1-800-222-1222.
# Pharmacology
## Mechanism of Action
- Lanreotide, the active component of Somatuline Depot is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin.
## Structure
- Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is:
- Somatuline Depot (lanreotide) Injection 60, 90 and 120 mg is a prolonged-release formulation for deep subcutaneous injection containing the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, and water for injection.
- Somatuline Depot is available as sterile, ready-to-use, pre-filled syringes containing lanreotide supersaturated bulk solution of 24.6% w/w lanreotide base.
## Pharmacodynamics
- Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions.
- The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [see Clinical Studies (14)]. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Somatuline Depot, plasma GH levels fall rapidly and are maintained for at least 28 days.
- Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits post-prandial secretion of pancreatic polypeptide, gastrin and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in post-prandial insulin secretion, resulting in transient, mild glucose intolerance.
- Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity.
- Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects.
- In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide.
- In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21 day) of lanreotide, serum glucose concentrations were temporarily decreased by 20-30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only.
- Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis.
## Pharmacokinetics
- Somatuline Depot is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the blood stream.
- After a single deep, subcutaneous administration, the mean absolute bioavailability of Somatuline Depot in healthy subjects was 73.4, 69.0 and 78.4%, for the 60, 90 and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Somatuline Depot showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL with 60 mg.
- In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Somatuline Depot between 60 and 120 mg linear pharmacokinetics were observed in acromegalic patients. At steady state mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7 and 7.7 ± 2.5 ng/mL increasing linearly with dose. The mean accumulation ratio index was 2.7 which is in line with the range of values for the half life of Somatuline Depot. The steady-state trough serum lanreotide concentrations in patients receiving Somatuline Depot every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60, 90 and 120 mg doses respectively. A limited initial burst effect and a low peak to trough fluctuation (81% to 108%) of the serum concentration at the plateau was observed.
- For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1 and 4.0 ± 1.4 ng/mL, respectively).
- Somatuline Depot has not been studied in special populations. For completeness, information on studies with an immediate-release formulation (IRF) of lanreotide administered intravenously is provided. A lthough some changes in elimination or distribution have been observed after IRF administration, no changes in the apparent half-life are expected with Somatuline Depot as the terminal phase is controlled by the release of lanreotide from the formulation.
- Subjects with end-stage renal disease requiring dialysis showed an approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC.
- Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects.
- In moderately to severely hepatically-impaired subjects, a 30% reduction in clearance of lanreotide was observed.
- Patients with moderate to severe renal impairment or moderate to severe hepatic impairment should begin treatment with Somatuline Depot 60 mg.
- In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion.
## Nonclinical Toxicology
- Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide acetate at 0.5, 1.5, 5, 10 and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30mg/kg/day resulting in exposures 3-times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide acetate at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant.
- Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay.
- Subcutaneous dosing (30mg/kg/2 wks) before mating and continuing into gestation in rats at doses 5 times the human clinical exposure (120 mg every 4 weeks) based on mg/m2 had reduced fertility. Gestation length was statistically significantly increased suggesting some delay in parturition at 3 times human exposure. The reduction in fertility in non-acromegalic animals is likely related to the pharmacologic activity (decreased growth hormone secretion) of lanreotide acetate.
# Clinical Studies
- The effect of Somatuline Depot on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in two long-term, multiple-dose, randomized multicenter studies.
- This one-year study included a 4-week double-blind, placebo-controlled phase, a 16-week single-blind, fixed-dose phase, and a 32-week open-label dose-titration phase. Patients with active acromegaly based on biochemical tests and medical history entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist.
- Upon entry, patients were randomly allocated to receive a single deep subcutaneous injection of Somatuline Depot 60, 90 or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of Somatuline Depot followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels.
- A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level > 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were to have a mean GH concentration >3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication.
- One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4).
- In the double-blind phase of study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a > 50% decrease in mean GH from baseline to Week 4 including 52%, 44% and 90% of patients in the 60, 90 and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of > 50% including 68% (23/34), 64% (23/36) and 84% (31/37) of patients in the 60, 90 and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see TABLE 3).
- This was a 48-week, open-label, uncontrolled multicenter study which enrolled patients who had an IGF-1 concentration ≥ 1.3 times the upper limit of the age-adjusted normal range. Patients receiving treatment with a somatostatin analog (other than Somatuline Depot) or a dopaminergic agonist had to attain this IGF-1 concentration after a washout period of up to 3 months.
- Patients were initially enrolled in a 4-month fixed-dose phase where they received four deep subcutaneous injections of Somatuline Depot, 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of Somatuline Depot was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again.
- A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48-weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1).
- After 48 weeks of treatment with Somatuline Depot at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline.
- The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations < 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of ≤ 2.5 ng/mL (see TABLE 4) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of <1 ng/mL.
- Examination of age and gender subgroups did not identify differences in response to Somatuline Depot among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of Somatuline Depot in these subgroups.
# How Supplied
- Somatuline Depot is supplied in strengths of 60 mg, 90 mg and 120 mg in a single, sterile, pre-filled, ready-to-use, polypropylene syringe fitted with a 20 mm needle covered by a dry natural rubber sheath. Each pre-filled syringe is sealed in a laminated pouch and packed in a carton.
- NDC 15054-060-01 60-mg, sterile, pre-filled syringe
- NDC 15054-090-01 90-mg, sterile, pre-filled syringe
- NDC 15054-120-02 120-mg, sterile,pre-filled syringe
## Storage
- Somatuline Depot must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light in its original package. Thirty (30) minutes prior to injection, remove sealed pouch of Somatuline Depot from refrigerator and allow it to come to room temperature. Keep pouch sealed until injection.
- Each syringe is intended for single use. Do not use beyond the expiration date on the packaging.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredientd and Appearance
# Patient Counseling Information
- The physician should provide a copy of the FDA-Approved Patient Labeling and review the contents with the patient. Patients should be advised to inform their doctor or pharmacist if they develop any unusual symptoms, or if any known symptom persists or worsens.
- Patients should be advised that response to Somatuline Depot should be monitored by periodic measurements of GH and IGF-1 levels, with a goal of decreasing these levels to the normal range.
### SUPPLEMENTAL PATIENT MATERIAL
- (lanreotide) Injection
- Read the Patient Information that comes with Somatuline® Depot before you receive the first injection and before each monthly injection. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.
- Somatuline® Depot is an injectable medicine used for the long-term treatment of patients with acromegaly:
- Somatuline® Depot contains the medicine lanreotide, which is similar to the hormone somatostatin (which is made in the body). Somatuline® Depot, like somatostatin, lowers the levels of certain hormones in the body such as growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Lowering these hormone levels can help treat patients with acromegaly.
- Somatuline Depot has not been studied in children.
- Tell your doctor about all of your medical conditions, including if you:
- have diabetes.
- have liver or kidney problems.
- have ever had heart problems.
- are allergic to latex or natural dry rubber. The pre-filled syringe needle cover contains rubber.
- are pregnant or can become pregnant. It is not known if Somatuline Depot could harm your unborn baby.
- are breast-feeding or planning to breast-feed. It is not known if Somatuline® Depot passes into your breast milk. Talk to your doctor about the best way to feed your baby if you receive Somatuline® Depot.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Somatuline® Depot and other medicines may affect each other causing side effects. Somatuline® Depot may affect the way other medicines work, and other medicines may affect how Somatuline® Depot works. The dose of Somatuline® Depot or your other medicines may need to be adjusted.
- Especially tell your doctor if you take:
- insulin or other diabetes medicines
- medicines that lower your heart rate such as beta blockers
- Cyclosporine (Gengraf, Neoral, Sandimmune)
- Bromocriptine (Parlodel)
- Know the medicines you take. Keep a list of your medicines and show it to your doctor..
- You will receive a Somatuline® Depot injection every 4 weeks as directed by your doctor. Your doctor will tell you how long you need to receive Somatuline Depot.
- Somatuline® Depot is injected deep under the skin of the upper outer area of your buttock.
- The injection site should change (alternate) between your right and left side each time you receive an injection of Somatuline® Depot.
- After 3 months, your doctor should check your levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), talk to you about your symptoms, and adjust your dose of Somatuline® Depot as needed.
- If you miss an injection, talk with your doctor as soon as possible to advise on another injection.
- Side effects include:
- Stomach and Intestinal problems. Diarrhea, stomach (abdominal) pain, nausea, gas, constipation and loose stools can occur. These side effects tend to diminish with continued treatment.
- Gallbladder problems. Gallstones can develop in the gallbladder. Tell your doctor if you get severe pain in the right upper area of your stomach (abdomen), along with nausea and vomiting. The pain may last for several hours.
- Skin reactions. Pain, itching or a lump may occur at the injection site.
- Heart problems including a low heart rate, high blood pressure, and new or worse heart valve problems.
- Change in blood sugar levels. Somatuline® Depot can cause low blood sugar (hypoglycemia) or high blood sugar (hyperglycemia) levels, especially when you first start receiving the injections or if the dose is changed. If you have diabetes, carefully follow your doctor's instructions for monitoring your blood sugar levels. Your diabetes medicines may need to be changed in order to control your blood sugar while you are receiving Somatuline® Depot.
- Other side effects include: headache, joint pain, anemia (decreased red blood cells), tiredness, and weight loss.
- Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Somatuline® Depot. Ask your doctor for more information.
- Medicines are sometimes prescribed for conditions other than those listed in the patient leaflet. This Patient Information leaflet summarizes the most important information about Somatuline® Depot. If you would like more information about Somatuline® Depot talk with your doctor. You can ask your doctor or healthcare provider for information on Somatuline® Depot that is written for health professionals.
- For more information call TERCICA at 1-866-837-2422 or visit the website at www.somatulinedepot.com.
# Precautions with Alcohol
- Alcohol-Lanreotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Somatuline Depot®[2]
# Look-Alike Drug Names
There is limited information regarding Lanreotide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lanreotide | |
36f775fc5468ca072e8f723bf3c864980064b443 | wikidoc | Lanthanide | Lanthanide
The lanthanoid (according to IUPAC terminology) (previously lanthanide) series comprises the 15 elements with atomic numbers 57 through 71, from lanthanum to lutetium. All lanthanoids are f-block elements, corresponding to the filling of the 4f electron shell, except for lutetium which is a d-block lanthanoid. The lanthanoid series (Ln) is named after lanthanum.
# Terminology
The trivial name "rare earths" is sometimes used to describe all the lanthanoids together with scandium and yttrium. The term "rare earths" arises from the minerals from which they were isolated, which were uncommon oxide-type minerals. The use of this name is deprecated by IUPAC, as they are neither rare in abundance nor "earths" (an obsolete term for water-insoluble strongly basic oxides of electropositive metals incapable of being smelted into metal using late 18th century technology). These elements are in fact fairly abundant in nature, although rare as compared to the "common" earths such as lime or magnesia. Cerium is the 26th most abundant element in the Earth's crust, neodymium is more abundant than gold and even thulium (the least common naturally-occurring lanthanoids) is more abundant than iodine. Despite their abundance, even the technical term "lanthanoids" reflects a sense of elusiveness on the part of these elements, as it comes from the Greek λανθανειν (lanthanein), "to lie hidden."
IUPAC currently recommends the name lanthanoid rather than lanthanide, as the suffix "-ide" generally indicates negative ions whereas the suffix "-oid" indicates similarity to one of the members of the containing family of elements. In the older literature, the name "lanthanon" was often used. There are alternative arrangements of the periodic table that exclude lanthanum or lutetium from appearing together with the other lanthanides.
# Chemistry
Lanthanoids are chemically similar to each other. Useful comparison can also be made with the actinoids, where the 5f shell is partially filled. The lanthanoids are typically placed below the main body of the periodic table in the manner of a footnote. The full-width version of the periodic table shows the position of the lanthanoids more clearly.
The ionic radii of the lanthanoids decrease through the period — the so-called lanthanoid contraction. Except for cerium (III and IV) and europium (III and II), the lanthanides occur as trivalent cations in nature. As a consequence, their geochemical behaviors are a regular function of ionic radius and, therefore, atomic number. This property results in variations in the abundances of lanthanides that trace natural materials through physical and chemical processes. In addition, two of the lanthanides have radioactive isotopes with long half-lives (147Sm and 176Lu) that date minerals and rocks from Earth, the Moon and meteorites. The lanthanide contraction is responsible for the great geochemical divide that splits the lanthanides into light and heavy-lanthanide enriched minerals, the latter being almost inevitably associated with and dominated by yttrium. This divide is reflected in the first two "rare earths" that were discovered: yttria (1794) and ceria (1803). The divide is driven by the decrease in coordination number as the ionic radius shrinks, and is dramatically illustrated by the two anhydrous phosphate minerals, monazite (monoclinic) and xenotime (tetragonal). The geochemical divide has put more of the light lanthanides in the earths crust, but more of the heavies in the earth's mantle. The result is that although large rich orebodies are found that are enriched in the light lanthanides, correspondingly large orebodies for the heavies are few. The lanthanides obey the Oddo-Harkins rule, which states that odd-numbered elements are less abundant than their even-numbered neighbors.
Most lanthanides are widely used in lasers. These elements deflect UV and Infrared electromagnetic radiation and are commonly used in the production of sunglass lenses.
Due to their specific electronic configurations, lanthanide atoms tend to lose three electrons, usually 5d1 and 6s2, to attain their most stable oxidation state as trivalent ions.
The lanthanide trications, feature a Xe core electronic configuration with the addition of n 4f electrons, with n varying from 0 to 14 . This 4fn sub-shell lies inside the ion, shielded by the 5s2 and 5p6 closed sub-shells. Thus, lanthanide trications are sometimes referred to as “triple-positively charged noble gases”.
The contracted nature of the 4f orbitals, coupled with their small overlap with the ligand atom orbitals, attaches a predominantly ionic character to lanthanide-ligand atom bonds in complexes. Thus, the mainly electrostatic interactions between the lanthanide trication and the atoms of the ligands result in irregular geometric arrangements and a handful of high coordination numbers. Indeed, this triple-positively charged closed shell inert gas electron density characteristic is the foundation of the lanthanide Sparkle Model, used in the computational chemistry of lanthanide complexes.
Several properties, such as ionization energies, optical properties, magnetic moments and geometries of complexes, etc, serve as proof that the 4f orbitals are indeed wholly shielded from ligand effects.
Lanthanides entering the human body due to exposure to various industrial processes can affect metabolic processes. Trivalent lanthanide ions, especially La3+ and Gd3+, can interfere with calcium channels in human and animal cells. Lanthanides can also alter or even inhibit the action of various enzymes. Lanthanide ions found in neurons can regulate synaptic transmition, as well as block some receptors (for example, glutamate receptors).
# Properties
All lanthanides closely resemble lanthanum. They are electropositive trivalent metals. They are shiny and silvery-white, and tarnish easily when exposed to air. Many make steel. They react violently with most nonmetals. They are relatively soft but their hardness increases with their atomic number. Lanthanides burn in air. They have high melting and boiling points.
# Mnemonics
To remember the sequence of the lanthanide elements, various mnemonic phrases have been used. This is the most common one:
Ladies Can't Put Nickels Properly into Slot-machines. Every Girl Tries Daily, However, Every Time You Look. | Lanthanide
The lanthanoid (according to IUPAC terminology) (previously lanthanide) series comprises the 15 elements with atomic numbers 57 through 71, from lanthanum to lutetium. [1] [2] All lanthanoids are f-block elements, corresponding to the filling of the 4f electron shell, except for lutetium which is a d-block lanthanoid. The lanthanoid series (Ln) is named after lanthanum.
# Terminology
The trivial name "rare earths" is sometimes used to describe all the lanthanoids together with scandium and yttrium. The term "rare earths" arises from the minerals from which they were isolated, which were uncommon oxide-type minerals. The use of this name is deprecated by IUPAC, as they are neither rare in abundance nor "earths" (an obsolete term for water-insoluble strongly basic oxides of electropositive metals incapable of being smelted into metal using late 18th century technology). These elements are in fact fairly abundant in nature, although rare as compared to the "common" earths such as lime or magnesia. Cerium is the 26th most abundant element in the Earth's crust, neodymium is more abundant than gold and even thulium (the least common naturally-occurring lanthanoids) is more abundant than iodine[3]. Despite their abundance, even the technical term "lanthanoids" reflects a sense of elusiveness on the part of these elements, as it comes from the Greek λανθανειν (lanthanein), "to lie hidden."
IUPAC currently recommends the name lanthanoid rather than lanthanide, as the suffix "-ide" generally indicates negative ions whereas the suffix "-oid" indicates similarity to one of the members of the containing family of elements. In the older literature, the name "lanthanon" was often used. There are alternative arrangements of the periodic table that exclude lanthanum or lutetium from appearing together with the other lanthanides.
# Chemistry
Lanthanoids are chemically similar to each other. Useful comparison can also be made with the actinoids, where the 5f shell is partially filled. The lanthanoids are typically placed below the main body of the periodic table in the manner of a footnote. The full-width version of the periodic table shows the position of the lanthanoids more clearly.
The ionic radii of the lanthanoids decrease through the period — the so-called lanthanoid contraction. Except for cerium (III and IV) and europium (III and II), the lanthanides occur as trivalent cations in nature. As a consequence, their geochemical behaviors are a regular function of ionic radius and, therefore, atomic number. This property results in variations in the abundances of lanthanides that trace natural materials through physical and chemical processes. In addition, two of the lanthanides have radioactive isotopes with long half-lives (147Sm and 176Lu) that date minerals and rocks from Earth, the Moon and meteorites. The lanthanide contraction is responsible for the great geochemical divide that splits the lanthanides into light and heavy-lanthanide enriched minerals, the latter being almost inevitably associated with and dominated by yttrium. This divide is reflected in the first two "rare earths" that were discovered: yttria (1794) and ceria (1803). The divide is driven by the decrease in coordination number as the ionic radius shrinks, and is dramatically illustrated by the two anhydrous phosphate minerals, monazite (monoclinic) and xenotime (tetragonal). The geochemical divide has put more of the light lanthanides in the earths crust, but more of the heavies in the earth's mantle. The result is that although large rich orebodies are found that are enriched in the light lanthanides, correspondingly large orebodies for the heavies are few. The lanthanides obey the Oddo-Harkins rule, which states that odd-numbered elements are less abundant than their even-numbered neighbors.
Most lanthanides are widely used in lasers. These elements deflect UV and Infrared electromagnetic radiation and are commonly used in the production of sunglass lenses.
Due to their specific electronic configurations, lanthanide atoms tend to lose three electrons, usually 5d1 and 6s2, to attain their most stable oxidation state as trivalent ions.
The lanthanide trications, feature a Xe core electronic configuration with the addition of n 4f electrons, with n varying from 0 [for La(III)] to 14 [for Lu(III)]. This 4fn sub-shell lies inside the ion, shielded by the 5s2 and 5p6 closed sub-shells. Thus, lanthanide trications are sometimes referred to as “triple-positively charged noble gases”.
The contracted nature of the 4f orbitals, coupled with their small overlap with the ligand atom orbitals, attaches a predominantly ionic character to lanthanide-ligand atom bonds in complexes. Thus, the mainly electrostatic interactions between the lanthanide trication and the atoms of the ligands result in irregular geometric arrangements and a handful of high coordination numbers. Indeed, this triple-positively charged closed shell inert gas electron density characteristic is the foundation of the lanthanide Sparkle Model, used in the computational chemistry of lanthanide complexes.
Several properties, such as ionization energies, optical properties, magnetic moments and geometries of complexes, etc, serve as proof that the 4f orbitals are indeed wholly shielded from ligand effects.
Lanthanides entering the human body due to exposure to various industrial processes can affect metabolic processes. Trivalent lanthanide ions, especially La3+ and Gd3+, can interfere with calcium channels in human and animal cells. Lanthanides can also alter or even inhibit the action of various enzymes. Lanthanide ions found in neurons can regulate synaptic transmition, as well as block some receptors (for example, glutamate receptors)[4].
# Properties
All lanthanides closely resemble lanthanum. They are electropositive trivalent metals. They are shiny and silvery-white, and tarnish easily when exposed to air. Many make steel. They react violently with most nonmetals. They are relatively soft but their hardness increases with their atomic number. Lanthanides burn in air. They have high melting and boiling points.
# Mnemonics
To remember the sequence of the lanthanide elements, various mnemonic phrases have been used. This is the most common one:
Ladies Can't Put Nickels Properly into Slot-machines. Every Girl Tries Daily, However, Every Time You Look. | https://www.wikidoc.org/index.php/Lanthanide | |
980e7f7b0ca2374b2d74f573ba000b59799d760b | wikidoc | Lanthanoid | Lanthanoid
The lanthanoid (according to IUPAC terminology) (previously lanthanide) series comprises the 15 elements with atomic numbers 57 through 71, from lanthanum to lutetium. All lanthanoids are f-block elements, corresponding to the filling of the 4f electron shell, except for lutetium which is a d-block lanthanoid. The lanthanoid series (Ln) is named after lanthanum.
# Terminology
The trivial name "rare earths" is sometimes used to describe all the lanthanoids together with scandium and yttrium. The term "rare earths" arises from the minerals from which they were isolated, which were uncommon oxide-type minerals. The use of this name is deprecated by IUPAC, as they are neither rare in abundance nor "earths" (an obsolete term for water-insoluble strongly basic oxides of electropositive metals incapable of being smelted into metal using late 18th century technology). These elements are in fact fairly abundant in nature, although rare as compared to the "common" earths such as lime or magnesia. Cerium is the 26th most abundant element in the Earth's crust, neodymium is more abundant than gold and even thulium (the least common naturally-occurring lanthanoid) is more abundant than iodine. Despite their abundance, even the technical term "lanthanoids" reflects a sense of elusiveness on the part of these elements, as it comes from the Greek λανθανειν (lanthanein), "to lie hidden."
IUPAC currently recommends the name lanthanoid rather than lanthanide, as the suffix "-ide" generally indicates negative ions whereas the suffix "-oid" indicates similarity to one of the members of the containing family of elements. In the older literature, the name "lanthanon" was often used. There are alternative arrangements of the periodic table that exclude lanthanum or lutetium from appearing together with the other lanthanides.
# Chemistry
Lanthanoids are chemically similar to each other. Useful comparison can also be made with the actinoids, where the 5f shell is partially filled. The lanthanoids are typically placed below the main body of the periodic table in the manner of a footnote. The full-width version of the periodic table shows the position of the lanthanoids more clearly.
The ionic radii of the lanthanoids decrease through the period — the so-called lanthanoid contraction. Except for cerium (III and IV) and europium (III and II), the lanthanides occur as trivalent cations in nature. As a consequence, their geochemical behaviors are a regular function of ionic radius and, therefore, atomic number. This property results in variations in the abundances of lanthanides that trace natural materials through physical and chemical processes. In addition, two of the lanthanides have radioactive isotopes with long half-lives (147Sm and 176Lu) that date minerals and rocks from Earth, the Moon and meteorites. The lanthanide contraction is responsible for the great geochemical divide that splits the lanthanides into light and heavy-lanthanide enriched minerals, the latter being almost inevitably associated with and dominated by yttrium. This divide is reflected in the first two "rare earths" that were discovered: yttria (1794) and ceria (1803). The divide is driven by the decrease in coordination number as the ionic radius shrinks, and is dramatically illustrated by the two anhydrous phosphate minerals, monazite (monoclinic) and xenotime (tetragonal). The geochemical divide has put more of the light lanthanides in the earths crust, but more of the heavies in the earth's mantle. The result is that although large rich orebodies are found that are enriched in the light lanthanides, correspondingly large orebodies for the heavies are few. The lanthanides obey the Oddo-Harkins rule, which states that odd-numbered elements are less abundant than their even-numbered neighbors.
Most lanthanides are widely used in lasers. These elements deflect UV and Infrared electromagnetic radiation and are commonly used in the production of sunglass lenses.
Due to their specific electronic configurations, lanthanide atoms tend to lose three electrons, usually 5d1 and 6s2, to attain their most stable oxidation state as trivalent ions.
The lanthanide trications, feature a Xe core electronic configuration with the addition of n 4f electrons, with n varying from 0 to 14 . This 4fn sub-shell lies inside the ion, shielded by the 5s2 and 5p6 closed sub-shells. Thus, lanthanide trications are sometimes referred to as “triple-positively charged noble gases”.
The contracted nature of the 4f orbitals, coupled with their small overlap with the ligand atom orbitals, attaches a predominantly ionic character to lanthanide-ligand atom bonds in complexes. Thus, the mainly electrostatic interactions between the lanthanide trication and the atoms of the ligands result in irregular geometric arrangements and a handful of high coordination numbers. Indeed, this triple-positively charged closed shell inert gas electron density characteristic is the foundation of the lanthanide Sparkle Model, used in the computational chemistry of lanthanide complexes.
Several properties, such as ionization energies, optical properties, magnetic moments and geometries of complexes, etc, serve as proof that the 4f orbitals are indeed wholly shielded from ligand effects.
Lanthanides entering the human body due to exposure to various industrial processes can affect metabolic processes. Trivalent lanthanide ions, especially La3+ and Gd3+, can interfere with calcium channels in human and animal cells. Lanthanides can also alter or even inhibit the action of various enzymes. Lanthanide ions found in neurons can regulate synaptic transmition, as well as block some receptors (for example, glutamate receptors).
# Properties
All lanthanides closely resemble lanthanum. They are electropositive trivalent metals. They are shiny and silvery-white, and tarnish easily when exposed to air. Many make steel. They react violently with most nonmetals. They are relatively soft but their hardness increases with their atomic number. Lanthanides burn in air. They have high melting and boiling points.
# Mnemonics
To remember the sequence of the lanthanide elements, various mnemonic phrases have been used. The most common one being:
Ladies Can't Put Nickels Properly into Slot-machines. Every Girl Tries Daily, However, Every Time You Look. | Lanthanoid
The lanthanoid (according to IUPAC terminology) (previously lanthanide) series comprises the 15 elements with atomic numbers 57 through 71, from lanthanum to lutetium. [1] [2] All lanthanoids are f-block elements, corresponding to the filling of the 4f electron shell, except for lutetium which is a d-block lanthanoid. The lanthanoid series (Ln) is named after lanthanum.
# Terminology
The trivial name "rare earths" is sometimes used to describe all the lanthanoids together with scandium and yttrium. The term "rare earths" arises from the minerals from which they were isolated, which were uncommon oxide-type minerals. The use of this name is deprecated by IUPAC, as they are neither rare in abundance nor "earths" (an obsolete term for water-insoluble strongly basic oxides of electropositive metals incapable of being smelted into metal using late 18th century technology)[citation needed]. These elements are in fact fairly abundant in nature, although rare as compared to the "common" earths such as lime or magnesia. Cerium is the 26th most abundant element in the Earth's crust, neodymium is more abundant than gold and even thulium (the least common naturally-occurring lanthanoid) is more abundant than iodine[3]. Despite their abundance, even the technical term "lanthanoids" reflects a sense of elusiveness on the part of these elements, as it comes from the Greek λανθανειν (lanthanein), "to lie hidden."
IUPAC currently recommends the name lanthanoid rather than lanthanide, as the suffix "-ide" generally indicates negative ions whereas the suffix "-oid" indicates similarity to one of the members of the containing family of elements. In the older literature, the name "lanthanon" was often used. There are alternative arrangements of the periodic table that exclude lanthanum or lutetium from appearing together with the other lanthanides.
# Chemistry
Lanthanoids are chemically similar to each other. Useful comparison can also be made with the actinoids, where the 5f shell is partially filled. The lanthanoids are typically placed below the main body of the periodic table in the manner of a footnote. The full-width version of the periodic table shows the position of the lanthanoids more clearly.
The ionic radii of the lanthanoids decrease through the period — the so-called lanthanoid contraction. Except for cerium (III and IV) and europium (III and II), the lanthanides occur as trivalent cations in nature. As a consequence, their geochemical behaviors are a regular function of ionic radius and, therefore, atomic number. This property results in variations in the abundances of lanthanides that trace natural materials through physical and chemical processes. In addition, two of the lanthanides have radioactive isotopes with long half-lives (147Sm and 176Lu) that date minerals and rocks from Earth, the Moon and meteorites. The lanthanide contraction is responsible for the great geochemical divide that splits the lanthanides into light and heavy-lanthanide enriched minerals, the latter being almost inevitably associated with and dominated by yttrium. This divide is reflected in the first two "rare earths" that were discovered: yttria (1794) and ceria (1803). The divide is driven by the decrease in coordination number as the ionic radius shrinks, and is dramatically illustrated by the two anhydrous phosphate minerals, monazite (monoclinic) and xenotime (tetragonal). The geochemical divide has put more of the light lanthanides in the earths crust, but more of the heavies in the earth's mantle. The result is that although large rich orebodies are found that are enriched in the light lanthanides, correspondingly large orebodies for the heavies are few. The lanthanides obey the Oddo-Harkins rule, which states that odd-numbered elements are less abundant than their even-numbered neighbors.
Most lanthanides are widely used in lasers. These elements deflect UV and Infrared electromagnetic radiation and are commonly used in the production of sunglass lenses.
Due to their specific electronic configurations, lanthanide atoms tend to lose three electrons, usually 5d1 and 6s2, to attain their most stable oxidation state as trivalent ions.
The lanthanide trications, feature a Xe core electronic configuration with the addition of n 4f electrons, with n varying from 0 [for La(III)] to 14 [for Lu(III)]. This 4fn sub-shell lies inside the ion, shielded by the 5s2 and 5p6 closed sub-shells. Thus, lanthanide trications are sometimes referred to as “triple-positively charged noble gases”.
The contracted nature of the 4f orbitals, coupled with their small overlap with the ligand atom orbitals, attaches a predominantly ionic character to lanthanide-ligand atom bonds in complexes. Thus, the mainly electrostatic interactions between the lanthanide trication and the atoms of the ligands result in irregular geometric arrangements and a handful of high coordination numbers. Indeed, this triple-positively charged closed shell inert gas electron density characteristic is the foundation of the lanthanide Sparkle Model, used in the computational chemistry of lanthanide complexes.
Several properties, such as ionization energies, optical properties, magnetic moments and geometries of complexes, etc, serve as proof that the 4f orbitals are indeed wholly shielded from ligand effects.
Lanthanides entering the human body due to exposure to various industrial processes can affect metabolic processes. Trivalent lanthanide ions, especially La3+ and Gd3+, can interfere with calcium channels in human and animal cells. Lanthanides can also alter or even inhibit the action of various enzymes. Lanthanide ions found in neurons can regulate synaptic transmition, as well as block some receptors (for example, glutamate receptors)[4].
# Properties
All lanthanides closely resemble lanthanum. They are electropositive trivalent metals. They are shiny and silvery-white, and tarnish easily when exposed to air. Many make steel. They react violently with most nonmetals. They are relatively soft but their hardness increases with their atomic number. Lanthanides burn in air. They have high melting and boiling points.
# Mnemonics
To remember the sequence of the lanthanide elements, various mnemonic phrases have been used. The most common[citation needed] one being:
Ladies Can't Put Nickels Properly into Slot-machines. Every Girl Tries Daily, However, Every Time You Look. | https://www.wikidoc.org/index.php/Lanthanides | |
5e36eccdb9b29068080b04df003dc23fe357fbf7 | wikidoc | Laparotomy | Laparotomy
# Overview
A laparotomy is a surgical procedure involving an incision through the abdominal wall to gain access into the abdominal cavity. It is also known as coeliotomy.
# Terminology
In diagnostic laparotomy (most often referred to as an exploratory laparotomy), the nature of the disease is unknown, and laparotomy is deemed the best way to identify the cause.
In therapeutic laparotomy, a cause has been identified (e.g. peptic ulcer, colon cancer) and laparotomy is required for its therapy.
Usually, only exploratory laparotomy is referred to as a surgical operation by itself; and when a specific operation is already planned, laparotomy is considered merely the first step of the procedure.
# Spaces accessed
Depending on incision placement, it may give access to any abdominal organ or space, and is the first step in any major diagnostic or therapeutic surgical procedure of these organs, which include:
- the lower part of the digestive tract (the stomach, duodenum, jejunum, ileum and colon)
- the liver, pancreas and spleen
- the bladder
- the female reproductive organs (the uterus and ovaries)
- the retroperitoneum (the kidneys, the aorta, abdominal lymph nodes)
# Types of incisions
## Midline
The most common incision for laparotomy is the midline incision, a vertical incision which follows the linea alba.
- The upper midline incision usually extends from the xiphoid process to the umbilicus.
- A typical lower midline incision is limited by the umbilicus superiorly and by the pubic symphysis inferiorly.
- Sometimes a single incision extending from xiphoid process to pubic symphysis is employed, especially in trauma surgery.
Midline incisions are particularly favoured in diagnostic laparotomy, as they allow wide access to most of the abdominal cavity.
## Other
Other common laparotomy incisions include:
- the Kocher (right subcostal) incision (after Emil Theodor Kocher); appropriate for certain operations on the liver, gallbladder and biliary tract;
- the Davis or Rockey-Davis "muscle-splitting" right lower quadrant incision for appendectomy;
- the Pfannenstiel incision, a transverse incision below the umbilicus and just above the pubic symphysis. In the classic Pfannenstiel incision, the skin and subcutaneous tissue are incised transversally, but the linea alba is opened vertically. It is the incision of choice for Cesarean section and for abdominal hysterectomy for benign disease. A variation of this incision is the Maylard incision in which the rectus abdominis muscles are sectioned transversally to permit wider access to the pelvis.
- Lumbotomy consists of a lumbar incision which permits access to the kidneys (which are retroperitoneal) without entering the peritoneal cavity. It is typically used only for benign renal lesions. It has also been proposed for surgery of the upper urological tract.
# Related procedures
A related procedure is laparoscopy, where cameras and other instruments are inserted into the peritoneal cavity via small holes in the abdomen. For example, an appendectomy can be done either by a laparotomy or by a laparoscopic approach. | Laparotomy
Template:Interventions infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A laparotomy is a surgical procedure involving an incision through the abdominal wall to gain access into the abdominal cavity. It is also known as coeliotomy.
# Terminology
In diagnostic laparotomy (most often referred to as an exploratory laparotomy), the nature of the disease is unknown, and laparotomy is deemed the best way to identify the cause.
In therapeutic laparotomy, a cause has been identified (e.g. peptic ulcer, colon cancer) and laparotomy is required for its therapy.
Usually, only exploratory laparotomy is referred to as a surgical operation by itself; and when a specific operation is already planned, laparotomy is considered merely the first step of the procedure.
# Spaces accessed
Depending on incision placement, it may give access to any abdominal organ or space, and is the first step in any major diagnostic or therapeutic surgical procedure of these organs, which include:
- the lower part of the digestive tract (the stomach, duodenum, jejunum, ileum and colon)
- the liver, pancreas and spleen
- the bladder
- the female reproductive organs (the uterus and ovaries)
- the retroperitoneum (the kidneys, the aorta, abdominal lymph nodes)
# Types of incisions
## Midline
The most common incision for laparotomy is the midline incision, a vertical incision which follows the linea alba.
- The upper midline incision usually extends from the xiphoid process to the umbilicus.
- A typical lower midline incision is limited by the umbilicus superiorly and by the pubic symphysis inferiorly.
- Sometimes a single incision extending from xiphoid process to pubic symphysis is employed, especially in trauma surgery.
Midline incisions are particularly favoured in diagnostic laparotomy, as they allow wide access to most of the abdominal cavity.
## Other
Other common laparotomy incisions include:
- the Kocher (right subcostal) incision (after Emil Theodor Kocher); appropriate for certain operations on the liver, gallbladder and biliary tract;[1][2]
- the Davis or Rockey-Davis "muscle-splitting" right lower quadrant incision for appendectomy;[3]
- the Pfannenstiel incision, a transverse incision below the umbilicus and just above the pubic symphysis.[4][5] In the classic Pfannenstiel incision, the skin and subcutaneous tissue are incised transversally, but the linea alba is opened vertically. It is the incision of choice for Cesarean section and for abdominal hysterectomy for benign disease. A variation of this incision is the Maylard incision in which the rectus abdominis muscles are sectioned transversally to permit wider access to the pelvis.[6]
- Lumbotomy consists of a lumbar incision which permits access to the kidneys (which are retroperitoneal) without entering the peritoneal cavity. It is typically used only for benign renal lesions. It has also been proposed for surgery of the upper urological tract.[7]
# Related procedures
A related procedure is laparoscopy, where cameras and other instruments are inserted into the peritoneal cavity via small holes in the abdomen. For example, an appendectomy can be done either by a laparotomy or by a laparoscopic approach. | https://www.wikidoc.org/index.php/Laparotomy | |
7e71de032f9a7838dd96ac756b0844c711854c46 | wikidoc | Laquinimod | Laquinimod
# Overview
Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is being investigated as an oral treatment for multiple sclerosis (MS).
Laquinimod is the successor of Active Biotech's failed experimental immunomodulator linomide.
The compound has been investigated in two Phase II trials using successive magnetic resonance scans (MRI). Laquinimod seems to be able to reduce the MS disease activity on MRI. However, the response to a given dose was discrepant between both studies.
Phase III studies for MS started in December 2007. In 2011, Teva announced its clinical trials involving laquinimod had failed, being unable to significantly reduce relapses into MS among patients beyond a placebo. However, the final results of above-mentioned phase III trial proved oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing–remitting multiple sclerosis. | Laquinimod
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is being investigated as an oral treatment for multiple sclerosis (MS).
Laquinimod is the successor of Active Biotech's failed experimental immunomodulator linomide.[1]
The compound has been investigated in two Phase II trials using successive magnetic resonance scans (MRI). Laquinimod seems to be able to reduce the MS disease activity on MRI.[2][3] However, the response to a given dose was discrepant between both studies.[4]
Phase III studies for MS started in December 2007.[5] In 2011, Teva announced its clinical trials involving laquinimod had failed, being unable to significantly reduce relapses into MS among patients beyond a placebo.[6] However, the final results of above-mentioned phase III trial proved oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing–remitting multiple sclerosis.[7] | https://www.wikidoc.org/index.php/Laquinimod | |
42c26bab3b91b326517061dc73fdbdd2d2a69fb6 | wikidoc | Laronidase | Laronidase
# 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
Laronidase is a Enzyme that is FDA approved for the treatment of Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pyrexia, chills, Hypertension, tachycardia, hypoxemia, rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ALDURAZYME® (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.
- ALDURAZYME has been shown to improve pulmonary function and walking capacity. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.
### Dosage
- The recommended dosage regimen of ALDURAZYME is 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both.
- Each vial of ALDURAZYME provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques. The final volume of the infusion is determined by the patient’s body weight. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL. For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting ALDURAZYME in a volume of 100 mL and administering at a decreased infusion rate.
- Prepare and use ALDURAZYME according to the following steps. Use aseptic techniques. Prepare ALDURAZYME using low-protein-binding containers and administer with a low-protein-binding infusion set equipped with an in-line, low-protein-binding 0.2 micrometer (µm) filter. There is no information on the compatibility of diluted ALDURAZYME with glass containers.
- Determine the number of vials to be diluted based on the patient's weight and the recommended dose of 0.58 mg/kg, using the following equation:
- Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials.
- Before withdrawing the ALDURAZYME from the vial, visually inspect each vial for particulate matter and discoloration. The ALDURAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution.
- Withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of ALDURAZYME concentrate to be added.
- Slowly withdraw the calculated volume of ALDURAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature ALDURAZYME, rendering it biologically inactive.
- Slowly add the ALDURAZYME solution to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle.
- Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME. Do not shake the solution.
- The entire infusion volume (100 mL for patients weighing 20 kg or less and 250 mL for patients weighing greater than 20 kg) should be delivered over approximately 3 to 4 hours. The initial infusion rate of 10 µg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 µg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours), as outlined in Tables 1 and 2.
- Administer the diluted ALDURAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Laronidase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Laronidase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Mucopolysaccharidosis, Type I (Hurler and Hurler-Scheie forms)
### Dosage
- (6 months or older) 0.58 mg/kg of body weight as an IV infusion once a week; pretreat 60 minutes before infusion with antihistamines and/or antipyretics
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Laronidase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Laronidase in pediatric patients.
# Contraindications
- None
# Warnings
- Anaphylaxis and severe allergic reactions have been observed in patients during or up to 3 hours after ALDURAZYME infusions. Some of these reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria. If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of ALDURAZYME and initiate appropriate medical treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.
- In clinical studies and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions. Due to the potential for severe allergic reactions, appropriate medical support should be readily available when Aldurazyme is administered. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.
- The risks and benefits of re-administering ALDURAZYME following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.
- Patients with an acute febrile or respiratory illness at the time of ALDURAZYME infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient’s clinical status prior to administration of ALDURAZYME and consider delaying ALDURAZYME infusion. One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first Aldurazyme infusion that resolved without intervention. The patient’s respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest, and died.
- Sleep apnea is common in MPS I patients. Evaluation of airway patency should be considered prior to initiation of treatment with ALDURAZYME. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.
- Caution should be exercised when administering ALDURAZYME to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ALDURAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.
- Because of the potential for infusion reactions, patients should receive antipyretics and/or antihistamines prior to infusion. If an infusion reaction occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms
# 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 serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and allergic reactions. Most adverse reactions reported in clinical trials were considered disease-related and unrelated to study drug. The most common adverse reactions were infusion reactions. The frequency of infusion reactions decreased over time with continued use of ALDURAZYME, and the majority of reactions were classified as being mild to moderate in severity. Most infusion reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, antipyretics, or both.
- A 26-week, double-blind, placebo-controlled clinical study (Study 1) of ALDURAZYME was conducted in 45 patients with MPS I, ages 6 to 43 years old, gender evenly distributed (N=23 females and 22 males). Of these 45 patients, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie, and 7 Scheie. Patients were randomized to receive either 0.58 mg/kg IV of ALDURAZYME per week for 26 weeks or placebo. All patients were treated with antipyretics and antihistamines prior to the infusions. Infusion reactions were reported in 32% (7 of 22) of ALDURAZYME-treated patients. The most commonly reported infusion reactions regardless of treatment group were flushing, pyrexia, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. Less common infusion reactions included angioedema (including face edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.
Table 3 enumerates adverse reactions and selected laboratory abnormalities that occurred during the placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.
- All 45 patients who completed the placebo-controlled study (Study 1) continued treatment in an open-label, uncontrolled extension study (Study 2). All patients received ALDURAZYME 0.58 mg/kg of body weight once weekly for up to 182 weeks. The most serious adverse reactions reported with ALDURAZYME infusions in Study 2 were anaphylactic and allergic reactions. The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME. The most commonly reported infusion reactions included rash (13%), flushing (11%), pyrexia (11%), headache (9%), abdominal pain or discomfort (9%), and injection site reaction (9%). Less commonly reported infusion reactions included nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4%), arthralgia (4%), and urticaria (4%). Additional common adverse reactions included back pain and musculoskeletal pain.
- Study 3 was a 52-week, open-label, uncontrolled study of 20 MPS I patients, ages 6 months to 5 years old (at enrollment). Sixteen patients were clinically assessed as having the Hurler form, and 4 had the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks and up to 52 weeks. All patients were treated with antipyretics and antihistamines prior to the infusions.
- The most commonly reported serious adverse events (regardless of relationship) reported with ALDURAZYME infusions in Study 3 were otitis media (20%), and central venous catheterization required for ALDURAZYME infusion (15%).
- The nature and severity of infusion reactions were similar between the older and less severely affected patients in Studies 1 and 2, and the younger, more severely affected patients in Study 3. The most commonly reported adverse reactions in Study 3 were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), hypertension (10%), tachycardia (10%), and hypoxemia (10%). Other commonly reported infusion reactions occurring in ≥ 5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritis, and rash.
- In clinical trials, 99 of 102 patients (97%) treated with ALDURAZYME were positive for IgG antibodies to ALDURAZYME. No correlation was demonstrated between the presence of IgG anti-ALDURAZYME antibodies and therapeutic response (6 MWT and FVC) or the occurrence of allergic reactions. Potential for antibody neutralization of cellular uptake has not been assessed. No consistent association was demonstrated between the presence of antibodies that neutralize enzymatic activity and therapeutic response.
- The data reflect the percentage of patients whose test results were considered positive for antibodies to ALDURAZYME using a specific enzyme-linked immunosorbent assay (ELISA) and confirmed by radio-immunoprecipitation (RIP). ALDURAZYME IgG antibodies were reported as titers. Drug specific antibody was detected in 42 of the 45 patients (93.3%) treated in Study 1 and Study 2. The mean time to seroconversion was 51 days in patients 6 years and older. In Study 3, all patients (100%) 5 years old or younger developed IgG antibodies against ALDURAZYME with a mean time to seroconversion of 26 days for the Study populations].
- Nine patients in Study 1 and Study 2, collectively, who experienced severe infusion reactions were tested for ALDURAZYME-specific IgE antibodies and complement activation. IgE testing was performed by ELISA, and complement activation was measured by the Quidel Enzyme Immunoassay. One of the nine patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgE binding antibodies and complement activation. None of the patients in the open-label clinical study of patients 5 years old or younger (Study 3) tested positive for IgE.
- Other allergic reactions were also seen in patients receiving ALDURAZYME.
- In the postmarketing setting, approximately 1% of patients experienced severe or serious infusion allergic reactions and tested positive for IgE. Of these IgE-positive patients, some have discontinued treatment, but some have been successfully re-challenged. The clinical significance of IgE antibodies has not been established.
- As with all the therapeutic proteins, there is potential for immunogenicity. The incidence 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, comparison of the incidence of antibodies to ALDURAZYME with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of ALDURAZYME. 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.
- In postmarketing experience with ALDURAZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock and laryngeal edema.
- Adverse reactions resulting in death reported in the postmarketing setting with ALDURAZYME treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, and pneumonia. These events have been reported in MPS I patients with significant underlying disease.
- Additional adverse reactions included fatigue, edema peripheral, erythema and cyanosis.
- There have been a small number of reports of extravasation in patients treated with ALDURAZYME. There have been no reports of tissue necrosis associated with extravasation.
# Drug Interactions
There is limited information regarding Laronidase Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- A developmental toxicity study has been performed in rats at doses up to 6.2 times the human dose and has revealed no evidence of impaired fertility or harm to the fetus due to ALDURAZYME. However, there are no adequate and well-controlled studies of ALDURAZYME 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.
- Pregnant women with MPS I should be encouraged to enroll in the MPS I Registry. For more information, visit www.MPSIregistry.com or call (800) 745-4447
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Laronidase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Laronidase during labor and delivery.
### Nursing Mothers
- It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALDURAZYME is administered to a nursing woman.
- Nursing mothers with MPS I should be encouraged to enroll in the MPS I Registry
### Pediatric Use
- The safety and effectiveness of ALDURAZYME was assessed in a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old, and was found to be similar to the safety and effectiveness of ALDURAZYME in pediatric patients 6 to 18 years, and adults
### Geriatic Use
Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Laronidase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Laronidase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Laronidase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Laronidase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Laronidase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Laronidase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.
# IV Compatibility
There is limited information regarding IV Compatibility of Laronidase in the drug label.
# Overdosage
- There have been no reports of overdose with ALDURAZYME. In clinical studies, a small number of patients received doses up to 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week. Adverse events reported in patients receiving 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week were similar to the adverse events reported by patients treated with 0.58 mg/kg body weight once weekly.
# Pharmacology
## Mechanism of Action
- Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis I (MPS I) is characterized by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyzes the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue, and organ dysfunction.
- The rationale of ALDURAZYME therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. ALDURAZYME uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors.
- Because many proteins in the blood are restricted from entry into the central nervous system (CNS) by the blood brain barrier, effects of intravenously administered ALDURAZYME on cells within the CNS cannot be inferred from activity in sites outside the CNS. The ability of ALDURAZYME to cross the blood brain barrier has not been evaluated in animal models or in clinical studies.
## Structure
- ALDURAZYME (laronidase) is a polymorphic variant of the human enzyme α‑l‑iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-l-iduronidase (glycosaminoglycan α-l-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyzes the hydrolysis of terminal α-l-iduronic acid residues of dermatan sulfate and heparan sulfate.
- Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME has a specific activity of approximately 172 U/mg.
- ALDURAZYME, for IV infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME does not contain preservatives; vials are for single use only.
## Pharmacodynamics
- The pharmacodynamic effect of ALDURAZYME was assessed by reductions in urinary GAG levels. The responsiveness of urinary GAG to dosage alterations of ALDURAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established
## Pharmacokinetics
- The pharmacokinetics of laronidase were evaluated in 6 year old or older patients (N = 10 to 12) with MPS I who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the placebo-controlled clinical study (Study 1). After the 1st, 12th, and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2 to 1.7 μg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC∞) ranged from 4.5 to 6.9 μg - hour/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.60 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.7 mL/min/kg, and the mean elimination half-life (t1/2) ranged from 1.5 to 3.6 hours.
- Most patients who received once weekly infusions of ALDURAZYME in Study 1 developed antibodies to laronidase by Week 12. Between Weeks 1 and 12, increases in the plasma clearance of laronidase were observed in some patients and appeared to be proportional to the antibody titer. At Week 26, plasma clearance of laronidase was comparable to that at Week 1, in spite of the continued and, in some cases, increased titers of antibodies.
- The pharmacokinetics of laronidase were evaluated in 6 year old or younger patients (N=7 to 9) with MPS I disease who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the open label clinical study (Study 3). After the 26th infusion, the 95% confidence interval of the geometric mean values of PK parameters ranged from 0.6 to 1.6 µg/mL for the maximum plasma concentrations (Cmax), from 1.3 to 4.4 µg - hour/mL for area under the plasma concentration-time curve (AUC∞), from 0.12 to 0.56 L/kg for volume of distribution (Vz), from 2.2 to 7.7 mL/min/kg for plasma clearance (CL), and from 0.3 to 1.9 hours for elimination half-life (t1/2).
## Nonclinical Toxicology
- Studies to assess the mutagenic and carcinogenic potential of laronidase have not been conducted.
- Laronidase at IV doses up to 3.6 mg/kg (6.2 times the human dose) was found to have no effect on the fertility and reproductive performance of male and female rats.
# Clinical Studies
- The safety and efficacy of ALDURAZYME were assessed in three clinical studies.
- Study 1 was a randomized, double-blind, placebo-controlled study in 45 patients with MPS I, ages 6 to 43 years old, including 1 patient with the Hurler form, 37 patients with Hurler-Scheie form, and 7 patients with Scheie form of MPS I. All patients had a baseline percent predicted forced vital capacity (FVC) less than or equal to 77%. Patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly or placebo once weekly for 26 weeks. All patients were treated with antipyretics and antihistamines prior to each infusion.
- The primary efficacy outcome assessments were percent predicted FVC and distance walked in 6 minutes (6-minute walk test). After 26 weeks, patients treated with ALDURAZYME showed improvement in percent predicted FVC and in 6-minute walk test compared to placebo-treated patients (see Table 4).
- Evaluations of bioactivity were changes in liver size and urinary GAG levels. Liver size and urinary GAG levels decreased in patients treated with ALDURAZYME compared to patients treated with placebo. No patient in the group receiving ALDURAZYME reached the normal range for urinary GAG levels during this 6-month study.
- Study 2 was a 182-week, open-label, uncontrolled extension study of all 45 patients who completed Study 1. Patients received ALDURAZYME at 0.58 mg/kg body weight once weekly. For patients treated with ALDURAZYME, the mean increase in 6-minute walk test distance was maintained for an additional 182 weeks through completion of Study 2.
- At the end of Study 2, the decrease in mean urinary GAG was similar to the decrease in urinary GAG reported in ALDURAZYME-treated patients at the end of Study 1. The relationship of urinary GAG to other measures of clinical response has not been established.
- Study 3 was a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old (at enrollment), including 16 patients (80%) with the Hurler form and 4 patients (20%) with the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks. After 26 weeks of treatment, 16 patients continued to receive 0.58 mg/kg of body weight once weekly through Week 52, and 4 patients received 1.16 mg/kg of body weight once weekly from Week 26 through Week 52.
- Reduction in mean urinary GAG was demonstrated at Week 13 and was maintained through Week 52. No patient receiving ALDURAZYME reached the normal range for urinary GAG levels during this 52-week study. Changes in urinary GAG levels in children 6 years and younger were similar to changes reported in older patients in Studies 1 and 2 (6 through 43 years old). The relationship of urinary GAG to other measures of clinical response has not been established.
# How Supplied
- ALDURAZYME is supplied as a sterile solution in single-use, clear Type I glass 5 mL vials, containing 2.9 mg laronidase per 5 mL solution. The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.
## Storage
- Refrigerate vials of ALDURAZYME at 2° to 8°C (36° to 46°F). Do not freeze or shake. Protect from light. Do not use ALDURAZYME after the expiration date on the vial. This product contains no preservatives.
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be counseled that allergic reactions may occur during ALDURAZYME treatment, including life-threatening anaphylaxis. Premedication and reduction of infusion rate may alleviate those allergic reactions associated with the infusion. The appropriate length of post-infusion monitoring is to be determined by the treating physician based on the individual patient’s clinical status and infusion history.
- Patients should be advised to report any adverse reactions experienced while on ALDURAZYME treatment.
- It is unknown how ALDURAZYME affects women during pregnancy, labor and delivery or while nursing, as no adequate and well-controlled clinical studies have been conducted in these patient populations.
- The full benefits of ALDURAZYME may not be evident for several months to years of treatment. To maintain treatment benefit, ALDURAZYME should be administered on a weekly basis as indicated.
- Patients should be informed that a registry for MPS I patients has been established in order to better understand the MPS I disease, and to track clinical outcomes of patients with MPS I over time. Patients should be encouraged to participate, and advised that their participation is voluntary and may involve long-term follow-up. Information regarding the registry program may be found at www.MPSIregistry.com or by calling (800) 745-4447.
# Precautions with Alcohol
- Alcohol-Laronidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ALDURAZYME®
# Look-Alike Drug Names
There is limited information for the look alike drug names.
# Drug Shortage Status
# Price | Laronidase
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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# Black Box Warning
# Overview
Laronidase is a Enzyme that is FDA approved for the treatment of Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pyrexia, chills, Hypertension, tachycardia, hypoxemia, rash, upper respiratory tract infection, injection site reaction, hyperreflexia, paresthesia, flushing.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ALDURAZYME® (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.
- ALDURAZYME has been shown to improve pulmonary function and walking capacity. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.
### Dosage
- The recommended dosage regimen of ALDURAZYME is 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion. Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both.
- Each vial of ALDURAZYME provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques. The final volume of the infusion is determined by the patient’s body weight. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL. For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting ALDURAZYME in a volume of 100 mL and administering at a decreased infusion rate.
- Prepare and use ALDURAZYME according to the following steps. Use aseptic techniques. Prepare ALDURAZYME using low-protein-binding containers and administer with a low-protein-binding infusion set equipped with an in-line, low-protein-binding 0.2 micrometer (µm) filter. There is no information on the compatibility of diluted ALDURAZYME with glass containers.
- Determine the number of vials to be diluted based on the patient's weight and the recommended dose of 0.58 mg/kg, using the following equation:
- Round up to the next whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials.
- Before withdrawing the ALDURAZYME from the vial, visually inspect each vial for particulate matter and discoloration. The ALDURAZYME solution should be clear to slightly opalescent and colorless to pale yellow. Some translucency may be present in the solution. Do not use if the solution is discolored or if there is particulate matter in the solution.
- Withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of ALDURAZYME concentrate to be added.
- Slowly withdraw the calculated volume of ALDURAZYME from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature ALDURAZYME, rendering it biologically inactive.
- Slowly add the ALDURAZYME solution to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle.
- Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME. Do not shake the solution.
- The entire infusion volume (100 mL for patients weighing 20 kg or less and 250 mL for patients weighing greater than 20 kg) should be delivered over approximately 3 to 4 hours. The initial infusion rate of 10 µg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 µg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours), as outlined in Tables 1 and 2.
- Administer the diluted ALDURAZYME solution to patients using a low-protein-binding infusion set equipped with a low-protein-binding 0.2 µm in-line filter.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Laronidase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Laronidase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Mucopolysaccharidosis, Type I (Hurler and Hurler-Scheie forms)
### Dosage
- (6 months or older) 0.58 mg/kg of body weight as an IV infusion once a week; pretreat 60 minutes before infusion with antihistamines and/or antipyretics
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Laronidase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Laronidase in pediatric patients.
# Contraindications
- None
# Warnings
- Anaphylaxis and severe allergic reactions have been observed in patients during or up to 3 hours after ALDURAZYME infusions. Some of these reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria. If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of ALDURAZYME and initiate appropriate medical treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.
- In clinical studies and postmarketing safety experience with ALDURAZYME, approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions. Due to the potential for severe allergic reactions, appropriate medical support should be readily available when Aldurazyme is administered. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.
- The risks and benefits of re-administering ALDURAZYME following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.
- Patients with an acute febrile or respiratory illness at the time of ALDURAZYME infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient’s clinical status prior to administration of ALDURAZYME and consider delaying ALDURAZYME infusion. One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first Aldurazyme infusion that resolved without intervention. The patient’s respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest, and died.
- Sleep apnea is common in MPS I patients. Evaluation of airway patency should be considered prior to initiation of treatment with ALDURAZYME. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.
- Caution should be exercised when administering ALDURAZYME to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ALDURAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.
- Because of the potential for infusion reactions, patients should receive antipyretics and/or antihistamines prior to infusion. If an infusion reaction occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms
# 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 serious adverse reactions reported with ALDURAZYME treatment during clinical trials were anaphylactic and allergic reactions. Most adverse reactions reported in clinical trials were considered disease-related and unrelated to study drug. The most common adverse reactions were infusion reactions. The frequency of infusion reactions decreased over time with continued use of ALDURAZYME, and the majority of reactions were classified as being mild to moderate in severity. Most infusion reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, antipyretics, or both.
- A 26-week, double-blind, placebo-controlled clinical study (Study 1) of ALDURAZYME was conducted in 45 patients with MPS I, ages 6 to 43 years old, gender evenly distributed (N=23 females and 22 males). Of these 45 patients, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie, and 7 Scheie. Patients were randomized to receive either 0.58 mg/kg IV of ALDURAZYME per week for 26 weeks or placebo. All patients were treated with antipyretics and antihistamines prior to the infusions. Infusion reactions were reported in 32% (7 of 22) of ALDURAZYME-treated patients. The most commonly reported infusion reactions regardless of treatment group were flushing, pyrexia, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. Less common infusion reactions included angioedema (including face edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.
Table 3 enumerates adverse reactions and selected laboratory abnormalities that occurred during the placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.
- All 45 patients who completed the placebo-controlled study (Study 1) continued treatment in an open-label, uncontrolled extension study (Study 2). All patients received ALDURAZYME 0.58 mg/kg of body weight once weekly for up to 182 weeks. The most serious adverse reactions reported with ALDURAZYME infusions in Study 2 were anaphylactic and allergic reactions. The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME. The most commonly reported infusion reactions included rash (13%), flushing (11%), pyrexia (11%), headache (9%), abdominal pain or discomfort (9%), and injection site reaction (9%). Less commonly reported infusion reactions included nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4%), arthralgia (4%), and urticaria (4%). Additional common adverse reactions included back pain and musculoskeletal pain.
- Study 3 was a 52-week, open-label, uncontrolled study of 20 MPS I patients, ages 6 months to 5 years old (at enrollment). Sixteen patients were clinically assessed as having the Hurler form, and 4 had the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks and up to 52 weeks. All patients were treated with antipyretics and antihistamines prior to the infusions.
- The most commonly reported serious adverse events (regardless of relationship) reported with ALDURAZYME infusions in Study 3 were otitis media (20%), and central venous catheterization required for ALDURAZYME infusion (15%).
- The nature and severity of infusion reactions were similar between the older and less severely affected patients in Studies 1 and 2, and the younger, more severely affected patients in Study 3. The most commonly reported adverse reactions in Study 3 were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), hypertension (10%), tachycardia (10%), and hypoxemia (10%). Other commonly reported infusion reactions occurring in ≥ 5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritis, and rash.
- In clinical trials, 99 of 102 patients (97%) treated with ALDURAZYME were positive for IgG antibodies to ALDURAZYME. No correlation was demonstrated between the presence of IgG anti-ALDURAZYME antibodies and therapeutic response (6 MWT and FVC) or the occurrence of allergic reactions. Potential for antibody neutralization of cellular uptake has not been assessed. No consistent association was demonstrated between the presence of antibodies that neutralize enzymatic activity and therapeutic response.
- The data reflect the percentage of patients whose test results were considered positive for antibodies to ALDURAZYME using a specific enzyme-linked immunosorbent assay (ELISA) and confirmed by radio-immunoprecipitation (RIP). ALDURAZYME IgG antibodies were reported as titers. Drug specific antibody was detected in 42 of the 45 patients (93.3%) treated in Study 1 and Study 2. The mean time to seroconversion was 51 days in patients 6 years and older. In Study 3, all patients (100%) 5 years old or younger developed IgG antibodies against ALDURAZYME with a mean time to seroconversion of 26 days for the Study populations].
- Nine patients in Study 1 and Study 2, collectively, who experienced severe infusion reactions were tested for ALDURAZYME-specific IgE antibodies and complement activation. IgE testing was performed by ELISA, and complement activation was measured by the Quidel Enzyme Immunoassay. One of the nine patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgE binding antibodies and complement activation. None of the patients in the open-label clinical study of patients 5 years old or younger (Study 3) tested positive for IgE.
- Other allergic reactions were also seen in patients receiving ALDURAZYME.
- In the postmarketing setting, approximately 1% of patients experienced severe or serious infusion allergic reactions and tested positive for IgE. Of these IgE-positive patients, some have discontinued treatment, but some have been successfully re-challenged. The clinical significance of IgE antibodies has not been established.
- As with all the therapeutic proteins, there is potential for immunogenicity. The incidence 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, comparison of the incidence of antibodies to ALDURAZYME with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of ALDURAZYME. 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.
- In postmarketing experience with ALDURAZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock and laryngeal edema.
- Adverse reactions resulting in death reported in the postmarketing setting with ALDURAZYME treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, and pneumonia. These events have been reported in MPS I patients with significant underlying disease.
- Additional adverse reactions included fatigue, edema peripheral, erythema and cyanosis.
- There have been a small number of reports of extravasation in patients treated with ALDURAZYME. There have been no reports of tissue necrosis associated with extravasation.
# Drug Interactions
There is limited information regarding Laronidase Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- A developmental toxicity study has been performed in rats at doses up to 6.2 times the human dose and has revealed no evidence of impaired fertility or harm to the fetus due to ALDURAZYME. However, there are no adequate and well-controlled studies of ALDURAZYME 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.
- Pregnant women with MPS I should be encouraged to enroll in the MPS I Registry. For more information, visit www.MPSIregistry.com or call (800) 745-4447
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Laronidase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Laronidase during labor and delivery.
### Nursing Mothers
- It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALDURAZYME is administered to a nursing woman.
- Nursing mothers with MPS I should be encouraged to enroll in the MPS I Registry
### Pediatric Use
- The safety and effectiveness of ALDURAZYME was assessed in a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old, and was found to be similar to the safety and effectiveness of ALDURAZYME in pediatric patients 6 to 18 years, and adults
### Geriatic Use
Clinical studies of ALDURAZYME did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Laronidase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Laronidase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Laronidase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Laronidase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Laronidase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Laronidase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.
# IV Compatibility
There is limited information regarding IV Compatibility of Laronidase in the drug label.
# Overdosage
- There have been no reports of overdose with ALDURAZYME. In clinical studies, a small number of patients received doses up to 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week. Adverse events reported in patients receiving 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week were similar to the adverse events reported by patients treated with 0.58 mg/kg body weight once weekly.
# Pharmacology
## Mechanism of Action
- Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis I (MPS I) is characterized by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyzes the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue, and organ dysfunction.
- The rationale of ALDURAZYME therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. ALDURAZYME uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors.
- Because many proteins in the blood are restricted from entry into the central nervous system (CNS) by the blood brain barrier, effects of intravenously administered ALDURAZYME on cells within the CNS cannot be inferred from activity in sites outside the CNS. The ability of ALDURAZYME to cross the blood brain barrier has not been evaluated in animal models or in clinical studies.
## Structure
- ALDURAZYME (laronidase) is a polymorphic variant of the human enzyme α‑l‑iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-l-iduronidase (glycosaminoglycan α-l-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyzes the hydrolysis of terminal α-l-iduronic acid residues of dermatan sulfate and heparan sulfate.
- Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME has a specific activity of approximately 172 U/mg.
- ALDURAZYME, for IV infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME does not contain preservatives; vials are for single use only.
## Pharmacodynamics
- The pharmacodynamic effect of ALDURAZYME was assessed by reductions in urinary GAG levels. The responsiveness of urinary GAG to dosage alterations of ALDURAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established
## Pharmacokinetics
- The pharmacokinetics of laronidase were evaluated in 6 year old or older patients (N = 10 to 12) with MPS I who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the placebo-controlled clinical study (Study 1). After the 1st, 12th, and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2 to 1.7 μg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC∞) ranged from 4.5 to 6.9 μg • hour/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.60 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.7 mL/min/kg, and the mean elimination half-life (t1/2) ranged from 1.5 to 3.6 hours.
- Most patients who received once weekly infusions of ALDURAZYME in Study 1 developed antibodies to laronidase by Week 12. Between Weeks 1 and 12, increases in the plasma clearance of laronidase were observed in some patients and appeared to be proportional to the antibody titer. At Week 26, plasma clearance of laronidase was comparable to that at Week 1, in spite of the continued and, in some cases, increased titers of antibodies.
- The pharmacokinetics of laronidase were evaluated in 6 year old or younger patients (N=7 to 9) with MPS I disease who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the open label clinical study (Study 3). After the 26th infusion, the 95% confidence interval of the geometric mean values of PK parameters ranged from 0.6 to 1.6 µg/mL for the maximum plasma concentrations (Cmax), from 1.3 to 4.4 µg • hour/mL for area under the plasma concentration-time curve (AUC∞), from 0.12 to 0.56 L/kg for volume of distribution (Vz), from 2.2 to 7.7 mL/min/kg for plasma clearance (CL), and from 0.3 to 1.9 hours for elimination half-life (t1/2).
## Nonclinical Toxicology
- Studies to assess the mutagenic and carcinogenic potential of laronidase have not been conducted.
- Laronidase at IV doses up to 3.6 mg/kg (6.2 times the human dose) was found to have no effect on the fertility and reproductive performance of male and female rats.
# Clinical Studies
- The safety and efficacy of ALDURAZYME were assessed in three clinical studies.
- Study 1 was a randomized, double-blind, placebo-controlled study in 45 patients with MPS I, ages 6 to 43 years old, including 1 patient with the Hurler form, 37 patients with Hurler-Scheie form, and 7 patients with Scheie form of MPS I. All patients had a baseline percent predicted forced vital capacity (FVC) less than or equal to 77%. Patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly or placebo once weekly for 26 weeks. All patients were treated with antipyretics and antihistamines prior to each infusion.
- The primary efficacy outcome assessments were percent predicted FVC and distance walked in 6 minutes (6-minute walk test). After 26 weeks, patients treated with ALDURAZYME showed improvement in percent predicted FVC and in 6-minute walk test compared to placebo-treated patients (see Table 4).
- Evaluations of bioactivity were changes in liver size and urinary GAG levels. Liver size and urinary GAG levels decreased in patients treated with ALDURAZYME compared to patients treated with placebo. No patient in the group receiving ALDURAZYME reached the normal range for urinary GAG levels during this 6-month study.
- Study 2 was a 182-week, open-label, uncontrolled extension study of all 45 patients who completed Study 1. Patients received ALDURAZYME at 0.58 mg/kg body weight once weekly. For patients treated with ALDURAZYME, the mean increase in 6-minute walk test distance was maintained for an additional 182 weeks through completion of Study 2.
- At the end of Study 2, the decrease in mean urinary GAG was similar to the decrease in urinary GAG reported in ALDURAZYME-treated patients at the end of Study 1. The relationship of urinary GAG to other measures of clinical response has not been established.
- Study 3 was a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old (at enrollment), including 16 patients (80%) with the Hurler form and 4 patients (20%) with the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks. After 26 weeks of treatment, 16 patients continued to receive 0.58 mg/kg of body weight once weekly through Week 52, and 4 patients received 1.16 mg/kg of body weight once weekly from Week 26 through Week 52.
- Reduction in mean urinary GAG was demonstrated at Week 13 and was maintained through Week 52. No patient receiving ALDURAZYME reached the normal range for urinary GAG levels during this 52-week study. Changes in urinary GAG levels in children 6 years and younger were similar to changes reported in older patients in Studies 1 and 2 (6 through 43 years old). The relationship of urinary GAG to other measures of clinical response has not been established.
# How Supplied
- ALDURAZYME is supplied as a sterile solution in single-use, clear Type I glass 5 mL vials, containing 2.9 mg laronidase per 5 mL solution. The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.
## Storage
- Refrigerate vials of ALDURAZYME at 2° to 8°C (36° to 46°F). Do not freeze or shake. Protect from light. Do not use ALDURAZYME after the expiration date on the vial. This product contains no preservatives.
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be counseled that allergic reactions may occur during ALDURAZYME treatment, including life-threatening anaphylaxis. Premedication and reduction of infusion rate may alleviate those allergic reactions associated with the infusion. The appropriate length of post-infusion monitoring is to be determined by the treating physician based on the individual patient’s clinical status and infusion history.
- Patients should be advised to report any adverse reactions experienced while on ALDURAZYME treatment.
- It is unknown how ALDURAZYME affects women during pregnancy, labor and delivery or while nursing, as no adequate and well-controlled clinical studies have been conducted in these patient populations.
- The full benefits of ALDURAZYME may not be evident for several months to years of treatment. To maintain treatment benefit, ALDURAZYME should be administered on a weekly basis as indicated.
- Patients should be informed that a registry for MPS I patients has been established in order to better understand the MPS I disease, and to track clinical outcomes of patients with MPS I over time. Patients should be encouraged to participate, and advised that their participation is voluntary and may involve long-term follow-up. Information regarding the registry program may be found at www.MPSIregistry.com or by calling (800) 745-4447.
# Precautions with Alcohol
- Alcohol-Laronidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ALDURAZYME®[1]
# Look-Alike Drug Names
There is limited information for the look alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Laronidase | |
4e13ccf0648dcc03663a0f815c3c12d9c178055c | wikidoc | Laterality | Laterality
Laterality is the preference that most humans show for one side of their body over the other. Examples include right-handedness or left-footedness. It may also apply to other animals, or to plants.
# Human laterality
The significant majority of humans are right-handed. Many are also right-sided in general (that is, they prefer to use their right eye, right foot and right ear if forced to make a choice between the two). The reasons for this are not fully understood, but it is thought that because the left cerebral hemisphere of the brain controls the right side of the body, the right side is generally stronger; it is suggested that the left cerebral hemisphere is dominant over the right in most humans because in 90-92% of all humans the left hemisphere is the language hemisphere.
Human cultures are predominantly right-handed, and so the right-sided trend may be socially as well as biologically enforced. This is quite apparent from a quick survey of languages. The English word "left" comes from the Anglo-Saxon word lyft which means "weak" or "useless". Similarly, the French word for left, gauche, is also used to mean "awkward" or "tactless". Also, sinistra, the Latin word from which the English word "sinister" was derived, means "left". Similarly, in many cultures the word for "right" also means "correct". The English word "right" comes from the Anglo-Saxon word riht which also means "straight" or "correct." The words "adroit" and "dextrous", both meaning skillful, come from the French droit and the Latin dexter respectively.
This linguistic and social bias is not restricted to European cultures: for example, Chinese characters are designed for right-handers to write, and no significant left-handed culture has ever been found in the world.
When a person is forced to use the hand opposite of the hand that they would naturally use, this is known as forced laterality, or forced dextrality. A study done by the Department of Neurology at Keele University, North Staffordshire Royal Infirmary suggests that forced dextrality may be part of the reason that the percentage of left-handed people decreases with higher age groups.
Ambidexterity is when a person has approximately equal strength in both hands and/or both sides of the body. True ambidexterity is very rare. Although a small number of people can write competently with both hands and use both sides of their body well, even these people usually show preference for one side of their body over the other. However, this preference is not necessarily consistent for all activities. Some people may for example use their right hand for writing, and their left hand for playing racket sports and eating (See also: cross-dominance).
Also, it is not uncommon that people preferring to use the right hand prefer to use the left leg, e.g. when using a shovel, kicking a football, or operating control pedals. In many cases, this may be because they are disposed for left-handedness but have been trained for right-handedness.
Approximate statistics are below:
- Favoring right hand: 88.2%
- Favoring right foot: 81.0%
- Favoring right eye: 71.1%
- Favoring right ear: 59.1%
- Same hand and foot: 84%
- Same ear and eye: 61.8%
Laterality of motor and sensory control has been the subject of a recent intense study and review. These may be viewed at mimickingmanman.com (review of papers). It turns out that the hemisphere of speech is the hemisphere of action in general and that the command hemisphere is located either in the right or the left hemisphere (never in both). Around eighty percent of people are left hemispheric for speech and the remainder right hemispheric. Ninety percent of right handers are left hemispheric for speech but only 50 percent of left handers are right hemispheric for speech (the remainder are left hemispheric). The reaction time of the neurally dominant side of the body (the side opposite to the major hemisphere or the command center, as just defined ) is shorter than that of the opposite side by an interval equal to the interhemispheric transfer time (IHTT). Thus, one in five persons has a handedness that is the opposite for which they are wired (per laterality of command center or brainedness, as determined by reaction time study mentioned above). I. Derakhshan, MD, Neurologist.
# Laterality in other animals
Laterality in animals is also called limb dominance. Most race tracks are run counter-clockwise, which favors right-side dominant horses, as they take a longer stride with the right foreleg, which helps them turn to the left. Trainers of left eye dominant horses may put a blinder on the left eye to encourage the horse to turn the head slightly to the left and to take a longer step with the right foreleg just as right-side dominant horses do.
Parrots tend to favor one foot when grasping objects (for example fruit when feeding). Some studies indicate that most parrots are left footed.
Polar bears generally kill their prey using their left paw.
Some types of mastodon indicate laterality through the fossil remains having differing tusk lengths. | Laterality
Laterality is the preference that most humans show for one side of their body over the other. Examples include right-handedness or left-footedness. It may also apply to other animals, or to plants.
# Human laterality
The significant majority of humans are right-handed. Many are also right-sided in general (that is, they prefer to use their right eye, right foot and right ear if forced to make a choice between the two). The reasons for this are not fully understood, but it is thought that because the left cerebral hemisphere of the brain controls the right side of the body, the right side is generally stronger; it is suggested that the left cerebral hemisphere is dominant over the right in most humans because in 90-92% of all humans the left hemisphere is the language hemisphere.
Human cultures are predominantly right-handed, and so the right-sided trend may be socially as well as biologically enforced. This is quite apparent from a quick survey of languages. The English word "left" comes from the Anglo-Saxon word lyft which means "weak" or "useless". Similarly, the French word for left, gauche, is also used to mean "awkward" or "tactless". Also, sinistra, the Latin word from which the English word "sinister" was derived, means "left". Similarly, in many cultures the word for "right" also means "correct". The English word "right" comes from the Anglo-Saxon word riht which also means "straight" or "correct." The words "adroit" and "dextrous", both meaning skillful, come from the French droit and the Latin dexter respectively.
This linguistic and social bias is not restricted to European cultures: for example, Chinese characters are designed for right-handers to write, and no significant left-handed culture has ever been found in the world.
When a person is forced to use the hand opposite of the hand that they would naturally use, this is known as forced laterality, or forced dextrality. A study done by the Department of Neurology at Keele University, North Staffordshire Royal Infirmary suggests that forced dextrality may be part of the reason that the percentage of left-handed people decreases with higher age groups. [1]
Ambidexterity is when a person has approximately equal strength in both hands and/or both sides of the body. True ambidexterity is very rare. Although a small number of people can write competently with both hands and use both sides of their body well, even these people usually show preference for one side of their body over the other. However, this preference is not necessarily consistent for all activities. Some people may for example use their right hand for writing, and their left hand for playing racket sports and eating[2] (See also: cross-dominance).
Also, it is not uncommon that people preferring to use the right hand prefer to use the left leg, e.g. when using a shovel, kicking a football, or operating control pedals. In many cases, this may be because they are disposed for left-handedness but have been trained for right-handedness.
Approximate statistics are below: [3]
- Favoring right hand: 88.2%
- Favoring right foot: 81.0%
- Favoring right eye: 71.1%
- Favoring right ear: 59.1%
- Same hand and foot: 84%
- Same ear and eye: 61.8%
Laterality of motor and sensory control has been the subject of a recent intense study and review. These may be viewed at mimickingmanman.com (review of papers). It turns out that the hemisphere of speech is the hemisphere of action in general and that the command hemisphere is located either in the right or the left hemisphere (never in both). Around eighty percent of people are left hemispheric for speech and the remainder right hemispheric. Ninety percent of right handers are left hemispheric for speech but only 50 percent of left handers are right hemispheric for speech (the remainder are left hemispheric). The reaction time of the neurally dominant side of the body (the side opposite to the major hemisphere or the command center, as just defined ) is shorter than that of the opposite side by an interval equal to the interhemispheric transfer time (IHTT). Thus, one in five persons has a handedness that is the opposite for which they are wired (per laterality of command center or brainedness, as determined by reaction time study mentioned above). I. Derakhshan, MD, Neurologist.
# Laterality in other animals
Laterality in animals is also called limb dominance. Most race tracks are run counter-clockwise, which favors right-side dominant horses, as they take a longer stride with the right foreleg, which helps them turn to the left. Trainers of left eye dominant horses may put a blinder on the left eye to encourage the horse to turn the head slightly to the left and to take a longer step with the right foreleg just as right-side dominant horses do.
Parrots tend to favor one foot when grasping objects (for example fruit when feeding). Some studies indicate that most parrots are left footed.
Polar bears generally kill their prey using their left paw.
Some types of mastodon indicate laterality through the fossil remains having differing tusk lengths. | https://www.wikidoc.org/index.php/Laterality | |
b0a97d780862326795e22f06590d80ef4755e9a2 | wikidoc | Leadership | Leadership
Leadership is "the function of directing or controlling the actions or attitudes of an individual or group with more or less willing acquiescence of the followers". It is possible that simply being an opinion leader may be effective.
Leadership styles have been reviewed
Leadership development in health care is perceived as being many years behind that of other industries.
Leadership affects organizational performance - about 5% to 20% of the variation in profitability is accounted for by leadership.
There is concern about whether the many proposed leadership theories have overlap and redundancies.
Co-leadership, or dual leaders may be advantageous.
The organization of leaders and managers maybe important for healthcare as diverse backgrounds of leaders are needed. In this study, physicians integrated into leadership spots was associated with clinical performance.
# Leadership vs management
An early description distinguishing leadership and management was by Zaleznik in 1977. This have more recently discussed by Petriglieri who argues that we have focused too much on leadership.
THe distinction between management and leadership has become blurred, "managerial work has, for example, been replaced by the more appealing label leadership, used to denote any act of a person in a formal authority position".
A helpful video of recent research on both concepts and the importance of both is available by the Academy of Management
## Informal leadership
Providing a positive voice has benefits:
- "employees can help peers get a status boost from voicing, while also raising their own status, by introducing the concept of amplification"
# Evidence-based management
A gap between what research shows and managers practice has been noted.
Evidence-based management (EBMgt) has been advocated to improve management practices and measurement. This is based on the success of evidence-based medicine and has been called the management-as-medicine motif (MAMM). Concern about the approach of EBMgt has been based on a Cochrane Collaboration review of nursing turnover that focused only on randomized data.
Concerns exists about how well MBA programs, bridge and practitioner journals, and textbooks teach EBMgt. Perhaps as a result, a gap has been documented between research and human resources practioners.
Alternative approaches to education have been suggested.
The "push, pull, process" approach has been advocated and refers to publishing and disseminating quality research (push), managers learning all to retrieve new research findings after they finish formal education (pull), and systematically assessing publications (process).
Systematic reviews have been encouraged as alternative to narrative reviews for summarizing evidence in business and management research.
Reporting standards have been proposed.
Registration of studies before data collection has been advocated.
## Barriers within leaders
Management students in Australia view evidence-based management (EBMgt) in one of 4 ways:
- EBMgt as an unrealistic way of doing management. 12% or respondents
- EBMgt as a way of doing management in particular situations. 34% or respondents
- EBMgt as a generally useful way of doing management. 45% or respondents
- EBMgt as an ideal way of being a manager. 9% or respondents
The leadership knowing-doing gap may be affected by "motivation, prioritization, and confidence to enact leadership".
# Selection and development of leaders
Individuals with promotive voices rather than a prohibitive voice are more likely to become leaders, especially if they are male.
Evolutionary biology may partly explain selection of leaders.
One study has validated the Peter Principle.
"Emergent leaders showed a higher amount of active gestures and less passive facial expressions than non-leaders" according to eye-tracking studies of teams.
## Personality traits
Among the following 'Big five' personality traits:
- Openness to experience
- Conscientiousness
- Extraversion
- Agreeableness
- Neuroticism
Narcissism may be selected for.
## Dunning-Kruger effect
The selection for narcissism may be related to the Dunning-Kruger effect which has been noted to occur in the self-assessment of leadership skills.
The overconfidence of some individuals may be viewed as competence by other individuals
Aphorisms about selection of leaders:
- Peter Principle
- Dilbert Principle
## Core-self evaluation
Core-self evaluation includes:
- Self-esteem
- Self-efficacy
- Locus of control
- Emotional stability (low neuroticism)
Hypercore self‐evaluation has a positive effect on innovation behavior by leaders; however, selfism and overconfidence has a negative effect.
Low managerial self-efficacy and ego defensivism makes managers less likely to solict employee voice, positively evaluate an employee who speaks up, and reduced implementation of employee voice
## Humility
The harm of narcissism in leaders may be mitigated by humility Humility, predicted by self-expansion theory, has been found to increase self-expansion and self-efficacy of followers. However, humility may not be effective in teams that expect a high power distance or expect dominating leaders.
Humility in leaders may be effective when teams have proactive personalities.
## Masters in Business Administration
CEOs with a MBA may or may not underperform other CEOs due to emphasizing short-term business outcomes or personal gain rather than sustainability.
It is not clear that the curricula in masters programs reflect best research.
## Leadership training
Leadership training can be effective.
In academic health center], the effect of leadership training may be more to the benefit to advancement of the trainee that to improvement of the institution.
The self-esteeem and mindset of the trainee may determine whether the trainee focuses improvement on self versus organization.
Leadership training in healthcare may be more effective if taught in conjunction with institutional projects.
# Leadership styles related to worksite climate
Leadership research is complicated by construct proliferation and construct redundancy
Leadership style affects work climate.
Leadership styles in health care may affect institutional finances, specifically operating margins.
Early categorization of leadership styles was by Lewin in 1938 who labeled styles as autocratic, democratic.
The terms transactional and transformation were introduced by Weber in 1947. Weber said the charismatic leader was a transformer and the bureaucratic leader was transactional.
Similar concepts are Theory X and Theory Y management by Douglas McGregor in 1960. Theory X is transactional and Theory Y is transformational.
The concept of transactional versus transformation leadership was using the Multifactor Leadership Questionnaire (MLQ) first proposed by Bass in 1978.
Measurement of transactional versus transformation leadership using the was first proposed by Bass in 1985.
Bass added the concept of laissez-faire leadership in 1997.
Leadership styles may effect burnout of employees who are physicians and non-physicians as well the burnout of the leaders themselves..
## Laissez-faire
Laissez-faire may be the most common of the destructive leadership patterns.
Laissez-faire, in health care, is associated with low subordinate job satisfaction and effort. In other industries, laissez-faire is also associated with reduced team performance.
Among physicians, management by passive exception and laissez-faire and may overlap.
## Transactional
The transactional style may have arose from early views of leadership:
- Adam Smith wrote about the worker, “It is the interest of every man to live as much at his ease as he can”.
- Frederick Taylor later added that the worker “is so stupid that the word ‘percentage’ has no meaning to him, and he must consequently be trained by a man more intelligent than himself.”
Transactional leadership is associated with the following of the Big 5 Personality Traits:
- Agreeableness
- Extraversion
- Openness (insignificant)
- Conscientiousness (insignificant)
- Neuroticism (negative association)
When converting from transactional to empowering leadership, teams may transiently function more slowly.
### Management by exception: active
### Management by exception: passive
Among physicians, management by passive exception and laissez-faire and may overlap and management by passive exception may be within laissez-faire.
### Outcomes of transactional leadership
Transactional leadership tactics were found by a meta-analysis in 2004 to positively and significantly affect the following compared to transformational leadership:
- Transformational leadership had a higher validity than did contingent reward: follower satisfaction with leader and leader effectiveness
- Contingent reward had significantly higher validity: follower job satisfaction and leader job performance
Other studies have found benefit from transactional leadership
Transactional leadership, if leading to zero-sum assessments by employees, can be problematic.
## Transformational
Transformational leadership has the following dimensions (4 I's), the first two, Idealised Influence and Inspirational Motivation, when combined are charisma:
- Idealized Influence (role modeling).
Attributed: “My supervisor acts in ways that build my respect” Note that Aviolo found that "displays power and confidence" was the lowest loading factor for charisma.
Behavior: "talks enthusiastically", “My supervisor talks to us about his/her most important values and beliefs”
- Attributed: “My supervisor acts in ways that build my respect” Note that Aviolo found that "displays power and confidence" was the lowest loading factor for charisma.
- Behavior: "talks enthusiastically", “My supervisor talks to us about his/her most important values and beliefs”
- Inspirational Motivation, “My supervisor expresses his/her confidence that we will achieve our goals”. Motivation may be better provided by beneficiaries of a company's services rather than the company's leadership.
- Individualized Consideration (of followers), "focuses your strengths", “My supervisor spends time teaching and coaching me”
- Intellectual Stimulation. "suggests different angles", “My supervisor seeks differing perspectives when solving problems”
Teaching charisma, Idealised Influence and Inspirational Motivation, has been studied.
Transformational leadership is associated with the following of the Big 5 Personality Traits:
- Extraversion (strongest)
- Openness
- Agreeableness
- Conscientiousness
- Neuroticism (negative association)
Authentic leadership and ethical leadership may actually be tranformational leadership.
This style may be the most effective in healthcare on employee responses and clinical outcomes.
Transformational leadership may increase employee thriving and decrease burnout.
Transformational style may better promote team learning behaviors than a transactional style.
Compared to transformational leadership, in transformational leadership the leader's focus is on the employees rather than the organization.
Transformational leadership may build on transactional leadership, "for transformational leadership to be effective,the leader must first build trust and follower responsiveness on the basis of tangible, transactional processes perceived as fair."
Transformational leadership may cause leader emotional exhaustion and subsequent leader turnover intentions, especially when followers are low in conscientiousness or competence.
### Measurement
Transformational leadership can be measured with the proprietary Multifactor Leadership Questionnaire (TLQ) or other instruments.
## Enabling or Empowering leadership
Enabling leadership attempts to bridge the needs to innovate and to produce. Enabling leadership is based on complexity leadership theory.
Empowering leadership is defined variably but includes:
- Autonomy support. Autonomy adds to mastery. Perceived autonomy is associated with less burnout.
A more detailed summary is proposed by Spreitzer:
- The First Discipline: Empower the Person Who Matters Most
- The Second Discipline: Continuous Vision and Challenge
- The Third Discipline: Continuous Support and Security
- The Fourth Discipline: Continuous Openness and Trust
- The Fifth Discipline: Continuous Guidance and Control
Similar concepts are:
- Gardener leadership
- Servant leadership Servant leadership may promote thriving.
Employee perception of servant leadership and the factors of self-determination theory are more likely to have extra-role behavior.
Covey describes the four roles of leadership—modeling, pathfinding, alignment, and empowerment—
Spears described the 10 characteristics of servant-leaders as" Listening, Empathy, Awareness, Healing, Foresight, Persuasion, Conceptualization, Stewardship, Community Building, and Commitment to People's Development
- Employee perception of servant leadership and the factors of self-determination theory are more likely to have extra-role behavior.
- Covey describes the four roles of leadership—modeling, pathfinding, alignment, and empowerment—
- Spears described the 10 characteristics of servant-leaders as" Listening, Empathy, Awareness, Healing, Foresight, Persuasion, Conceptualization, Stewardship, Community Building, and Commitment to People's Development
- Types of leadership that focus on giving employees decision-making but may not include giving employees information to guide their decision-making.
Shared Leadership
Distributed leadership
Servant leadership
Participative Leadership
Democratic leadership
- Shared Leadership
- Distributed leadership
- Servant leadership
- Participative Leadership
- Democratic leadership
Empowering leadership may be compatible with AGILE development, which may conflict with command and control leadership.
The World Health Organization recommends participatory leadership as one of 4 reforms needed for primary health care, “leadership reforms need to steer away from either ‘command and control’ or ‘laissez-faire disengagement’ towards a participatory style”
In health care administration, physician leaders have difficulty relinquishing control and feel threatened by empowering others.
### Impact
Shared leadership may improve team performance according to a meta-analysis of 42 studies.
Empowering leadership may improve performnce
Empowering leadership is consistent with the principle of subsidiarity.
- "Just as it is gravely wrong to take from individuals what they can accomplish by their own initiative and industry and give it to the community, so also it is an injustice and at the same time a grave evil and disturbance of right order to assign to a greater and higher association what lesser and subordinate organizations can do. For every social activity ought of its very nature to furnish help to the members of the body social, and never destroy and absorb them."
### Measuring empowerment
Multiple instruments are available.
The Empowering Leadership Questionnaire (ELQ) has been proposed to measure this style. The ELQ measures either categories:
- Coaching
- Informing. Examination of the 6 questions in this scale suggest informing here does not fit with information sharing as proposed by complexity science.
- Leading By Example
- Showing Concern/Interacting with the Team
- Participative Decision-Making
Servant leadership can be measure with a 28-item or an abbreviated 7-item servant leadership scale:
- My manager can tell if something work-related is going wrong
- My manager makes my career development a priority
- I would seek help from my manager if I had a personal problem
- My manager emphasizes the importance of giving back to the community
- My manager puts my best interests ahead of his/her own
- My manager gives me the freedom to handle difficult situations in the way that I feel is best
- My manager would NOT compromise ethical principles in order to achieve success
### Benefits
Empowering leadership is associated with:
- Performance, organizational citizenship behavior, and creativity according to a meta-analysis as compared transformational leadership and leader–member exchange
- Creativity and innovative behavior (ρ = .36), contextual performance (ρ = .33), withdrawal behaviors (ρ = .28), and job performance (ρ = .25) according to a meta-analysis.
- Increased employee intrinsic motivation and creativity
- Increased productivity by implementing Strategic Human Resource Management (SHRM) as compared to initiating operational improvements
- Increased knowledge sharing and team efficacy which led to increased performance.
- Increases work engagement via work meaningfulness or empowering leadership has been proposed for healthcare.
Servant leadership behavior may be more effective than narcissism and a serving culture is positively related both to restaurant performance and employee job performance.
### Harm
Servant leadership may be costly to the leader
Two contradictory faces of empowerment are :
- Enabling
- Burdening
# Contingency or situational theories
In this approach, the role of the leader is contingent on the situation.
This includes:
- Tannenbaurm's and Schmidt's continuum introduced in 1958
- Hersey's and Blanchard's situational leadership in 1969.
- Vroon and Yetton's contingency model in 1973
- Heifetz's Adaptive leadership introduced in 1997
# Modulators of impact of leadership styles
## Characteristics of subordinates
Goal diversity of subordinates moderator relative effectiveness of leadership styles, "low authority differentiation is beneficial for teams homogeneous in goal orientations and detrimental for teams diverse in goal orientations."
Regulatory fit theory has found:
- Subordinates high in locomotion prefer leaders who have "'forceful' leadership style, represented by 'coercive', 'legitimate', and 'directive' kinds of strategic influence'
- Subordinates high in assessment prefer leaders who have "'advisory' leadership style, represented by 'expert', 'referent', and 'participative' kinds of strategic influence'
### Regulatory focus
Regulatory focus theory poses that people vary in their goals:
- Promotion-focus on hopes and accomplishments, also known as gains
- Prevention-focus based on safety and responsibilities, also known as non-losses
Focus may also predict jealousy and envy.
### Core-self evaluation
Core-self evaluation includes:
- Self-esteem
- Self-efficacy
- Locus of control
- Emotional stability (low neuroticism)
Hypercore-self evaluation predicts job satisfaction and performance.
## Characteristics of leaders
### Leaders'encoding processes
Leaders' encoding processes may be important:
- Mindsets: fixed and growth
- Goal orientations
- Mindsets: deliberative and implemental mindsets
- Regulatory focus.
Mindset interventions have been reviewed.
### Learning-from-failure / optimism
Leadership change behavior is key for post-failure success. This includes sensemaking and problem formulation and reformulation to fine innovation post-failure.
Leader optimism is associated with performance and citizenship behavior.
### Leader humility
Leaders who share criticism of themselves can increase the sense of psychological safety of their workforce.
Sharing personal stories may increase workforce trust in leaders via authenticity and empathy.
### Leader narcissism
Leader narcissism may be harmful.
### Leader information sharing
In general, leaders do not share enough informatoin.
## Leaders' work load
Executive job demands may hinder innovation.
# Complexity leadership theory
Enabling leadership is based on complexity leadership theory.
Complexity science has been proposed as a framework for health care organization since early this century.
Complexity science has been proposed as a framework for Learning Health Systems.
Complexity leadership has been criticized for explaining organizational behavior rather than managing organizations.
Complexity leadership theory has varying descriptions of the metatheme of leadership (see table).
Anderson and McDaniel proposed in 2000 that key leadership tasks are:
- Relationship building
- Loose coupling
- Complicating
- Diversifying
- Sense making (such as positive and negative feedback)
- Learning
- Improvising
- Thinking about the future
A model of of learning based on complexity science has been developed.
Complexity Leadership Theory, also called Complex systems leadership theory, was proposed in 2006. Based on this theory, Hazy has proposed leadership skills similar to Anderson and McDaniel:
- Generative (information gathering/generative/ functions)
- Administrative (information using/convergence/administrative functions)
- Community-building
- Information gathering
- Information using (such as positive and negative feedback)
Uhl-Bien has proposed that tasks of enabling leadership, which is an outgrowth of complexity leadership are:
- Brokerage - fostering of ideas that are triggered at the intersection of networks
- Leveraging Tension
- Linking Up - "Creating or energizing network connections that enable information flows, or amplify movements, to feed and fuel emergence."
- Tags and Attractors - "Listening for language (messages, stories) and symbols (pictures, objects) that ‘stick’ in a system and attract energy & using them to create tags to amplify and channel emergence"
- Simple Rules
- Network Closure
Complexity Leadership Theory is consistent with open book management.
Complexity leadership is consistent with positive deviance.
Complexity Leadership Theory may be seen as an evolution of Heifetz's adaptive leadershi
Complexity Leadership Theory is consistent with knowledge-oriented leadership, which is defined as "an attitude or action, observed or imputed, that prompts the creation, sharing, and utilization of new knowledge in a way that seems to bring a shift in thinking and collective outcomes."
## Implementations
### Agile and constructive deviance
Constructive deviations are "ad hoc experiments performed with the intention of achieving some purpose; this idea is distinct from the notion of “positive deviance” which is a post hoc analysis and intervention technique used to identify positively performing subgroups (outliers) in populations facing many of the same challenges".
Agile coaches are consistent with complexity leadership theory and enabling leadership.
### Fractal
Fractal organization is consistent with complexity leadership and includes:
### Positive deviance
Positive deviance is consistent with complexity leadership theory and learning health systems.
## Measurement
Complexity Leadership tactics can be measured with 3 concepts:
- Knowledge-oriented Leadership
- Knowledge Management Capability (technological, structural, cultural, application, acquisition, sharing)
Example: cultural (highest loading questions):
My organization takes advantage of new knowledge.
My organization quickly applies knowledge to critical competitive needs.
My organization quickly links sources of knowledge in solving problems.
- Example: cultural (highest loading questions):
My organization takes advantage of new knowledge.
My organization quickly applies knowledge to critical competitive needs.
My organization quickly links sources of knowledge in solving problems.
- My organization takes advantage of new knowledge.
- My organization quickly applies knowledge to critical competitive needs.
- My organization quickly links sources of knowledge in solving problems.
- Open Innovation
Another survey has been proposed and construct validated. The instrument consists of 10 items in 2 scales. Response format asks frequency that employees observe leadership tactics with Likert responses ranging from 'Never' to an average of daily:
- Generative (information gathering). Hazy also describes this as "Resilience Leadership Mode...to address risk (variance) by promoting the value potential of optionality"
Supporting difference of opinion
Providing resources and time to try new things
Encouraging learning visits to other organizations
Encouraging new approaches
Forgiving failure
- Supporting difference of opinion
- Providing resources and time to try new things
- Encouraging learning visits to other organizations
- Encouraging new approaches
- Forgiving failure
- Administrative (information using). Hazy also describes this as "Effectiveness Leadership Mode...to maximize return (expected value) by driving the potential value of efficient operations"
Driving accountability
Setting objective metrics of success or failure
Quieting voices which distract from the purpose
Asking people to invest more time and energy
Establishing specific targets and deliverables.
- Driving accountability
- Setting objective metrics of success or failure
- Quieting voices which distract from the purpose
- Asking people to invest more time and energy
- Establishing specific targets and deliverables.
Practice Reserve (PAR) can be measured.
Reciprocal learning may be measured.
## Compoenents of complexity leadership
### Community building / networking / linking up
"Network leaders engage in brokering connections across the network of jazz musicians; or building status through connections to central people," the latter may be more important.
### Sensemaking
Sensemaking includes semantic sensemaking.
# Persuasion and issue selling
Aristotle's rhetoric can be a framework for persuasion Green proposes:
- "a rhetorical sequence that starts with pathos, moves to logos, and ends with ethos will have a rapid rate of initial adoption, a broad diffusion, and a slow abandonment"
- "pathos may initiate change, logos implement it, and ethos sustain it"
Issue selling has been studied by Dutton and Ashford and updated by Lu Lu proposes the use of:
- Influence tactics
Rational persuasion, for example, “Use facts and logic to try to make a persuasive case for your proposed idea”
Inspirational appeal, for example, “Say your proposed idea is an opportunity to do something really exciting and worthwhile”
Consultation, for example, “Ask your supervisor to suggest how you could make your idea more helpful to him or her with a task or problem”
Collaboration, for example, “Offer to provide any assistance the supervisor would need to make the idea happen”
- Rational persuasion, for example, “Use facts and logic to try to make a persuasive case for your proposed idea”
- Inspirational appeal, for example, “Say your proposed idea is an opportunity to do something really exciting and worthwhile”
- Consultation, for example, “Ask your supervisor to suggest how you could make your idea more helpful to him or her with a task or problem”
- Collaboration, for example, “Offer to provide any assistance the supervisor would need to make the idea happen”
- Enactment behaviors
Drawings: “Illustrate the idea through such means as written descriptions, PowerPoint presentations, drawings, or storyboards”
Enacting: “Conduct a pilot or simulation to show how the idea could work”
Prototypes: “Develop a prototype or other sample to demonstrate the value of the idea.”
- Drawings: “Illustrate the idea through such means as written descriptions, PowerPoint presentations, drawings, or storyboards”
- Enacting: “Conduct a pilot or simulation to show how the idea could work”
- Prototypes: “Develop a prototype or other sample to demonstrate the value of the idea.”
# Leadership tactics related to worksite innovation
(see enabling leadership and complexity leadership above)
Innovation can be classified as:
- "Inbound OI involves identifying and acquiring knowledge from external sources"
- "Outbound OI involves exploitation of a firm’s knowledge and technology through commercialization in the external market"
Organizational cultural influences on innovation has been systematically reviewed. Cultural attributes include:
- Learning culture
- Adhocracy culture
- Clan rather than hierarchical culture
- Low power distance culture
Once tactic to foster innovation is to concentrate on lead users
# Religion and faith in leadership
The role of religion and faith in leadership is being increasingly explored.
The Bhagavad Gita may inform positive leadership
, especially verse 2:47.
Religiosity may widen gender pay gaps.
# Comparison of leadership approaches
Directive leadership and hierarchy may help in the short run, but harm in the long run.
# Complications of leadership
Power may lead cerebral changes in those given power. This may lead to hubristic syndrome
The Earned Dogmatism Effect may lead to close-mindedness.
## Employee turnover
Leadership affects employee turnover
Rates of employee turnover, especially voluntary turnover, affects organizational performance. | Leadership
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Robert G. Badgett, M.D.[2]
Leadership is "the function of directing or controlling the actions or attitudes of an individual or group with more or less willing acquiescence of the followers".[1] It is possible that simply being an opinion leader may be effective[2].
Leadership styles have been reviewed
Leadership development in health care is perceived as being many years behind that of other industries.[3]
Leadership affects organizational performance - about 5% to 20% of the variation in profitability is accounted for by leadership[4].
There is concern about whether the many proposed leadership theories have overlap and redundancies[5][6].
Co-leadership, or dual leaders may be advantageous[7].
The organization of leaders and managers maybe important for healthcare as diverse backgrounds of leaders are needed[8]. In this study, physicians integrated into leadership spots was associated with clinical performance.
# Leadership vs management
An early description distinguishing leadership and management was by Zaleznik in 1977[9]. This have more recently discussed by Petriglieri who argues that we have focused too much on leadership[10].
THe distinction between management and leadership has become blurred, "managerial work has, for example, been replaced by the more appealing label leadership, used to denote any act of a person in a formal authority position"[11].
A helpful video of recent research on both concepts and the importance of both is available by the Academy of Management[12]
## Informal leadership
Providing a positive voice has benefits:
- "employees can help peers get a status boost from voicing, while also raising their own status, by introducing the concept of amplification"[13]
# Evidence-based management
A gap between what research shows and managers practice has been noted[14][15][16][17].
Evidence-based management (EBMgt) has been advocated to improve management practices[18] and measurement[19]. This is based on the success of evidence-based medicine and has been called the management-as-medicine motif (MAMM)[20]. Concern about the approach of EBMgt has been based on a Cochrane Collaboration review of nursing turnover[21] that focused only on randomized data[20].
Concerns exists about how well MBA programs[22], bridge and practitioner journals[23], and textbooks[24] teach EBMgt. Perhaps as a result, a gap has been documented between research and human resources practioners[25].
Alternative approaches to education have been suggested[26].
The "push, pull, process" approach has been advocated and refers to publishing and disseminating quality research (push), managers learning all to retrieve new research findings after they finish formal education (pull), and systematically assessing publications (process)[27].
Systematic reviews have been encouraged as alternative to narrative reviews for summarizing evidence in business and management research.[28]
Reporting standards have been proposed[29].
Registration of studies before data collection has been advocated[30].
## Barriers within leaders
Management students in Australia view evidence-based management (EBMgt) in one of 4 ways[31]:
- EBMgt as an unrealistic way of doing management. 12% or respondents
- EBMgt as a way of doing management in particular situations. 34% or respondents
- EBMgt as a generally useful way of doing management. 45% or respondents
- EBMgt as an ideal way of being a manager. 9% or respondents
The leadership knowing-doing gap may be affected by "motivation, prioritization, and confidence to enact leadership"[32].
# Selection and development of leaders
Individuals with promotive voices rather than a prohibitive voice are more likely to become leaders, especially if they are male[33].
Evolutionary biology may partly explain selection of leaders[34].
One study has validated the Peter Principle[35].
"Emergent leaders showed a higher amount of active gestures and less passive facial expressions than non-leaders" according to eye-tracking studies of teams.[36]
## Personality traits
Among the following 'Big five' personality traits[37]:
- Openness to experience
- Conscientiousness
- Extraversion
- Agreeableness
- Neuroticism
Narcissism may be selected for.[38][39]
## Dunning-Kruger effect
The selection for narcissism may be related to the Dunning-Kruger effect which has been noted to occur in the self-assessment of leadership skills.[40][41][42][43][44]
The overconfidence of some individuals may be viewed as competence by other individuals[45]
.
Aphorisms about selection of leaders:
- Peter Principle
- Dilbert Principle
## Core-self evaluation
Core-self evaluation includes[46]:
- Self-esteem
- Self-efficacy
- Locus of control
- Emotional stability (low neuroticism)
Hypercore self‐evaluation has a positive effect on innovation behavior by leaders; however, selfism and overconfidence has a negative effect[47].
Low managerial self-efficacy and ego defensivism makes managers less likely to solict employee voice, positively evaluate an employee who speaks up, and reduced implementation of employee voice[48]
.
## Humility
The harm of narcissism in leaders may be mitigated by humility[49] Humility, predicted by self-expansion theory, has been found to increase self-expansion and self-efficacy of followers[50]. However, humility may not be effective in teams that expect a high power distance or expect dominating leaders.[51]
Humility in leaders may be effective when teams have proactive personalities[52].
## Masters in Business Administration
CEOs with a MBA may[53][54] or may not[55] underperform other CEOs due to emphasizing short-term business outcomes[56] or personal gain[57] rather than sustainability.[58]
It is not clear that the curricula in masters programs reflect best research[59].
## Leadership training
Leadership training can be effective[60].
In academic health center], the effect of leadership training may be more to the benefit to advancement of the trainee that to improvement of the institution[61].
The self-esteeem and mindset of the trainee may determine whether the trainee focuses improvement on self versus organization[62].
Leadership training in healthcare may be more effective if taught in conjunction with institutional projects[63].
# Leadership styles related to worksite climate
Leadership research is complicated by construct proliferation and construct redundancy[6]
Leadership style affects work climate.
Leadership styles in health care may affect institutional finances, specifically operating margins.[64]
Early categorization of leadership styles was by Lewin in 1938 who labeled styles as autocratic, democratic.[65]
The terms transactional and transformation were introduced by Weber in 1947.[66] Weber said the charismatic leader was a transformer and the bureaucratic leader was transactional.
Similar concepts are Theory X and Theory Y management by Douglas McGregor in 1960[67]. Theory X is transactional and Theory Y is transformational.
The concept of transactional versus transformation leadership was using the Multifactor Leadership Questionnaire (MLQ) first proposed by Bass in 1978.[68]
Measurement of transactional versus transformation leadership using the was first proposed by Bass in 1985.[69]
Bass added the concept of laissez-faire leadership in 1997.[70][71]
Leadership styles may effect burnout of employees who are physicians[72] and non-physicians[73] as well the burnout of the leaders themselves.[74][75].
## Laissez-faire
Laissez-faire may be the most common of the destructive leadership patterns[76].
Laissez-faire, in health care, is associated with low subordinate job satisfaction and effort.[77] In other industries, laissez-faire is also associated with reduced team performance[78].
Among physicians, management by passive exception and laissez-faire and may overlap.[79]
## Transactional
The transactional style may have arose from early views of leadership:
- Adam Smith wrote about the worker, “It is the interest of every man to live as much at his ease as he can”.
- Frederick Taylor later added that the worker “is so stupid that the word ‘percentage’ has no meaning to him, and he must consequently be trained by a man more intelligent than himself.”
Transactional leadership is associated with the following of the Big 5 Personality Traits[80]:
- Agreeableness
- Extraversion
- Openness (insignificant)
- Conscientiousness (insignificant)
- Neuroticism (negative association)
When converting from transactional to empowering leadership, teams may transiently function more slowly.[81]
### Management by exception: active
### Management by exception: passive
Among physicians, management by passive exception and laissez-faire and may overlap and management by passive exception may be within laissez-faire.[79]
### Outcomes of transactional leadership
Transactional leadership tactics were found by a meta-analysis in 2004 to positively and significantly affect the following compared to transformational leadership[82]:
- Transformational leadership had a higher validity than did contingent reward: follower satisfaction with leader and leader effectiveness
- Contingent reward had significantly higher validity: follower job satisfaction and leader job performance
Other studies have found benefit from transactional leadership[83]
Transactional leadership, if leading to zero-sum assessments by employees, can be problematic[84].
## Transformational
Transformational leadership has the following dimensions (4 I's), the first two, Idealised Influence and Inspirational Motivation, when combined are charisma:
- Idealized Influence (role modeling).
Attributed: “My supervisor acts in ways that build my respect”[85] Note that Aviolo found that "displays power and confidence" was the lowest loading factor for charisma[86].
Behavior: "talks enthusiastically"[86], “My supervisor talks to us about his/her most important values and beliefs”[85]
- Attributed: “My supervisor acts in ways that build my respect”[85] Note that Aviolo found that "displays power and confidence" was the lowest loading factor for charisma[86].
- Behavior: "talks enthusiastically"[86], “My supervisor talks to us about his/her most important values and beliefs”[85]
- Inspirational Motivation, “My supervisor expresses his/her confidence that we will achieve our goals”[85]. Motivation may be better provided by beneficiaries of a company's services rather than the company's leadership[87].
- Individualized Consideration (of followers), "focuses your strengths"[86], “My supervisor spends time teaching and coaching me”[85]
- Intellectual Stimulation. "suggests different angles"[86], “My supervisor seeks differing perspectives when solving problems”[85]
Teaching charisma, Idealised Influence and Inspirational Motivation, has been studied[88].
Transformational leadership is associated with the following of the Big 5 Personality Traits[80]:
- Extraversion (strongest)
- Openness
- Agreeableness
- Conscientiousness
- Neuroticism (negative association)
Authentic leadership and ethical leadership may actually be tranformational leadership[6].
This style may be the most effective in healthcare on employee responses and clinical outcomes.[89]
Transformational leadership may increase employee thriving and decrease burnout.[90]
Transformational style may better promote team learning behaviors than a transactional style.[91]
Compared to transformational leadership, in transformational leadership the leader's focus is on the employees rather than the organization.[92]
Transformational leadership may build on transactional leadership, "for transformational leadership to be effective,the leader must first build trust and follower responsiveness on the basis of tangible, transactional processes perceived as fair."[77]
Transformational leadership may cause leader emotional exhaustion and subsequent leader turnover intentions, especially when followers are low in conscientiousness or competence[93].
### Measurement
Transformational leadership can be measured with the proprietary Multifactor Leadership Questionnaire (TLQ) [94] or other instruments[95].
## Enabling or Empowering leadership
Enabling leadership attempts to bridge the needs to innovate and to produce[96][97][98]. Enabling leadership is based on complexity leadership theory[99].
Empowering leadership is defined variably[100][101][102] but includes:
- Autonomy support[103]. Autonomy adds to mastery.[103] Perceived autonomy is associated with less burnout.[104]
A more detailed summary is proposed by Spreitzer[96]:
- The First Discipline: Empower the Person Who Matters Most
- The Second Discipline: Continuous Vision and Challenge
- The Third Discipline: Continuous Support and Security
- The Fourth Discipline: Continuous Openness and Trust
- The Fifth Discipline: Continuous Guidance and Control
Similar concepts are[105]:
- Gardener leadership[106]
- Servant leadership[107][108] Servant leadership may promote thriving[109].
Employee perception of servant leadership and the factors of self-determination theory are more likely to have extra-role behavior[110].
Covey describes the four roles of leadership—modeling, pathfinding, alignment, and empowerment—[111]
Spears described the 10 characteristics of servant-leaders as" Listening, Empathy, Awareness, Healing, Foresight, Persuasion, Conceptualization, Stewardship, Community Building, and Commitment to People's Development [112]
- Employee perception of servant leadership and the factors of self-determination theory are more likely to have extra-role behavior[110].
- Covey describes the four roles of leadership—modeling, pathfinding, alignment, and empowerment—[111]
- Spears described the 10 characteristics of servant-leaders as" Listening, Empathy, Awareness, Healing, Foresight, Persuasion, Conceptualization, Stewardship, Community Building, and Commitment to People's Development [112]
- Types of leadership that focus on giving employees decision-making but may not include giving employees information to guide their decision-making.
Shared Leadership[113][114]
Distributed leadership
Servant leadership
Participative Leadership[115]
Democratic leadership
- Shared Leadership[113][114]
- Distributed leadership
- Servant leadership
- Participative Leadership[115]
- Democratic leadership
Empowering leadership may be compatible with AGILE development, which may conflict with command and control leadership[116].
The World Health Organization recommends participatory leadership as one of 4 reforms needed for primary health care, “leadership reforms need to steer away from either ‘command and control’ or ‘laissez-faire disengagement’ towards a participatory style”[117]
In health care administration, physician leaders have difficulty relinquishing control and feel threatened by empowering others[118].
### Impact
Shared leadership may improve team performance according to a meta-analysis of 42 studies[119].
Empowering leadership may improve performnce[120][121][100][122]
Empowering leadership is consistent with the principle of subsidiarity[123].
- "Just as it is gravely wrong to take from individuals what they can accomplish by their own initiative and industry and give it to the community, so also it is an injustice and at the same time a grave evil and disturbance of right order to assign to a greater and higher association what lesser and subordinate organizations can do. For every social activity ought of its very nature to furnish help to the members of the body social, and never destroy and absorb them."[124]
### Measuring empowerment
Multiple instruments are available[125].
The Empowering Leadership Questionnaire (ELQ) has been proposed to measure this style.[126] The ELQ measures either categories:
- Coaching
- Informing. Examination of the 6 questions in this scale suggest informing here does not fit with information sharing as proposed by complexity science.
- Leading By Example
- Showing Concern/Interacting with the Team
- Participative Decision-Making
Servant leadership can be measure with a 28-item or an abbreviated 7-item servant leadership scale[127]:
- My manager can tell if something work-related is going wrong
- My manager makes my career development a priority
- I would seek help from my manager if I had a personal problem
- My manager emphasizes the importance of giving back to the community
- My manager puts my best interests ahead of his/her own
- My manager gives me the freedom to handle difficult situations in the way that I feel is best
- My manager would NOT compromise ethical principles in order to achieve success
### Benefits
Empowering leadership is associated with:
- Performance, organizational citizenship behavior, and creativity according to a meta-analysis as compared transformational leadership and leader–member exchange[128]
- Creativity and innovative behavior (ρ = .36), contextual performance (ρ = .33), withdrawal behaviors (ρ = .28), and job performance (ρ = .25) according to a meta-analysis.[129]
- Increased employee intrinsic motivation and creativity[130]
- Increased productivity by implementing Strategic Human Resource Management (SHRM) as compared to initiating operational improvements[131]
- Increased knowledge sharing and team efficacy which led to increased performance.[132]
- Increases work engagement via work meaningfulness[133] or empowering leadership has been proposed for healthcare.[134][135][136]
Servant leadership behavior may be more effective than narcissism[137] and a serving culture is positively related both to restaurant performance and employee job performance[138].
### Harm
Servant leadership may be costly to the leader[139]
Two contradictory faces of empowerment are [140]:
- Enabling
- Burdening
# Contingency or situational theories
In this approach, the role of the leader is contingent on the situation.
This includes:
- Tannenbaurm's and Schmidt's continuum introduced in 1958[141][142]
- Hersey's and Blanchard's situational leadership in 1969.[143]
- Vroon and Yetton's contingency model in 1973[144]
- Heifetz's Adaptive leadership introduced in 1997[145]
# Modulators of impact of leadership styles
## Characteristics of subordinates
Goal diversity of subordinates moderator relative effectiveness of leadership styles, "low authority differentiation is beneficial for teams homogeneous in goal orientations and detrimental for teams diverse in goal orientations."[146]
Regulatory fit theory has found[147]:
- Subordinates high in locomotion prefer leaders who have "'forceful' leadership style, represented by 'coercive', 'legitimate', and 'directive' kinds of strategic influence'
- Subordinates high in assessment prefer leaders who have "'advisory' leadership style, represented by 'expert', 'referent', and 'participative' kinds of strategic influence'
### Regulatory focus
Regulatory focus theory poses that people vary in their goals[148]:
- Promotion-focus on hopes and accomplishments, also known as gains
- Prevention-focus based on safety and responsibilities, also known as non-losses
Focus may also predict jealousy and envy[149].
### Core-self evaluation
Core-self evaluation includes[46]:
- Self-esteem
- Self-efficacy
- Locus of control
- Emotional stability (low neuroticism)
Hypercore-self evaluation predicts job satisfaction and performance[46].
## Characteristics of leaders
### Leaders'encoding processes
Leaders' encoding processes may be important[150][151]:
- Mindsets: fixed and growth[152][153]
- Goal orientations
- Mindsets: deliberative and implemental mindsets
- Regulatory focus.
Mindset interventions have been reviewed[154].
### Learning-from-failure / optimism
Leadership change behavior is key for post-failure success. This includes sensemaking and problem formulation and reformulation to fine innovation post-failure[155].
Leader optimism is associated with performance and citizenship behavior[156].
### Leader humility
Leaders who share criticism of themselves can increase the sense of psychological safety of their workforce[157].
Sharing personal stories may increase workforce trust in leaders via authenticity and empathy[158].
### Leader narcissism
Leader narcissism may be harmful[159].
### Leader information sharing
In general, leaders do not share enough informatoin[160].
## Leaders' work load
Executive job demands may hinder innovation[161].
# Complexity leadership theory
Enabling leadership is based on complexity leadership theory[99].
Complexity science has been proposed as a framework for health care organization since early this century.[162][163]
Complexity science has been proposed as a framework for Learning Health Systems[164].
Complexity leadership has been criticized for explaining organizational behavior rather than managing organizations[165].
Complexity leadership theory has varying descriptions of the metatheme of leadership (see table).
Anderson and McDaniel proposed in 2000 that key leadership tasks are[162][170]:
- Relationship building
- Loose coupling
- Complicating
- Diversifying
- Sense making (such as positive and negative feedback)
- Learning
- Improvising
- Thinking about the future
A model of of learning based on complexity science has been developed.[171]
Complexity Leadership Theory, also called Complex systems leadership theory, was proposed in 2006.[172][173][174] Based on this theory, Hazy has proposed leadership skills similar to Anderson and McDaniel:[168]
- Generative (information gathering/generative/ functions)
- Administrative (information using/convergence/administrative functions)
- Community-building
- Information gathering
- Information using (such as positive and negative feedback)
Uhl-Bien has proposed that tasks of enabling leadership, which is an outgrowth of complexity leadership are[99]:
- Brokerage - fostering of ideas that are triggered at the intersection of networks
- Leveraging Tension
- Linking Up - "Creating or energizing network connections that enable information flows, or amplify movements, to feed and fuel emergence."
- Tags and Attractors - "Listening for language (messages, stories) and symbols (pictures, objects) that ‘stick’ in a system and attract energy & using them to create tags to amplify and channel emergence"
- Simple Rules
- Network Closure
Complexity Leadership Theory is consistent with open book management.
Complexity leadership is consistent with positive deviance[165].
Complexity Leadership Theory may be seen as an evolution of Heifetz's adaptive leadershi[97][175]
Complexity Leadership Theory is consistent with knowledge-oriented leadership, which is defined as "an attitude or action, observed or imputed, that prompts the creation, sharing, and utilization of new knowledge in a way that seems to bring a shift in thinking and collective outcomes."[176]
## Implementations
### Agile and constructive deviance
Constructive deviations are "ad hoc experiments performed with the intention of achieving some purpose; this idea is distinct from the notion of “positive deviance” which is a post hoc analysis and intervention technique used to identify positively performing subgroups (outliers) in populations facing many of the same challenges"[177].
Agile coaches are consistent with complexity leadership theory and enabling leadership[178].
### Fractal
Fractal organization is consistent with complexity leadership and includes[179][180]:
### Positive deviance
Positive deviance is consistent with complexity leadership theory[165][181][182] and learning health systems[183].
## Measurement
Complexity Leadership tactics can be measured with 3 concepts[176]:
- Knowledge-oriented Leadership
- Knowledge Management Capability (technological, structural, cultural, application, acquisition, sharing)
Example: cultural (highest loading questions):
My organization takes advantage of new knowledge.
My organization quickly applies knowledge to critical competitive needs.
My organization quickly links sources of knowledge in solving problems.
- Example: cultural (highest loading questions):
My organization takes advantage of new knowledge.
My organization quickly applies knowledge to critical competitive needs.
My organization quickly links sources of knowledge in solving problems.
- My organization takes advantage of new knowledge.
- My organization quickly applies knowledge to critical competitive needs.
- My organization quickly links sources of knowledge in solving problems.
- Open Innovation
Another survey has been proposed and construct validated. The instrument consists of 10 items in 2 scales[167]. Response format asks frequency that employees observe leadership tactics with Likert responses ranging from 'Never' to an average of daily:
- Generative (information gathering). Hazy also describes this as "Resilience Leadership Mode...to address risk (variance) by promoting the value potential of optionality"[184]
Supporting difference of opinion
Providing resources and time to try new things
Encouraging learning visits to other organizations
Encouraging new approaches
Forgiving failure
- Supporting difference of opinion
- Providing resources and time to try new things
- Encouraging learning visits to other organizations
- Encouraging new approaches
- Forgiving failure
- Administrative (information using). Hazy also describes this as "Effectiveness Leadership Mode...to maximize return (expected value) by driving the potential value of efficient operations"[184]
Driving accountability
Setting objective metrics of success or failure
Quieting voices which distract from the purpose
Asking people to invest more time and energy
Establishing specific targets and deliverables.
- Driving accountability
- Setting objective metrics of success or failure
- Quieting voices which distract from the purpose
- Asking people to invest more time and energy
- Establishing specific targets and deliverables.
Practice Reserve (PAR) can be measured[185].
Reciprocal learning may be measured[186].
## Compoenents of complexity leadership
### Community building / networking / linking up
"Network leaders engage in brokering connections across the network of jazz musicians; or building status through connections to central people," the latter may be more important[187].
### Sensemaking
Sensemaking includes semantic sensemaking[188].
# Persuasion and issue selling
Aristotle's rhetoric can be a framework for persuasion[189][190][191] Green proposes[192]:
- "a rhetorical sequence that starts with pathos, moves to logos, and ends with ethos will have a rapid rate of initial adoption, a broad diffusion, and a slow abandonment"
- "pathos may initiate change, logos implement it, and ethos sustain it"
Issue selling has been studied by Dutton and Ashford[193][194] and updated by Lu[195] Lu proposes the use of:
- Influence tactics
Rational persuasion, for example, “Use facts and logic to try to make a persuasive case for your proposed idea”
Inspirational appeal, for example, “Say your proposed idea is an opportunity to do something really exciting and worthwhile”
Consultation, for example, “Ask your supervisor to suggest how you could make your idea more helpful to him or her with a task or problem”
Collaboration, for example, “Offer to provide any assistance the supervisor would need to make the idea happen”
- Rational persuasion, for example, “Use facts and logic to try to make a persuasive case for your proposed idea”
- Inspirational appeal, for example, “Say your proposed idea is an opportunity to do something really exciting and worthwhile”
- Consultation, for example, “Ask your supervisor to suggest how you could make your idea more helpful to him or her with a task or problem”
- Collaboration, for example, “Offer to provide any assistance the supervisor would need to make the idea happen”
- Enactment behaviors
Drawings: “Illustrate the idea through such means as written descriptions, PowerPoint presentations, drawings, or storyboards”
Enacting: “Conduct a pilot or simulation to show how the idea could work”
Prototypes: “Develop a prototype or other sample to demonstrate the value of the idea.”
- Drawings: “Illustrate the idea through such means as written descriptions, PowerPoint presentations, drawings, or storyboards”
- Enacting: “Conduct a pilot or simulation to show how the idea could work”
- Prototypes: “Develop a prototype or other sample to demonstrate the value of the idea.”
.
.
# Leadership tactics related to worksite innovation
(see enabling leadership and complexity leadership above)
Innovation can be classified as[176][196]:
- "Inbound OI involves identifying and acquiring knowledge from external sources"
- "Outbound OI involves exploitation of a firm’s knowledge and technology through commercialization in the external market"
Organizational cultural influences on innovation has been systematically reviewed[197]. Cultural attributes include:
- Learning culture
- Adhocracy culture
- Clan rather than hierarchical culture
- Low power distance culture
Once tactic to foster innovation is to concentrate on lead users[198]
.
# Religion and faith in leadership
The role of religion and faith in leadership is being increasingly explored[199][200].
The Bhagavad Gita may inform positive leadership[201]
, especially verse 2:47.
Religiosity may widen gender pay gaps[202].
# Comparison of leadership approaches
Directive leadership and hierarchy may help in the short run, but harm in the long run[203][204].
# Complications of leadership
Power may lead cerebral changes in those given power[205]. This may lead to hubristic syndrome[206]
The Earned Dogmatism Effect may lead to close-mindedness[207].
## Employee turnover
Leadership affects employee turnover[208]
.
Rates of employee turnover, especially voluntary turnover, affects organizational performance[209]. | https://www.wikidoc.org/index.php/Leadership | |
6a3bb1b629887dcfb696aeeedf73aba9e12cc924 | wikidoc | Lefetamine | Lefetamine
Lefetamine (Santenol) is a psychoactive drug which is both a stimulant and an analgesic with effects comparable to both morphine and methylphenidate.
Lefetamine was invented in the 1940s and was widely abused in Japan during the 1950s. It has been researched for medicinal use but showed little advantage over other analgesics, although it did seem promising for treating opiate withdrawal it was not as good as buprenorphine for this purpose. More recently it has been abused in Europe, but it remains an obscure drug on the illicit market.
Due to its chemical structure, it binds to opioid receptors while simultaneously inhibiting reuptake of dopamine and norepinephrine. Lefetamine has the necessary tertiary amine functional group required for opioid receptor recognition, as well as a phenethylamine skeleton (which is responsible for its amphetamine-like effects). It is also reported to have some NMDA antagonist effects and to have neurotoxic properties.
Boiling Point: 142-147° C
Optical Rotation: D20 -124.2° (ethanol).
CAS number of hydrochloride: 14148-99-3 | Lefetamine
Lefetamine (Santenol) is a psychoactive drug which is both a stimulant and an analgesic with effects comparable to both morphine and methylphenidate.
Lefetamine was invented in the 1940s[1] and was widely abused in Japan [2] during the 1950s. [3] It has been researched for medicinal use but showed little advantage over other analgesics, although it did seem promising for treating opiate withdrawal it was not as good as buprenorphine for this purpose. [4] More recently it has been abused in Europe, but it remains an obscure drug on the illicit market.
Due to its chemical structure, it binds to opioid receptors while simultaneously inhibiting reuptake of dopamine and norepinephrine.[5] Lefetamine has the necessary tertiary amine functional group required for opioid receptor recognition, as well as a phenethylamine skeleton (which is responsible for its amphetamine-like effects). [6] It is also reported to have some NMDA antagonist effects and to have neurotoxic properties. [7]
Boiling Point: 142-147° C
Optical Rotation: [α]D20 -124.2° (ethanol).
CAS number of hydrochloride: 14148-99-3 | https://www.wikidoc.org/index.php/Lefetamine | |
be0634c02808a3c92704f52d90c4575d37cd5c42 | wikidoc | Left heart | Left heart
Left heart is a term used to refer collectively to the left atrium and left ventricle of the heart; occasionally, this term is intended to reference the left atrium, left ventricle, and the aorta collectively.
The left atrium receives oxygenated pulmonic blood from the pulmonary veins. The blood is then pumped through the mitral valve into the left ventricle, which in turn pumps the blood through the aortic valve into the aorta.
The left side of the heart is thicker than the right because of the requirement to pump blood from the left throughout the body, as opposed to the right side pumping only through the lungs.
See also: Right heart
ta:இடது இதயம் | Left heart
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Left heart is a term used to refer collectively to the left atrium and left ventricle of the heart; occasionally, this term is intended to reference the left atrium, left ventricle, and the aorta collectively.
The left atrium receives oxygenated pulmonic blood from the pulmonary veins. The blood is then pumped through the mitral valve into the left ventricle, which in turn pumps the blood through the aortic valve into the aorta.
The left side of the heart is thicker than the right because of the requirement to pump blood from the left throughout the body, as opposed to the right side pumping only through the lungs.
See also: Right heart
ta:இடது இதயம்
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Left_heart | |
00b8d7fc40187a7ca3f4b4c6de645bd653729379 | wikidoc | Renal vein | Renal vein
The renal veins are veins that drain the kidney. They connect the kidney to the inferior vena cava.
It is usually singular to each kidney, except in the condition "multiple renal veins".
# Asymmetry
Because the inferior vena cava is on the right half of the body, the left renal vein is generally the longer of the two.
Because the inferior vena cava is not laterally symmetrical, the left renal vein often receives the following veins:
- left inferior phrenic vein
- left suprarenal vein
- left gonadal vein (left testicular vein in males, left ovarian vein in females)
- left 2nd lumbar vein
This is in contrast to the right side of the body, where these veins drain directly into the IVC.
# Pathology
Diseases associated with the renal vein include renal vein thrombosis (RVT) and nutcracker syndrome (renal vein entrapment syndrome). | Renal vein
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The renal veins are veins that drain the kidney. They connect the kidney to the inferior vena cava.
It is usually singular to each kidney, except in the condition "multiple renal veins".[1]
# Asymmetry
Because the inferior vena cava is on the right half of the body, the left renal vein is generally the longer of the two.
Because the inferior vena cava is not laterally symmetrical, the left renal vein often receives the following veins:[2]
- left inferior phrenic vein
- left suprarenal vein
- left gonadal vein (left testicular vein in males, left ovarian vein in females)
- left 2nd lumbar vein
This is in contrast to the right side of the body, where these veins drain directly into the IVC.
# Pathology
Diseases associated with the renal vein include renal vein thrombosis (RVT) and nutcracker syndrome (renal vein entrapment syndrome). | https://www.wikidoc.org/index.php/Left_renal_vein | |
92b3b58f284b9c1150f8afe49caaad478e48d49e | wikidoc | Left shift | Left shift
# Overview
Left shift or blood shift is an increase in the number of immature leukocytes in the peripheral blood, particularly neutrophil band cells.
Less commonly, left shift may also refer to a similar phenomenon in severe erythroanemia, when reticulocytes and immature erythrocyte precursors appear in the peripheral circulation.
# Definition
The standard definition of a left shift is an absolute band form count greater than 700/microL. The term itself refers to the historical practice, in paper laboratory reports, of recording band form counts on the far left side of the page.
# Morphology
It is usually noted on microscopic examination of a blood smear. This systemic effect of inflammation is most often seen in the course of an active infection and during other severe illnesses such as hypoxia and shock. Döhle bodies may also be present in the neutrophil's cytoplasm in the setting of sepsis or severe inflammatory responses.
# Pathogenesis
It is believed that cytokines (including IL-1 and TNF) accelerate the release of cells from the postmitotic reserve pool in the bone marrow, leading to an increased number of immature cells.
# See Also
- Band cell
- Bandemia
- Leukocytosis
- Reticulocyte | Left shift
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Left shift or blood shift is an increase in the number of immature leukocytes in the peripheral blood, particularly neutrophil band cells.[1]
Less commonly, left shift may also refer to a similar phenomenon in severe erythroanemia, when reticulocytes and immature erythrocyte precursors appear in the peripheral circulation.[2]
# Definition
The standard definition of a left shift is an absolute band form count greater than 700/microL.[3] The term itself refers to the historical practice, in paper laboratory reports, of recording band form counts on the far left side of the page.[reference needed]
# Morphology
It is usually noted on microscopic examination of a blood smear. This systemic effect of inflammation is most often seen in the course of an active infection and during other severe illnesses such as hypoxia and shock. Döhle bodies may also be present in the neutrophil's cytoplasm in the setting of sepsis or severe inflammatory responses.[4]
# Pathogenesis
It is believed that cytokines (including IL-1 and TNF) accelerate the release of cells from the postmitotic reserve pool in the bone marrow, leading to an increased number of immature cells.[1]
# See Also
- Band cell
- Bandemia
- Leukocytosis
- Reticulocyte | https://www.wikidoc.org/index.php/Left_shift | |
9076ad0a7a95ec8a0f0f0fea67d1a939f1246891 | wikidoc | Vena cavae | Vena cavae
# Overview
The superior and inferior vena cava are collectively called the venae cavae. They are the veins that return de-oxygenated blood from the body into the heart. They both empty into the right atrium.
The inferior vena cava (or posterior vena cava) travels up alongside the abdominal aorta with blood from the lower part of the body.
The superior vena cava (or anterior) is above the heart, and forms from a convergence of the left and right brachiocephalic veins that contain blood from the head and the arms. The vena cavae carry deoxygenated blood from the body to the right atrium of the heart.
The venae cavae is the largest blood vessel in the heart.
de:Hohlvene
eu:Kaba zain
id:Vena cava
it:Vena cava
nl:Holle lichaamsader
no:Vena cava
nn:Holvene
nds:Hollveen | Vena cavae
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The superior and inferior vena cava are collectively called the venae cavae. They are the veins that return de-oxygenated blood from the body into the heart. They both empty into the right atrium.
The inferior vena cava (or posterior vena cava) travels up alongside the abdominal aorta with blood from the lower part of the body.
The superior vena cava (or anterior) is above the heart, and forms from a convergence of the left and right brachiocephalic veins that contain blood from the head and the arms. The vena cavae carry deoxygenated blood from the body to the right atrium of the heart.
The venae cavae is the largest blood vessel in the heart.
Template:Veins
de:Hohlvene
eu:Kaba zain
id:Vena cava
it:Vena cava
nl:Holle lichaamsader
no:Vena cava
nn:Holvene
nds:Hollveen
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Left_vena_cava | |
a947c71ebec930c1b76e4b58f178c2b550a821bd | wikidoc | Legionella | Legionella
# Overview
Legionella is a Gram negative bacterium, including species that cause legionellosis or Legionnaires' disease, most notably L. pneumophila.
Legionella are common in many environments, with at least 50 species and 70 serogroups identified. The side-chains of the cell wall carry the bases responsible for the somatic antigen specificity of these organisms. The chemical composition of these side chains both with respect to components as well as arrangement of the different sugars determines the nature of the somatic or O antigen determinants, which are essential means of serologically classifying many Gram-negative bacteria.
Legionella acquired its name after a July, 1976 outbreak among people attending a convention of the American Legion in Philadelphia. The mystery disease sickened 221 persons, causing 34 deaths. In that bicentennial year, a pandemic among U.S. war veterans was widely publicized and produced a national panic
On January 18, 1977 the causative agent was identified as a previously unknown bacterium, subsequently named Legionella. See Legionnaire's Disease for full details.
# Historical Perspective
In 1976, legionella was discovered after an outbreak among people who attended the Philadelphia convention of the American Legion. Those affected had a type of pneumonia that eventually became known as Legionnaires’ disease.
# Classification
The genus Legionella is made up of 58 species and 3 subspecies (pneumophila, fraseri, and pascullei ).
Legionella is a Gram-negative bacteria with strict growth requirements.
Monoclonal antibodies against lipopolysaccharide epitopes on the bacterial cell surface detect L pneumophila serogroup 1.
# Pathophysiology
Legionella reside in drinking and surface water and are transmitted in aerosols to humans. It multiplies intracellularly in alveolar macrophages leading to an immune reaction that produces destructive alveolar inflammation. Inoculation of surgical wounds via contaminated tap water has been recorded.
# Causes
Legionella can become a health concern when it grows and spreads in human-made water systems example
- Decorative fountains and water features
- Showerheads and sink faucets
- Hot water tanks and heaters
- Cooling towers
- Large, complex plumbing systems
# Detection
Legionella is traditionally detected by culture on buffered charcoal yeast extract (BCYE) agar. Legionellae require the presence of cysteine to grow and therefore do not grow on common blood agar media used for laboratory based total viable counts or on site displides. Common laboratory procedures for the detection of Legionella in water concentrate the bacteria (by centrifugation and/or filtration through 0.2 micron filters) before innoculation onto a charcoal yeast extract agar containing antibiotics (e.g. glycine vancomycim polymixin cyclohexamide, GVPC) to suppress other flora in the sample. Heat or acid treatment are also used to reduce interference from other microbes in the sample.
After incubation for up to 10 days, suspect colonies are confirmed as Legionellae if they grow on BCYE containing cysteine, but not on agar without cysteine added. Immunological techniques are then commonly used to establish the species and/or serogroups of bacteria present in the sample.
New techniques for the rapid detection of Legionella in water samples are emerging including the use of polymerase chain reaction (PCR) and rapid immunological assays. These technologies can typically provide much faster results.
# Pathogenesis
Legionella have been known for some time to live within amoebae in the natural environment. Legionella species are the causative agent of the human Legionnaires' disease and the lesser form, Pontiac fever. Legionella transmission is via aerosols—the inhalation of mist droplets containing the bacteria. Common sources include cooling towers, domestic hot-water systems, fountains, and similar disseminators that tap into a public water supply. Natural sources of Legionella include freshwater ponds and creeks. Person-to-person transmission of Legionella has not been demonstrated.
Once inside a host, incubation may take up to two weeks. Initial symptoms are flu-like, including fever, chills, and dry cough. Advanced stages of the disease cause problems with the gastrointestinal tract and the nervous system and lead to diarrhea and nausea. Other advanced symptoms of pneumonia may also present.
However, the disease is generally not a threat to most healthy individuals, and tends to lead to harmful symptoms only in those with a compromised immune system and the elderly. Consequently, it is actively checked for in the water systems of hospitals and nursing homes. In the United States, the disease affects between 8,000 to 18,000 individuals a year.
# Molecular biology
With the application of modern molecular genetic and cell biological techniques, the mechanisms used by Legionella to multiply within macrophages are beginning to be understood. The specific regulatory cascades that govern differentiation as well as the gene regulation are being studied. The genome sequences of four L. pneumophila strains have been published and it is now possible to investigate the whole genome by modern molecular methods. The molecular studies are contributing to the fields of clinical research, diagnosis, treatment, epidemiology, and prevention of disease.
# Controlling potential sources of Legionella
Common sources of Legionella include cooling towers used in industrial cooling water systems as well as in large central air conditioning systems, domestic hot water systems, fountains, and similar disseminators that draw upon a public water supply. Natural sources include freshwater ponds and creeks.
Recent research in the Journal of Infectious Diseases provides evidence that Legionella pneumophila, the causative agent of Legionnaires disease, can travel at least 6 km from its source by airborne spread. It was previously believed that transmission of the bacterium was restricted to much shorter distances. A team of French scientists reviewed the details of an epidemic of Legionnaires disease that took place in Pas-de-Calais in northern France in 2003–2004. There were 86 confirmed cases during the outbreak, of whom 18 perished. The source of infection was identified as a cooling tower in a petrochemical plant, and an analysis of those affected in the outbreak revealed that some infected people lived as far as 6–7 km from the plant.
Several European countries established a working group known as the European Working Group for Legionella Infections (EWGLI) to share knowledge and experience about monitoring potential sources of Legionella. That group has published guidelines about the actions to be taken to limit the number of colony forming units (i.e. live bacteria that are able to multiply) of Legionella per litre
Temperature affects the survival of Legionellae as follows:
- 70 to 80 °C (158 to 176 °F) - Disinfection range
- At 66 °C (151 °F) - Legionellae die within 2 minutes
- At 60 °C (140 °F) - Legionellae die within 32 minutes
- At 55 °C (131 °F) - Legionellae die within 5 to 6 hours
- 50 to 55 °C (122 to 131 °F) - They can survive but do not multiply
- 20 to 50 °C (68 to 122 °F)- Legionellae growth range
- 35 to 46 °C (95 to 115 °F) - Ideal growth range
- Below 20 °C (68 °F) - Legionellae can survive but are dormant
The above data can be confirmed in an online article by Reliance World Wide.
Control of Legionella growth can be through :
A. Chemical Treatment
1. Short term - Cl2, must be repeated every 3 to 5 weeks, corrosion factors
2. Long term - ClO2, takes up to 1 month for system saturation
B. Non-Chemical Treatment
1. Short term - Thermal eradication - must be repeated every 3 to 5 weeks
2. Long term - Industrial size copper silver ionisation (Ionization) technology such as 1-AquaLyse.ca, 2-Liquitech or 3-TarnPure.
Units have provisional EPA approval. No copper-silver has yet had efficacy data approved by EPA or received final EPA approval.
## Guidelines for control of Legionella in cooling towers
Many governmental agencies, cooling tower manufacturers and industrial trade organizations have developed design and maintenance guidelines for preventing or controlling the growth of Legionella in cooling towers. Below is a list of sources for such guidelines:
- Legionella control in Ornamental Fountains
- ASHRAE Guideline
- Centers for Disease Control and Prevention - Procedure for Cleaning Cooling Towers and Related Equipment (pages 239 and 240 of 249)
- Cooling Technology Institute - Best Practices for Control of Legionella
- Association of Water Technologies - Legionella 2003
- California Energy Commission - Cooling Water Management Program Guidelines For Wet and Hybrid Cooling Towers at Power Plants
- Marley Cooling Technologies - Cooling Towers Maintenance Procedures
- Marley Cooling Technologies - ASHRAE Guideline 12-2000 - Minimizing the Risk of Legionellosis
- Marley Cooling Technologies - Cooling Tower Inspection Tips {especially page 3 of 7}
- - TEC: Cooling tower company with all certificates needed for handling legionalla
- Tower Tech Modular Cooling Towers - Legionella Control
- GE Infrastructure Water & Process Technologies - Chemical Water Treatment Recommendations For Reduction of Risks Associated with Legionella in Open Recirculating Cooling Water Systems | Legionella
Template:Seealso
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Legionella is a Gram negative bacterium, including species that cause legionellosis or Legionnaires' disease, most notably L. pneumophila.[1][2]
Legionella are common in many environments, with at least 50 species and 70 serogroups identified. The side-chains of the cell wall carry the bases responsible for the somatic antigen specificity of these organisms. The chemical composition of these side chains both with respect to components as well as arrangement of the different sugars determines the nature of the somatic or O antigen determinants, which are essential means of serologically classifying many Gram-negative bacteria.
Legionella acquired its name after a July, 1976 outbreak among people attending a convention of the American Legion in Philadelphia. The mystery disease sickened 221 persons, causing 34 deaths. In that bicentennial year, a pandemic among U.S. war veterans was widely publicized and produced a national panic
[3].
On January 18, 1977 the causative agent was identified as a previously unknown bacterium, subsequently named Legionella. See Legionnaire's Disease for full details.
# Historical Perspective
In 1976, legionella was discovered after an outbreak among people who attended the Philadelphia convention of the American Legion. Those affected had a type of pneumonia that eventually became known as Legionnaires’ disease.
# Classification
The genus Legionella is made up of 58 species and 3 subspecies (pneumophila, fraseri, and pascullei ).
Legionella is a Gram-negative bacteria with strict growth requirements.
Monoclonal antibodies against lipopolysaccharide epitopes on the bacterial cell surface detect L pneumophila serogroup 1.
# Pathophysiology
Legionella reside in drinking and surface water and are transmitted in aerosols to humans. It multiplies intracellularly in alveolar macrophages leading to an immune reaction that produces destructive alveolar inflammation. Inoculation of surgical wounds via contaminated tap water has been recorded.
# Causes
Legionella can become a health concern when it grows and spreads in human-made water systems example
- Decorative fountains and water features
- Showerheads and sink faucets
- Hot water tanks and heaters
- Cooling towers
- Large, complex plumbing systems
# Detection
Legionella is traditionally detected by culture on buffered charcoal yeast extract (BCYE) agar. Legionellae require the presence of cysteine to grow and therefore do not grow on common blood agar media used for laboratory based total viable counts or on site displides. Common laboratory procedures for the detection of Legionella in water[4] concentrate the bacteria (by centrifugation and/or filtration through 0.2 micron filters) before innoculation onto a charcoal yeast extract agar containing antibiotics (e.g. glycine vancomycim polymixin cyclohexamide, GVPC) to suppress other flora in the sample. Heat or acid treatment are also used to reduce interference from other microbes in the sample.
After incubation for up to 10 days, suspect colonies are confirmed as Legionellae if they grow on BCYE containing cysteine, but not on agar without cysteine added. Immunological techniques are then commonly used to establish the species and/or serogroups of bacteria present in the sample.
New techniques for the rapid detection of Legionella in water samples are emerging including the use of polymerase chain reaction (PCR)[5] and rapid immunological assays[6]. These technologies can typically provide much faster results.
# Pathogenesis
Legionella have been known for some time to live within amoebae in the natural environment.[7] Legionella species are the causative agent of the human Legionnaires' disease and the lesser form, Pontiac fever. Legionella transmission is via aerosols—the inhalation of mist droplets containing the bacteria. Common sources include cooling towers, domestic hot-water systems, fountains, and similar disseminators that tap into a public water supply. Natural sources of Legionella include freshwater ponds and creeks. Person-to-person transmission of Legionella has not been demonstrated.[8]
Once inside a host, incubation may take up to two weeks. Initial symptoms are flu-like, including fever, chills, and dry cough. Advanced stages of the disease cause problems with the gastrointestinal tract and the nervous system and lead to diarrhea and nausea. Other advanced symptoms of pneumonia may also present.
However, the disease is generally not a threat to most healthy individuals, and tends to lead to harmful symptoms only in those with a compromised immune system and the elderly. Consequently, it is actively checked for in the water systems of hospitals and nursing homes. In the United States, the disease affects between 8,000 to 18,000 individuals a year.
# Molecular biology
With the application of modern molecular genetic and cell biological techniques, the mechanisms used by Legionella to multiply within macrophages are beginning to be understood. The specific regulatory cascades that govern differentiation as well as the gene regulation are being studied. The genome sequences of four L. pneumophila strains have been published and it is now possible to investigate the whole genome by modern molecular methods. The molecular studies are contributing to the fields of clinical research, diagnosis, treatment, epidemiology, and prevention of disease.[2]
# Controlling potential sources of Legionella
Common sources of Legionella include cooling towers used in industrial cooling water systems as well as in large central air conditioning systems, domestic hot water systems, fountains, and similar disseminators that draw upon a public water supply. Natural sources include freshwater ponds and creeks.
Recent research in the Journal of Infectious Diseases provides evidence that Legionella pneumophila, the causative agent of Legionnaires disease, can travel at least 6 km from its source by airborne spread. It was previously believed that transmission of the bacterium was restricted to much shorter distances. A team of French scientists reviewed the details of an epidemic of Legionnaires disease that took place in Pas-de-Calais in northern France in 2003–2004. There were 86 confirmed cases during the outbreak, of whom 18 perished. The source of infection was identified as a cooling tower in a petrochemical plant, and an analysis of those affected in the outbreak revealed that some infected people lived as far as 6–7 km from the plant.[9]
Several European countries established a working group known as the European Working Group for Legionella Infections (EWGLI)[10] to share knowledge and experience about monitoring potential sources of Legionella. That group has published guidelines about the actions to be taken to limit the number of colony forming units (i.e. live bacteria that are able to multiply) of Legionella per litre
Temperature affects the survival of Legionellae as follows:
- 70 to 80 °C (158 to 176 °F) - Disinfection range
- At 66 °C (151 °F) - Legionellae die within 2 minutes
- At 60 °C (140 °F) - Legionellae die within 32 minutes
- At 55 °C (131 °F) - Legionellae die within 5 to 6 hours
- 50 to 55 °C (122 to 131 °F) - They can survive but do not multiply
- 20 to 50 °C (68 to 122 °F)- Legionellae growth range
- 35 to 46 °C (95 to 115 °F) - Ideal growth range
- Below 20 °C (68 °F) - Legionellae can survive but are dormant
The above data can be confirmed in an online article by Reliance World Wide.[11]
Control of Legionella growth can be through :
A. Chemical Treatment
1. Short term - Cl2, must be repeated every 3 to 5 weeks, corrosion factors
2. Long term - ClO2, takes up to 1 month for system saturation
B. Non-Chemical Treatment
1. Short term - Thermal eradication - must be repeated every 3 to 5 weeks
2. Long term - Industrial size copper silver ionisation (Ionization) technology such as 1-AquaLyse.ca, 2-Liquitech or 3-TarnPure.
Units have provisional EPA approval. No copper-silver has yet had efficacy data approved by EPA or received final EPA approval.
## Guidelines for control of Legionella in cooling towers
Many governmental agencies, cooling tower manufacturers and industrial trade organizations have developed design and maintenance guidelines for preventing or controlling the growth of Legionella in cooling towers. Below is a list of sources for such guidelines:
- [2]
- [3] Legionella control in Ornamental Fountains
- [4] ASHRAE Guideline
- Centers for Disease Control and Prevention - Procedure for Cleaning Cooling Towers and Related Equipment (pages 239 and 240 of 249)
- Cooling Technology Institute - Best Practices for Control of Legionella
- Association of Water Technologies - Legionella 2003
- California Energy Commission - Cooling Water Management Program Guidelines For Wet and Hybrid Cooling Towers at Power Plants
- Marley Cooling Technologies - Cooling Towers Maintenance Procedures
- Marley Cooling Technologies - ASHRAE Guideline 12-2000 - Minimizing the Risk of Legionellosis
- Marley Cooling Technologies - Cooling Tower Inspection Tips {especially page 3 of 7}
- [5] - TEC: Cooling tower company with all certificates needed for handling legionalla
- Tower Tech Modular Cooling Towers - Legionella Control
- GE Infrastructure Water & Process Technologies - Chemical Water Treatment Recommendations For Reduction of Risks Associated with Legionella in Open Recirculating Cooling Water Systems | https://www.wikidoc.org/index.php/Legionella | |
1fa4e92b46fd7baafccca306be3c5c317ad03050 | wikidoc | Lensometry | Lensometry
Lensometry is a technique that measures the dioptric power of spectacle lenses.
# How to Perform the Test?
- Adjust the focusing eyepiece of the lensometer so that it reads 0 D on the measuring drum with the target crisply in focus.
- Place the spectacles in the lensometer with the ocular surface away from the examiner.
- Measure the right lens first. Then measure the left lens.
- Center the spectacles within the carriage of the instrument so that the target is centrally aligned within the eyepiece reticle.
- From an excess plus power direction, rotate the power drum of the lensometer so that the target comes to a sharp focus in the first meridian,
simultaneously rotating the axis drum and making its target lines contiguous. This is the first meridian. Note the position of the power drum.
- Continue rotating the power drum until the second meridian comes into sharp, contiguous focus. This is the second meridian. Note the position of the
power and axis drums.
- If both meridians come to a sharp focus simultaneously, the lens is spherical. If there are two distinctly different foci, the lens is spherocylindrical.
- If there is an add, measure it.
- The spherical or spherocylindrical power and axis is recorded in minus cylinder form.
- The multifocal add, if present, is recorded as a plus add.
## Useful Tips
- Focus the lensometer before each reading.
- Carefully fine-tune the power and the axis drums.
- If the lens is a multifocal lens, look carefully for the maximum plus power position of the lens. | Lensometry
Lensometry is a technique that measures the dioptric power of spectacle lenses.
# How to Perform the Test?
- Adjust the focusing eyepiece of the lensometer so that it reads 0 D on the measuring drum with the target crisply in focus.
- Place the spectacles in the lensometer with the ocular surface away from the examiner.
- Measure the right lens first. Then measure the left lens.
- Center the spectacles within the carriage of the instrument so that the target is centrally aligned within the eyepiece reticle.
- From an excess plus power direction, rotate the power drum of the lensometer so that the target comes to a sharp focus in the first meridian,
simultaneously rotating the axis drum and making its target lines contiguous. This is the first meridian. Note the position of the power drum.
- Continue rotating the power drum until the second meridian comes into sharp, contiguous focus. This is the second meridian. Note the position of the
power and axis drums.
- If both meridians come to a sharp focus simultaneously, the lens is spherical. If there are two distinctly different foci, the lens is spherocylindrical.
- If there is an add, measure it.
- The spherical or spherocylindrical power and axis is recorded in minus cylinder form.
- The multifocal add, if present, is recorded as a plus add. [1]
## Useful Tips
- Focus the lensometer before each reading.
- Carefully fine-tune the power and the axis drums.
- If the lens is a multifocal lens, look carefully for the maximum plus power position of the lens. [2] | https://www.wikidoc.org/index.php/Lensometry | |
06d802b9ccc50098fed14b9a6ca07f236fc56a9c | wikidoc | Lenticonus | Lenticonus
# Overview
'Lenticonus' is a bulging of the lens capsule and the underlying cortex. The diagnosis of lenticonus is essentially a clinical diagnosis made by bio-microscopic examination.
# Classification scheme
- Lenticonus anterior: lenticonus anterior is part of the Alport's syndrome
- Lenticonus posterior; lenticonus posterior is more common than lenticonus anterior and is not associated with systemic disease. | Lenticonus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: :Aarti Narayan, M.B.B.S [2]
# Overview
'Lenticonus' is a bulging of the lens capsule and the underlying cortex. The diagnosis of lenticonus is essentially a clinical diagnosis made by bio-microscopic examination.
# Classification scheme
- Lenticonus anterior: lenticonus anterior is part of the Alport's syndrome
- Lenticonus posterior; lenticonus posterior is more common than lenticonus anterior and is not associated with systemic disease. | https://www.wikidoc.org/index.php/Lenticonus | |
83a9c63e0e89d261dd904febc82b3909e4022c49 | wikidoc | Lentivirus | Lentivirus
Lentivirus (lenti-, Latin for "slow") is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.
# Classification
Five serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). The primate lentiviruses are distinguished by the use of CD4 protein as receptor and the absence of dUTPase. Some groups have cross-reactive gag antigens (e.g., the ovine, caprine and feline lentiviruses). Antibodies to gag antigens in lions and other large felids indicate the existence of other viruses related to FIV and the ovine/caprine lentiviruses. Description is on taxonomic level of genus.
# Morphology
Virions enveloped; slightly pleomorphic; spherical; 80-100 nm in diameter. Surface projections of envelope small (surface appears rough), or barely visible; spikes (of about 8nm); dispersed evenly over all the surface. Nucleocapsids (cores) isometric. Nucleoid concentric and rod-shaped, or shaped like a truncated cone.
# Genome Organization and Replication
Features of the genome: infectious viruses have 3 main genes coding for the viral proteins in the order: 5´-gag-pol-env-3´. There are additional genes depending on the virus (e.g., for HIV-1: vif, vpr, vpu, tat, rev, nef) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The LTR is about 600nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.
Viral proteins involved in early stages of replication include Reverse Transcriptase and Integrase. Reverse Transcriptase (RT) is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. RT also has RNaseH activity for destruction of the RNA-template. Integrase (IN) binds both the viral cDNA generated by RT and the host DNA. Processing of the LTR by IN is performed prior to insertion of the viral genome into the host DNA.
Although transmission is generally via infectious particles, lentiviruses are capable of infecting neighboring cells in direct contact with the host cells, without having to form extracellular particles.
# Antigenic Properties
Serological Relationships: Antigen determinants are type-specific and group-specific. Antigen determinants that possess type-specific reactivity are found on the envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on the glycoproteins. Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon is infrequently based on their antigenic properties.
# Biological
- Symptoms and Host Range: Host of virus belongs to the Domain Eucarya. Host of virus belongs to the Kingdom Animalia. Phylum Chordata. Subphylum Vertebrata. Class Mammalia. Order Primates, Perissodactyla, Carnivora, and Artiodactyla.
- Transmission: Transmitted by means not involving a vector.
- Geographic Distribution: World-wide.
# Physicochemical and Physical Properties
- General
Buoyant density 1.16-1.18 g cm-3 in sucrose
Virions sensitive to heat, detergents, and formaldehyde
Infectivity not affected by irradiation
- Buoyant density 1.16-1.18 g cm-3 in sucrose
- Virions sensitive to heat, detergents, and formaldehyde
- Infectivity not affected by irradiation
Classed as having class c morphology
- Nucleic Acid
Virions contain 2 % nucleic acid
Genome consists of a dimer
Virions contain one molecule of (each) linear positive-sense single stranded RNA.
Total genome length is of one monomer 9200 nt
Genome sequence has terminal repeated sequences; long terminal repeats (LTR) (of about 600 nt
The 5' end of the genome has a cap
Cap sequence of type 1 m7G5ppp5'GmpNp
3' end of each monomer has a poly (A) tract; 3'-terminus has a tRNA-like structure (and accepts lysin)
Encapsidated nucleic acid solely genomic
2 copies packed per particle (held together by hydrogen bonds to form a dimer).
- Virions contain 2 % nucleic acid
- Genome consists of a dimer
- Virions contain one molecule of (each) linear positive-sense single stranded RNA.
- Total genome length is of one monomer 9200 nt
- Genome sequence has terminal repeated sequences; long terminal repeats (LTR) (of about 600 nt
- The 5' end of the genome has a cap
- Cap sequence of type 1 m7G5ppp5'GmpNp
- 3' end of each monomer has a poly (A) tract; 3'-terminus has a tRNA-like structure (and accepts lysin)
- Encapsidated nucleic acid solely genomic
- 2 copies packed per particle (held together by hydrogen bonds to form a dimer).
- Proteins 11
Virions contain 60 % protein
Five structural virion proteins found (major)
Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
Usually four non-structural proteins found, or three non-structural proteins found (in the primate lentiviruses).
Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Virions contain 60 % protein
- Five structural virion proteins found (major)
Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
- Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
- Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
- Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
- Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
- Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
- Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
- Usually four non-structural proteins found, or three non-structural proteins found (in the primate lentiviruses).
Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
- Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
- Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Lipids: Virions contain 35 % lipid.
- Carbohydrates: Other compounds detected in the particles 3% carbohydrates.
# Practical applications
Lentivirus is primarily a research tool used to introduce a gene product into in vitro systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference technology in high-throughput formats . The expression of short-hairpin RNA (shRNA) reduces the expression of a specific gene, thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can be a precursor to the development of novel drugs which aim to block a gene-product to treat a disease.
Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophillia is corrected by expressing wild-type platlet-factor VIII, the gene that is mutated in human hemophillia . Lentiviral infection have advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity.
Lentiviruses have also been successfully used for transfection of diabetic mice with the gene encoding PDGF (platelet-derived growth factor) , a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. | Lentivirus
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Lentivirus (lenti-, Latin for "slow") is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.
# Classification
Five serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). The primate lentiviruses are distinguished by the use of CD4 protein as receptor and the absence of dUTPase. Some groups have cross-reactive gag antigens (e.g., the ovine, caprine and feline lentiviruses). Antibodies to gag antigens in lions and other large felids indicate the existence of other viruses related to FIV and the ovine/caprine lentiviruses. Description is on taxonomic level of genus.
# Morphology
Virions enveloped; slightly pleomorphic; spherical; 80-100 nm in diameter. Surface projections of envelope small (surface appears rough), or barely visible; spikes (of about 8nm); dispersed evenly over all the surface. Nucleocapsids (cores) isometric. Nucleoid concentric and rod-shaped, or shaped like a truncated cone.
# Genome Organization and Replication
Features of the genome: infectious viruses have 3 main genes coding for the viral proteins in the order: 5´-gag-pol-env-3´. There are additional genes depending on the virus (e.g., for HIV-1: vif, vpr, vpu, tat, rev, nef) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The LTR is about 600nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.
Viral proteins involved in early stages of replication include Reverse Transcriptase and Integrase. Reverse Transcriptase (RT) is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. RT also has RNaseH activity for destruction of the RNA-template. Integrase (IN) binds both the viral cDNA generated by RT and the host DNA. Processing of the LTR by IN is performed prior to insertion of the viral genome into the host DNA.
Although transmission is generally via infectious particles, lentiviruses are capable of infecting neighboring cells in direct contact with the host cells, without having to form extracellular particles.
# Antigenic Properties
Serological Relationships: Antigen determinants are type-specific and group-specific. Antigen determinants that possess type-specific reactivity are found on the envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on the glycoproteins. Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon is infrequently based on their antigenic properties.
# Biological
- Symptoms and Host Range: Host of virus belongs to the Domain Eucarya. Host of virus belongs to the Kingdom Animalia. Phylum Chordata. Subphylum Vertebrata. Class Mammalia. Order Primates, Perissodactyla, Carnivora, and Artiodactyla.
- Transmission: Transmitted by means not involving a vector.
- Geographic Distribution: World-wide.
# Physicochemical and Physical Properties
- General
Buoyant density 1.16-1.18 g cm-3 in sucrose
Virions sensitive to heat, detergents, and formaldehyde
Infectivity not affected by irradiation
- Buoyant density 1.16-1.18 g cm-3 in sucrose
- Virions sensitive to heat, detergents, and formaldehyde
- Infectivity not affected by irradiation
Classed as having class c morphology
- Nucleic Acid
Virions contain 2 % nucleic acid
Genome consists of a dimer
Virions contain one molecule of (each) linear positive-sense single stranded RNA.
Total genome length is of one monomer 9200 nt
Genome sequence has terminal repeated sequences; long terminal repeats (LTR) (of about 600 nt
The 5' end of the genome has a cap
Cap sequence of type 1 m7G5ppp5'GmpNp
3' end of each monomer has a poly (A) tract; 3'-terminus has a tRNA-like structure (and accepts lysin)
Encapsidated nucleic acid solely genomic
2 copies packed per particle (held together by hydrogen bonds to form a dimer).
- Virions contain 2 % nucleic acid
- Genome consists of a dimer
- Virions contain one molecule of (each) linear positive-sense single stranded RNA.
- Total genome length is of one monomer 9200 nt
- Genome sequence has terminal repeated sequences; long terminal repeats (LTR) (of about 600 nt
- The 5' end of the genome has a cap
- Cap sequence of type 1 m7G5ppp5'GmpNp
- 3' end of each monomer has a poly (A) tract; 3'-terminus has a tRNA-like structure (and accepts lysin)
- Encapsidated nucleic acid solely genomic
- 2 copies packed per particle (held together by hydrogen bonds to form a dimer).
- Proteins 11
Virions contain 60 % protein
Five structural virion proteins found (major)
Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
Usually four non-structural proteins found, or three non-structural proteins found (in the primate lentiviruses).
Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Virions contain 60 % protein
- Five structural virion proteins found (major)
Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
- Protein size largest 120000 Da. Gp120 glycosylated surface envelope protein SU, encoded by the viral gene env
- Protein size of 2nd largest 41000 Da. Gp41 glycosylated transmembrane envelope protein TM, also encoded by the viral gene env.
- Protein size of 3rd largest 24000 Da. P24 non-glycosylated capsid protein CA.
- Protein size of 4th largest 17000 Da. P17 non-glycosylated matrix protein MA.
- Protein size of 5th largest 7000-11000 Da. Non-glycosylated capsid protein NC.
- Proteins MA, CA and NC are all encoded by the gag gene. Virion structural proteins are glycosylated. Are the following: the envelope proteins SU and TM.
- Usually four non-structural proteins found, or three non-structural proteins found (in the primate lentiviruses).
Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Protein size 66000 Da. Reverse transcriptase RT encoded by the pol gene.
- Protein size of 2nd largest 32000 Da. Integrase IN also encoded by the pol gene.
- Protein size of 3rd 14000 Da. Protease PR encoded by the pro gene. dUPTase DU, the role of which is still unknown.
- Lipids: Virions contain 35 % lipid.
- Carbohydrates: Other compounds detected in the particles 3% carbohydrates.
# Practical applications
Lentivirus is primarily a research tool used to introduce a gene product into in vitro systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference technology in high-throughput formats [1]. The expression of short-hairpin RNA (shRNA) reduces the expression of a specific gene, thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can be a precursor to the development of novel drugs which aim to block a gene-product to treat a disease.
Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophillia is corrected by expressing wild-type platlet-factor VIII, the gene that is mutated in human hemophillia [2]. Lentiviral infection have advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity.
Lentiviruses have also been successfully used for transfection of diabetic mice with the gene encoding PDGF (platelet-derived growth factor) [3], a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. | https://www.wikidoc.org/index.php/Lentivirus | |
3250c50dc38b0a4111f53fb5f044567f59d9bc6c | wikidoc | Lenvatinib | Lenvatinib
# Disclaimer
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# Overview
Lenvatinib is an tyrosine kinase inhibitor that is FDA approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). Common adverse reactions include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. pneumonia, hypertension , and dehydration ..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Lenvatinib is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
- The recommended daily dose of Lenvatinib is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food . Continue Lenvatinib until disease progression or until unacceptable toxicity occurs.
- Take Lenvatinib at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.
- Severe Renal or Hepatic Impairment
- The recommended dose of Lenvatinib is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C).
- Hypertension
- Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment
- Withhold Lenvatinib for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2.
- Discontinue Lenvatinib for life-threatening hypertension.
- Cardiac dysfunction or hemorrhage
- Discontinue for a Grade 4 event.
- Withhold Lenvatinib for development of Grade 3 event until improved to Grade 0 or 1 or baseline.
- Either resume at a reduced dose (see Table 1) or discontinue Lenvatinib depending on the severity and persistence of the adverse event.
- Arterial thrombotic event
- Discontinue Lenvatinib following an arterial thrombotic event.
- Renal failure and impairment or hepatotoxicity
- Withhold Lenvatinib for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline.
- Either resume at a reduced dose (see Table 1) or discontinue Lenvatinib depending on the severity and persistence of renal impairment or hepatotoxicity.
- Discontinue Lenvatinib for hepatic failure.
- proteinuria
- Withhold Lenvatinib for ≥2 grams of proteinuria/24 hours.
- Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours.
- Discontinue Lenvatinib for nephrotic syndrome. Gastrointestinal perforation or fistula formation
- Discontinue Lenvatinib in patients who develop gastrointestinal perforation or lifethreatening fistula.
- QT prolongation
- Withhold Lenvatinib for the development of Grade 3 or greater QT interval prolongation.
- Resume Lenvatinib at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline.
- Reversible posterior leukoencephalopathy syndrome (RPLS)
- Withhold for RPLS until fully resolved.
- Upon resolution, resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of neurologic symptoms.
- Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenvatinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lenvatinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lenvatinib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenvatinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lenvatinib in pediatric patients.
# Contraindications
- None.
# Warnings
- In Study 1 hypertension was reported in 73% of Lenvatinib-treated patients and 16% of patients in the placebo group . The median time to onset of new or worsening hypertension was 16 days for Lenvatinib-treated patients. The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in Lenvatinib-treated patients and none in the placebo group.
- Control blood pressure prior to treatment with Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with Lenvatinib. Withhold Lenvatinib for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue Lenvatinib for life-threatening hypertension .
- In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of Lenvatinib-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in Lenvatinib-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) Lenvatinib-treated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo.
- Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold Lenvatinib for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of cardiac dysfunction. Discontinue Lenvatinib for Grade 4 cardiac dysfunction .
- In Study 1, arterial thromboembolic events were reported in 5% of Lenvatinib-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in Lenvatinib-treated patients and 1% in the placebo group.
- Discontinue Lenvatinib following an arterial thromboembolic events. The safety of resuming Lenvatinib after an arterial thromboembolic events has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic events within the previous 6 months
- In Study 1, 4% of Lenvatinib-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 patients received Lenvatinib, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient.
- Monitor liver function before initiation of Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold Lenvatinib for the development of Grade 3 or greater liver impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of hepatotoxicity. Discontinue Lenvatinib for hepatic failure .
- In Study 1, proteinuria was reported in 34% of Lenvatinib-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in Lenvatinib-treated patients was 11% compared to none in the placebo group.
- Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold Lenvatinib for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue Lenvatinib for nephrotic syndrome .
- In Study 1, events of renal impairment were reported in 14% of Lenvatinib-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in Lenvatinib-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in Lenvatinib-treated patients was dehydration/hypovolemia due to diarrhea and vomiting.
- Withhold Lenvatinib for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of renal impairment
- Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of Lenvatinib-treated patients and 0.8% of patients in the placebo group.
- Discontinue Lenvatinib in patients who develop gastrointestinal perforation or lifethreatening fistula
- In Study 1, QT/QTc interval prolongation was reported in 9% of Lenvatinib-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in Lenvatinib-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics.
- Monitor and correct electrolyte abnormalities in all patients. Withhold Lenvatinib for the development of Grade 3 or greater QT interval prolongation. Resume Lenvatinib at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline
- In Study 1, 9% of Lenvatinib-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction .
- Monitor blood calcium levels at least monthly and replace calcium as necessary during Lenvatinib treatment. Interrupt and adjust Lenvatinib dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia
- Across clinical studies in which 1108 patients received Lenvatinib, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of neurologic symptoms
- In Study 1, hemorrhagic events occurred in 35% of Lenvatinib-treated patients and in 18% of the placebo group. However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of Lenvatinib-treated patients.
- Across clinical studies in which 1108 patients received Lenvatinib, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.
- Withhold Lenvatinib for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of hemorrhage. Discontinue Lenvatinib in patients who experience Grade 4 hemorrhage .
- Lenvatinib impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of Lenvatinib-treated patients as compared with 14% of patients receiving placebo.
- Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.
- Based on its mechanism of action and data from animal reproduction studies, Lenvatinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed elsewhere in the label
- Hypertension
- Cardiac Dysfunction
- Arterial Thromboembolic Events
- Hepatotoxicity
- proteinuria
- Renal Failure and Impairment
- Gastrointestinal Perforation and fistula Formation
- QT interval prolongation
- Hypocalcemia
- Reversible Posterior Leukoencephalopathy Syndrome
- Hemorrhagic Events
- Impairment of Thyroid Stimulating Hormone Suppression
- 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 obtained in 1108 patients with advanced solid tumors who received Lenvatinib as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions . The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months.
- The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to Lenvatinib (n=261) or placebo (n=131) . The median treatment duration was 16.1 months for Lenvatinib and 3.9 months for placebo. Among 261 patients who received Lenvatinib in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.
- In Study 1, the most common adverse reactions observed in Lenvatinib-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
- Adverse reactions led to dose reductions in 68% of patients receiving Lenvatinib and 5% of patients receiving placebo; 18% of patients discontinued Lenvatinib and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of Lenvatinib were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of Lenvatinib were hypertension (1%) and asthenia (1%).
- Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in Lenvatinib-treated patients than patients receiving placebo in the double-blind phase of the DTC study.
- In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of Lenvatinib-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lenvatinib in the drug label.
# Drug Interactions
- Effect of Other Drugs on Lenvatinib No dose adjustment of Lenvatinib is recommended when co-administered with CYP3A, Pglycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducer
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Risk Summary Based on its mechanism of action and data from animal reproduction studies, Lenvatinib can cause fetal harm when administered to a pregnant woman . In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits . There are no available human data informing the drug-associated risk. 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 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
- In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and doserelated increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).
- Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased postimplantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lenvatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lenvatinib during labor and delivery.
### Nursing Mothers
- It is not known whether Lenvatinib is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma
Because of the potential for serious adverse reactions in nursing infants from Lenvatinib, advise women to discontinue breastfeeding during treatment with Lenvatinib.
- Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.
### Pediatric Use
- The safety and effectiveness of Lenvatinib in pediatric patients have not been established.
- Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.
### Geriatic Use
- Of 261 patients who received Lenvatinib in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Lenvatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lenvatinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied
### Hepatic Impairment
- No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily
### Females of Reproductive Potential and Males
- Based on its mechanism of action, Lenvatinib can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy.
- Lenvatinib may result in reduced fertility in females of reproductive potential .
- Lenvatinib may result in damage to male reproductive tissues leading to reduced fertility of unknown duration
### Immunocompromised Patients
There is no FDA guidance one the use of Lenvatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lenvatinib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lenvatinib in the drug label.
# Overdosage
- There is no specific antidote for overdose with Lenvatinib. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable .Adverse reactions in patients receiving single doses of Lenvatinib as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose.
# Pharmacology
There is limited information regarding Lenvatinib Pharmacology in the drug label.
## Mechanism of Action
- Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.
## Structure
- Lenvatinib, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4--7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula is C21H19ClN4O4 - CH4O3S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is:
- Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.30. Each Lenvatinib capsule contains lenvatinib mesylate equivalent to 4 mg or 10 mg of lenvatinib, and the following inactive ingredients: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl cellulose (type H), and talc. The hypromellose capsule shell contains titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink contains shellac, black iron oxide, potassium hydroxide, and propylene glycol
## Pharmacodynamics
- A single 32 mg dose (1.3 times the recommended daily dose) of lenvatinib did not prolong the QT/QTc interval in a thorough QT study in healthy subjects. However, QT prolongation was observed in Study 1
## Pharmacokinetics
- After oral administration of Lenvatinib, time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.
- In patients with solid tumors administered single and multiple doses of Lenvatinib once daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration- time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).
- In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 μg/mL). In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 μg/mL).
- Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump (BSEP).
- Plasma concentrations declined bi-exponentially following Cmax. The terminal elimination half-life of lenvatinib was approximately 28 hours.
- CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.
- Ten days after a single administration of radiolabeled lenvatinib to 6 patients with solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.
- The pharmacokinetics of lenvatinib following a single 24 mg dose were evaluated in subjects with mild (CLcr 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr <30 mL/min) renal impairment, and compared to healthy subjects. Subjects with end stage renal disease were not studied. After a single 24 mg oral dose of Lenvatinib, the AUC0-inf for subjects with renal impairment were similar compared to those for healthy subjects .
- The pharmacokinetics of lenvatinib following a single 10 mg dose of Lenvatinib were evaluated in subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment. The pharmacokinetics of a single 5 mg dose were evaluated in subjects with severe (Child Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively .
- Based on a population PK analysis, age, sex, and race did not have a significant effect on apparent clearance (Cl/F) of lenvatinib.
- CYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC by 15% and Cmax by 19% in a dedicated clinical trial.
- P-gp Inhibitors: Rifampicin (400 mg as a single dose) increased lenvatinib (24 mg as a single dose)AUC by 31% and Cmax by 33% in a dedicated clinical trial.
- CYP3A and P-gp Inducers: Rifampicin (400 mg administered daily for 21 days) decreased lenvatinib (a single 24 mg administered on Day 15) AUC by 18% in a dedicated clinical trial. The Cmax was unchanged.
- CYP3A4 or CYP2C8 Substrates: There is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).
- In Vitro Studies with CYP or UDP-glucuronosyltransferase (UGT) Substrates: Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, but an increase in lenvatinib exposure that impacts safety is unlikely. Lenvatinib does not inhibit CYP2A6 and CYP2E1.
- Lenvatinib induces CYP3A, but a decrease in lenvatinib exposure that impacts efficacy is unlikely. Lenvatinib does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. *Lenvatinib directly inhibits UGT1A1 and UGT1A4. The clinical implication of this finding is unknown. Lenvatinibshows little or no inhibition on UGT1A6, UGT1A9, UGT2B7, or aldehyde oxidase.
- Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
- In Vitro Studies with Drug Transporter System Substrates: Lenvatinib inhibits OAT1, OAT3, OCT1, OCT2, OATP1B1, and BSEP. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on OATP1B3.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.
- No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the clinical exposure by AUC at the recommended human dose. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the clinical exposure by AUC at the 24 mg clinical dose, respectively. In addition, in monkeys, a decreased incidence of menstruation was reported at lenvatinib exposures lower than those in humans at the 24 mg clinical dose.
# Clinical Studies
- A multicenter, randomized (2:1), double-blind, placebo-controlled trial was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review. Radioactive iodine-refractory was defined as 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity of >400 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry. Patients were randomized to receive Lenvatinib 24 mg once daily (n=261) or placebo (n=131) until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age. The major efficacy outcome measure was progression-free survival as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Independent review confirmation of disease progression was required prior to discontinuing patients from the randomization phase of the study. Other efficacy outcome measures included objective response rate and overall survival. Patients in the placebo arm could receive lenvatinib following independent review confirmation of disease progression.
- Of the 392 patients randomized, 51% were male, the median age was 63 years, 40% were older than 65 years, 79% were White, 54% had an ECOG performance status of 0, and 24% had received 1 prior VEGF/VEGFR-targeted therapy. Metastases were present in 99% of the patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. The histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. In the Lenvatinib arm, 67% of patients did not demonstrate iodine uptake on any radioiodine scan compared to 77% in the placebo arm. Additionally, 59% of patients on the Lenvatinib arm and 61% of patients on placebo arm progressed, according to RECIST 1.1, within 12 months of prior 131I therapy; 19.2% of patients on the Lenvatinib arm and 17.6% of patients on placebo arm received prior cumulative activity of >400 mCi or 22 gigabecquerels (GBq) 131I, with the last dose administered at least 6 months prior to study entry. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq).
- A statistically significant prolongation in PFS was demonstrated in Lenvatinib-treated patients compared to those receiving placebo (see Table 4 and Figure 1). Upon confirmation of progression, 109 (83%) patients randomly assigned to placebo crossed over to receive open-label Lenvatinib.
# How Supplied
- Lenvatinib 4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on the body.
- Lenvatinib 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on the body.
- Lenvatinib capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows:
- NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card).
- NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card).
- NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card).
- NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card).
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated .
- Cardiac Dysfunction: Advise patients that Lenvatinib can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles .
- Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke .
- Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure .
- proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine.
- Gastrointestinal perforation or fistula formation: Advise patients that Lenvatinib can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain .
- Hemorrhagic Events: Advise patients that Lenvatinib can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding .
- Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy . Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy
- Lactation: Advise nursing women to discontinue breastfeeding during treatment with Lenvatinib
# Precautions with Alcohol
- Alcohol-Lenvatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lenvima®
# Look-Alike Drug Names
There is limited information regarding Lenvatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Lenvatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Lenvatinib is an tyrosine kinase inhibitor that is FDA approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). Common adverse reactions include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. pneumonia, hypertension , and dehydration ..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Lenvatinib is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
- The recommended daily dose of Lenvatinib is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food . Continue Lenvatinib until disease progression or until unacceptable toxicity occurs.
- Take Lenvatinib at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.
- Severe Renal or Hepatic Impairment
- The recommended dose of Lenvatinib is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C).
- Hypertension
- Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment
- Withhold Lenvatinib for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2.
- Discontinue Lenvatinib for life-threatening hypertension.
- Cardiac dysfunction or hemorrhage
- Discontinue for a Grade 4 event.
- Withhold Lenvatinib for development of Grade 3 event until improved to Grade 0 or 1 or baseline.
- Either resume at a reduced dose (see Table 1) or discontinue Lenvatinib depending on the severity and persistence of the adverse event.
- Arterial thrombotic event
- Discontinue Lenvatinib following an arterial thrombotic event.
- Renal failure and impairment or hepatotoxicity
- Withhold Lenvatinib for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline.
- Either resume at a reduced dose (see Table 1) or discontinue Lenvatinib depending on the severity and persistence of renal impairment or hepatotoxicity.
- Discontinue Lenvatinib for hepatic failure.
- proteinuria
- Withhold Lenvatinib for ≥2 grams of proteinuria/24 hours.
- Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours.
- Discontinue Lenvatinib for nephrotic syndrome. Gastrointestinal perforation or fistula formation
- Discontinue Lenvatinib in patients who develop gastrointestinal perforation or lifethreatening fistula.
- QT prolongation
- Withhold Lenvatinib for the development of Grade 3 or greater QT interval prolongation.
- Resume Lenvatinib at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline.
- Reversible posterior leukoencephalopathy syndrome (RPLS)
- Withhold for RPLS until fully resolved.
- Upon resolution, resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of neurologic symptoms.
- Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenvatinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lenvatinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lenvatinib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenvatinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lenvatinib in pediatric patients.
# Contraindications
- None.
# Warnings
- In Study 1 hypertension was reported in 73% of Lenvatinib-treated patients and 16% of patients in the placebo group . The median time to onset of new or worsening hypertension was 16 days for Lenvatinib-treated patients. The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in Lenvatinib-treated patients and none in the placebo group.
- Control blood pressure prior to treatment with Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with Lenvatinib. Withhold Lenvatinib for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue Lenvatinib for life-threatening hypertension .
- In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of Lenvatinib-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in Lenvatinib-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) Lenvatinib-treated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo.
- Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold Lenvatinib for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of cardiac dysfunction. Discontinue Lenvatinib for Grade 4 cardiac dysfunction .
- In Study 1, arterial thromboembolic events were reported in 5% of Lenvatinib-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in Lenvatinib-treated patients and 1% in the placebo group.
- Discontinue Lenvatinib following an arterial thromboembolic events. The safety of resuming Lenvatinib after an arterial thromboembolic events has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic events within the previous 6 months
- In Study 1, 4% of Lenvatinib-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 patients received Lenvatinib, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient.
- Monitor liver function before initiation of Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold Lenvatinib for the development of Grade 3 or greater liver impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of hepatotoxicity. Discontinue Lenvatinib for hepatic failure .
- In Study 1, proteinuria was reported in 34% of Lenvatinib-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in Lenvatinib-treated patients was 11% compared to none in the placebo group.
- Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold Lenvatinib for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue Lenvatinib for nephrotic syndrome .
- In Study 1, events of renal impairment were reported in 14% of Lenvatinib-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in Lenvatinib-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in Lenvatinib-treated patients was dehydration/hypovolemia due to diarrhea and vomiting.
- Withhold Lenvatinib for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of renal impairment
- Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of Lenvatinib-treated patients and 0.8% of patients in the placebo group.
- Discontinue Lenvatinib in patients who develop gastrointestinal perforation or lifethreatening fistula
- In Study 1, QT/QTc interval prolongation was reported in 9% of Lenvatinib-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in Lenvatinib-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics.
- Monitor and correct electrolyte abnormalities in all patients. Withhold Lenvatinib for the development of Grade 3 or greater QT interval prolongation. Resume Lenvatinib at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline
- In Study 1, 9% of Lenvatinib-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction .
- Monitor blood calcium levels at least monthly and replace calcium as necessary during Lenvatinib treatment. Interrupt and adjust Lenvatinib dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia
- Across clinical studies in which 1108 patients received Lenvatinib, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of neurologic symptoms
- In Study 1, hemorrhagic events occurred in 35% of Lenvatinib-treated patients and in 18% of the placebo group. However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of Lenvatinib-treated patients.
- Across clinical studies in which 1108 patients received Lenvatinib, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.
- Withhold Lenvatinib for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue Lenvatinib depending on the severity and persistence of hemorrhage. Discontinue Lenvatinib in patients who experience Grade 4 hemorrhage .
- Lenvatinib impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of Lenvatinib-treated patients as compared with 14% of patients receiving placebo.
- Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.
- Based on its mechanism of action and data from animal reproduction studies, Lenvatinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed elsewhere in the label
- Hypertension
- Cardiac Dysfunction
- Arterial Thromboembolic Events
- Hepatotoxicity
- proteinuria
- Renal Failure and Impairment
- Gastrointestinal Perforation and fistula Formation
- QT interval prolongation
- Hypocalcemia
- Reversible Posterior Leukoencephalopathy Syndrome
- Hemorrhagic Events
- Impairment of Thyroid Stimulating Hormone Suppression
- 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 obtained in 1108 patients with advanced solid tumors who received Lenvatinib as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions . The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months.
- The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to Lenvatinib (n=261) or placebo (n=131) . The median treatment duration was 16.1 months for Lenvatinib and 3.9 months for placebo. Among 261 patients who received Lenvatinib in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.
- In Study 1, the most common adverse reactions observed in Lenvatinib-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
- Adverse reactions led to dose reductions in 68% of patients receiving Lenvatinib and 5% of patients receiving placebo; 18% of patients discontinued Lenvatinib and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of Lenvatinib were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of Lenvatinib were hypertension (1%) and asthenia (1%).
- Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in Lenvatinib-treated patients than patients receiving placebo in the double-blind phase of the DTC study.
- In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of Lenvatinib-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lenvatinib in the drug label.
# Drug Interactions
- Effect of Other Drugs on Lenvatinib No dose adjustment of Lenvatinib is recommended when co-administered with CYP3A, Pglycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducer
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Risk Summary Based on its mechanism of action and data from animal reproduction studies, Lenvatinib can cause fetal harm when administered to a pregnant woman . In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits . There are no available human data informing the drug-associated risk. 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 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
- In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and doserelated increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).
- Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased postimplantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lenvatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lenvatinib during labor and delivery.
### Nursing Mothers
- It is not known whether Lenvatinib is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma
Because of the potential for serious adverse reactions in nursing infants from Lenvatinib, advise women to discontinue breastfeeding during treatment with Lenvatinib.
- Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.
### Pediatric Use
- The safety and effectiveness of Lenvatinib in pediatric patients have not been established.
- Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.
### Geriatic Use
- Of 261 patients who received Lenvatinib in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Lenvatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lenvatinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied
### Hepatic Impairment
- No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily
### Females of Reproductive Potential and Males
- Based on its mechanism of action, Lenvatinib can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy.
- Lenvatinib may result in reduced fertility in females of reproductive potential .
- Lenvatinib may result in damage to male reproductive tissues leading to reduced fertility of unknown duration
### Immunocompromised Patients
There is no FDA guidance one the use of Lenvatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lenvatinib in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lenvatinib in the drug label.
# Overdosage
- There is no specific antidote for overdose with Lenvatinib. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable .Adverse reactions in patients receiving single doses of Lenvatinib as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose.
# Pharmacology
There is limited information regarding Lenvatinib Pharmacology in the drug label.
## Mechanism of Action
- Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.
## Structure
- Lenvatinib, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3 chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is:
- Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.30. Each Lenvatinib capsule contains lenvatinib mesylate equivalent to 4 mg or 10 mg of lenvatinib, and the following inactive ingredients: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl cellulose (type H), and talc. The hypromellose capsule shell contains titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink contains shellac, black iron oxide, potassium hydroxide, and propylene glycol
## Pharmacodynamics
- A single 32 mg dose (1.3 times the recommended daily dose) of lenvatinib did not prolong the QT/QTc interval in a thorough QT study in healthy subjects. However, QT prolongation was observed in Study 1
## Pharmacokinetics
- After oral administration of Lenvatinib, time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.
- In patients with solid tumors administered single and multiple doses of Lenvatinib once daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration- time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).
- In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 μg/mL). In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 μg/mL).
- Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump (BSEP).
- Plasma concentrations declined bi-exponentially following Cmax. The terminal elimination half-life of lenvatinib was approximately 28 hours.
- CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.
- Ten days after a single administration of radiolabeled lenvatinib to 6 patients with solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.
- The pharmacokinetics of lenvatinib following a single 24 mg dose were evaluated in subjects with mild (CLcr 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr <30 mL/min) renal impairment, and compared to healthy subjects. Subjects with end stage renal disease were not studied. After a single 24 mg oral dose of Lenvatinib, the AUC0-inf for subjects with renal impairment were similar compared to those for healthy subjects .
- The pharmacokinetics of lenvatinib following a single 10 mg dose of Lenvatinib were evaluated in subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment. The pharmacokinetics of a single 5 mg dose were evaluated in subjects with severe (Child Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively .
- Based on a population PK analysis, age, sex, and race did not have a significant effect on apparent clearance (Cl/F) of lenvatinib.
- CYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC by 15% and Cmax by 19% in a dedicated clinical trial.
- P-gp Inhibitors: Rifampicin (400 mg as a single dose) increased lenvatinib (24 mg as a single dose)AUC by 31% and Cmax by 33% in a dedicated clinical trial.
- CYP3A and P-gp Inducers: Rifampicin (400 mg administered daily for 21 days) decreased lenvatinib (a single 24 mg administered on Day 15) AUC by 18% in a dedicated clinical trial. The Cmax was unchanged.
- CYP3A4 or CYP2C8 Substrates: There is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).
- In Vitro Studies with CYP or UDP-glucuronosyltransferase (UGT) Substrates: Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, but an increase in lenvatinib exposure that impacts safety is unlikely. Lenvatinib does not inhibit CYP2A6 and CYP2E1.
- Lenvatinib induces CYP3A, but a decrease in lenvatinib exposure that impacts efficacy is unlikely. Lenvatinib does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. *Lenvatinib directly inhibits UGT1A1 and UGT1A4. The clinical implication of this finding is unknown. Lenvatinibshows little or no inhibition on UGT1A6, UGT1A9, UGT2B7, or aldehyde oxidase.
- Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
- In Vitro Studies with Drug Transporter System Substrates: Lenvatinib inhibits OAT1, OAT3, OCT1, OCT2, OATP1B1, and BSEP. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on OATP1B3.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.
- No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the clinical exposure by AUC at the recommended human dose. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the clinical exposure by AUC at the 24 mg clinical dose, respectively. In addition, in monkeys, a decreased incidence of menstruation was reported at lenvatinib exposures lower than those in humans at the 24 mg clinical dose.
# Clinical Studies
- A multicenter, randomized (2:1), double-blind, placebo-controlled trial was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review. Radioactive iodine-refractory was defined as 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity of >400 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry. Patients were randomized to receive Lenvatinib 24 mg once daily (n=261) or placebo (n=131) until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age. The major efficacy outcome measure was progression-free survival as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Independent review confirmation of disease progression was required prior to discontinuing patients from the randomization phase of the study. Other efficacy outcome measures included objective response rate and overall survival. Patients in the placebo arm could receive lenvatinib following independent review confirmation of disease progression.
- Of the 392 patients randomized, 51% were male, the median age was 63 years, 40% were older than 65 years, 79% were White, 54% had an ECOG performance status of 0, and 24% had received 1 prior VEGF/VEGFR-targeted therapy. Metastases were present in 99% of the patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. The histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. In the Lenvatinib arm, 67% of patients did not demonstrate iodine uptake on any radioiodine scan compared to 77% in the placebo arm. Additionally, 59% of patients on the Lenvatinib arm and 61% of patients on placebo arm progressed, according to RECIST 1.1, within 12 months of prior 131I therapy; 19.2% of patients on the Lenvatinib arm and 17.6% of patients on placebo arm received prior cumulative activity of >400 mCi or 22 gigabecquerels (GBq) 131I, with the last dose administered at least 6 months prior to study entry. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq).
- A statistically significant prolongation in PFS was demonstrated in Lenvatinib-treated patients compared to those receiving placebo (see Table 4 and Figure 1). Upon confirmation of progression, 109 (83%) patients randomly assigned to placebo crossed over to receive open-label Lenvatinib.
# How Supplied
- Lenvatinib 4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on the body.
- Lenvatinib 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on the body.
- Lenvatinib capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows:
- NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card).
- NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card).
- NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card).
- NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card).
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated .
- Cardiac Dysfunction: Advise patients that Lenvatinib can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles .
- Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke .
- Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure .
- proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine.
- Gastrointestinal perforation or fistula formation: Advise patients that Lenvatinib can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain .
- Hemorrhagic Events: Advise patients that Lenvatinib can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding .
- Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy . Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy
- Lactation: Advise nursing women to discontinue breastfeeding during treatment with Lenvatinib
# Precautions with Alcohol
- Alcohol-Lenvatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Lenvima®
# Look-Alike Drug Names
There is limited information regarding Lenvatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lenvatinib | |
95bfdedd4931df0eacca657203fed2c8097e1836 | wikidoc | Leptomycin | Leptomycin
Leptomycin B is a secondary metabolite produced by Streptomyces spp.
Leptomycin B (LMB) was originally discovered as a potent anti-fungal antibiotic. Leptomycin B was found to cause cell elongation of the fission yeast Schizosaccharomyces pombe. Since then this elongation effect is being used for the bioassay of Leptomycin. However, recent data (2003) showed that Leptomycin causes G1 cell cycle arrest in mammalian cells and is a potent anti-tumor agent against murine experimental tumors
Therefore Leptomycin B became a potent and specific nuclear export inhibitor. Leptomycin B alkylates and inhibits CRM1 (chromosomal region maintenance)/exportin 1 (XPO1), a protein required for nuclear export of proteins containing a nuclear export sequence (NES). In addition to antifungal and antibacterial activities, Leptomycin B blocks the cell cycle and is a potent anti-tumor agent. At low nM concentrations, Leptomycin B blocks the nuclear export of many proteins including HIV-1 Rev, MAPK/ERK, and NF-κB/IκB, and it stabilizes the expression of p53. Leptomycin B also inhibits the export and translation of many RNAs, including COX-2 and c-Fos mRNAs, by inhibiting export of ribonucleoproteins.
Leptomycin A (LPA) was discovered together with LMB. LMB is twice as potent as LPA. | Leptomycin
Leptomycin B is a secondary metabolite produced by Streptomyces spp.
Leptomycin B (LMB) was originally discovered as a potent anti-fungal antibiotic. Leptomycin B was found to cause cell elongation of the fission yeast Schizosaccharomyces pombe. Since then this elongation effect is being used for the bioassay of Leptomycin. However, recent data (2003) showed that Leptomycin causes G1 cell cycle arrest in mammalian cells and is a potent anti-tumor agent against murine experimental tumors
Therefore Leptomycin B became a potent and specific nuclear export inhibitor. Leptomycin B alkylates and inhibits CRM1 (chromosomal region maintenance)/exportin 1 (XPO1), a protein required for nuclear export of proteins containing a nuclear export sequence (NES). In addition to antifungal and antibacterial activities, Leptomycin B blocks the cell cycle and is a potent anti-tumor agent. At low nM concentrations, Leptomycin B blocks the nuclear export of many proteins including HIV-1 Rev, MAPK/ERK, and NF-κB/IκB, and it stabilizes the expression of p53. Leptomycin B also inhibits the export and translation of many RNAs, including COX-2 and c-Fos mRNAs, by inhibiting export of ribonucleoproteins.
Leptomycin A (LPA) was discovered together with LMB. LMB is twice as potent as LPA. | https://www.wikidoc.org/index.php/Leptomycin | |
094932c74e9697fc0baa3f42e4ad03fd5d3d8f8d | wikidoc | Leptospira | Leptospira
# Overview
Leptospira (from the Greek leptos, meaning fine or thin, and the Latin spira, meaning coil) is a genus of spirochaete bacteria, including a small number of pathogenic and saprophytic species. Leptospira was first observed in 1907 in kidney tissue slices of a leptospirosis victim who was described as having died of "yellow fever."
# Taxonomy
Leptospira, together with the genera Leptonema and Turneria, is a member of the family Leptospiraceae. The genus Leptospira is divided into 17 genomospecies based on DNA hybridization studies. However, at least one additional species which is yet to be named has been identified.
Known pathogenic Leptospira
Intermediates or opportunistic Leptospira
Non-pathogenic Leptospira
Members of Leptospira are also grouped into serovars according to their antigenic relatedness. There are currently over 200 recognized serovars. A few serovars are found in more than one species of Leptospira.
At its 2002 meeting, the Committee on the Taxonomy of Leptospira of the International Union of Microbiological Societies approved the following nomenclature for serovars of Leptospira. Genus and species must of course be italicized, with the serovar name not italicized and with an upper case first letter.
For example:
- Leptospira interrogans serovar Australis
- Leptospira biflexa serovar Patoc
# Morphology
Although over 200 serovars of Leptospira have been described, all members of the genus have similar morphology. Leptospira are spiral-shaped bacteria that are 6-20 μm long and 0.1 μm in diameter with a wavelength of about 0.5 μm. One or both ends of the spirochete are usually hooked. Because they are so thin, live Leptospira are best observed by darkfield microscopy.
The bacteria have a number of freedom degrees; when ready to proliferate via binary fission, the bacterium noticeably bends in the place of the future split.
# Cellular structure
Leptospira have a Gram-negative-like cell envelope consisting of a cytoplasmic and outer membrane. However, the peptidoglycan layer is associated with the cytoplasmic rather than the outer membrane, an arrangement that is unique to spirochetes. The two flagella of Leptospira extend from the cytoplasmic membrane at the ends of the bacteria into the periplasmic space and are necessary for the motility of Leptospira.
The outer membrane contains a variety of lipoproteins and transmembrane outer membrane proteins. As expected, the protein composition of the outer membrane differs when comparing Leptospira growing in artificial medium with Leptospira present in an infected animal. Several leptospiral outer membrane proteins have been shown to attach to the host extracellular matrix and to factor H. These proteins may be important for adhesion of Leptospira to host tissues and in resisting complement, respectively.
The outer membrane of Leptospira, like those of most other Gram-negative bacteria, contains lipopolysaccharide (LPS). Differences in the highly immunogenic LPS structure account for the numerous serovars of Leptospira.. Consequently, immunity is serovar specific; current leptospiral vaccines, which consist of one or several serovars of Leptospira endemic in the population to be immunized, protect only against the serovars contained in the vaccine preparation. Leptospiral LPS has low endotoxin activity.. An unusual feature of leptospiral LPS is that it activates host cells via TLR2 rather than TLR4. The unique structure of the lipid A portion of the LPS molecule may acccount for this observation. Finally, the LPS O antigen content of L. interrogans differs in an acutely infected versus a chronically infected animal. The role of O antigen changes in the establishment or maintenance of acute or chronic infection, if any, is unknown.
# Habitat
Leptospira, both pathogenic and saprotrophic, can occupy diverse environments, habitats and life cycles; it generally recognized these bacteria are virtually ubiquitous in terms of geographic distribution (present everywhere except Antarctica).
Most of Leptospira, however, are hydrophilic - high humidity and neutral (6.9-7.4) pH are essential for their survival in the environment, with stagnant water reservoirs - bogs, shallow lakes, ponds, puddles, etc - being natural placeholder for the bacteria.
# Nutrition
Leptospira are typically cultivated at 30 °C in Ellinghausen-McCullough-Johnson-Harris (EMJH) medium, which can be supplemented with 0.2-1% rabbit serum to enhance growth of fastidious strains. Growth of pathogenic Leptospira in an artificial nutrient environment such as EMJH becomes noticeable in 4-7 days; growth of saprophytic strains occur within 2-3 days. The minimal growth temperature of pathogenic species is 13-15 °C. Because the minimal growth temperature of the saprophytes is 5-10 °C, the ability of Leptospira to grow at 13 °C can be used to distinguish saprophytic from pathogenic Leptospira species. The optimal pH for growth of Leptospira is 7.2-7.6.
Leptospira are aerobes whose major carbon and energy source during in vitro growth is long-chain fatty acids, which are metabolized by beta-oxidation. Fatty acids are provided in EMJH in the form of Tween. Fatty acid molecules are bound by albumin in EMJH and are released slowly into the medium to prevent its toxic accumulation.
Like most bacteria, Leptospira require iron for growth. L. interrogans and L. biflexa have the ability to acquire iron in different forms. A TonB-dependent receptor required for utilization of the ferrous form of the iron has been identified in L. biflexa, and an ortholog of the receptor is encoded in the genome of L. interrogans. L. interrogans can also obtain iron from heme, which is bound to most of the iron in the human body. The HbpA hemin-binding protein, which may be involved in the uptake of hemin, has been identified on the surface of L. interrogans Although other pathogenic species of Leptospira and L. biflexa lack HbpA, yet another hemin-binding protein, LipL41, may account for their ability to use hemin as a source of iron. Although they do not secrete siderophores, L. biflexa and L. interrogans may be capable of obtaining iron from siderophores secreted by other microorganisms.
# Genome
The genome of pathogenic Leptospira consists of two chromosomes. The size of the genomes of L. interrogans serovars Copenhageni and Lai is approximately 4.6 Mb. However, the genome of L. borgpetersenii serovar Hardjo is only 3.9 Mb in size with a large number of pseudogenes, gene fragments, and insertion sequences relative to the genomes of L. interrogans. L. borgpetersenii serovar Hardjo is usually transmitted by direct exposure to infected tissues, whereas L. interrogans is often acquired from water or soil contaminated by the urine of carrier animals harboring Leptospira in their kidneys. The high number of defective genes and insertion sequences in L. borgpetersenii Hardjo together with the poor survival outside of the host and difference in transmission patterns compared to L. interrogans suggest that L. borgpetersenii is undergoing insertion-sequence mediated genomic decay, with ongoing loss of genes necessary for survival outside of the host animal. | Leptospira
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Leptospira (from the Greek leptos, meaning fine or thin, and the Latin spira, meaning coil)[1] is a genus of spirochaete bacteria, including a small number of pathogenic and saprophytic species.[2] Leptospira was first observed in 1907 in kidney tissue slices of a leptospirosis victim who was described as having died of "yellow fever."[3]
# Taxonomy
Leptospira, together with the genera Leptonema and Turneria, is a member of the family Leptospiraceae. The genus Leptospira is divided into 17 genomospecies based on DNA hybridization studies.[4][5][6] However, at least one additional species which is yet to be named has been identified.[7]
Known pathogenic Leptospira
Intermediates or opportunistic Leptospira
Non-pathogenic Leptospira
Members of Leptospira are also grouped into serovars according to their antigenic relatedness. There are currently over 200 recognized serovars. A few serovars are found in more than one species of Leptospira.
At its 2002 meeting, the Committee on the Taxonomy of Leptospira of the International Union of Microbiological Societies approved the following nomenclature for serovars of Leptospira. Genus and species must of course be italicized, with the serovar name not italicized and with an upper case first letter.
For example:
- Leptospira interrogans serovar Australis
- Leptospira biflexa serovar Patoc
# Morphology
Although over 200 serovars of Leptospira have been described, all members of the genus have similar morphology. Leptospira are spiral-shaped bacteria that are 6-20 μm long and 0.1 μm in diameter with a wavelength of about 0.5 μm.[8] One or both ends of the spirochete are usually hooked. Because they are so thin, live Leptospira are best observed by darkfield microscopy.
The bacteria have a number of freedom degrees; when ready to proliferate via binary fission, the bacterium noticeably bends in the place of the future split.
# Cellular structure
Leptospira have a Gram-negative-like cell envelope consisting of a cytoplasmic and outer membrane. However, the peptidoglycan layer is associated with the cytoplasmic rather than the outer membrane, an arrangement that is unique to spirochetes. The two flagella of Leptospira extend from the cytoplasmic membrane at the ends of the bacteria into the periplasmic space and are necessary for the motility of Leptospira.[9]
The outer membrane contains a variety of lipoproteins and transmembrane outer membrane proteins.[10] As expected, the protein composition of the outer membrane differs when comparing Leptospira growing in artificial medium with Leptospira present in an infected animal.[11][12][13] Several leptospiral outer membrane proteins have been shown to attach to the host extracellular matrix and to factor H. These proteins may be important for adhesion of Leptospira to host tissues and in resisting complement, respectively.[14][15][16]
The outer membrane of Leptospira, like those of most other Gram-negative bacteria, contains lipopolysaccharide (LPS). Differences in the highly immunogenic LPS structure account for the numerous serovars of Leptospira.[8]. Consequently, immunity is serovar specific; current leptospiral vaccines, which consist of one or several serovars of Leptospira endemic in the population to be immunized, protect only against the serovars contained in the vaccine preparation. Leptospiral LPS has low endotoxin activity.[8]. An unusual feature of leptospiral LPS is that it activates host cells via TLR2 rather than TLR4.[17] The unique structure of the lipid A portion of the LPS molecule may acccount for this observation.[18] Finally, the LPS O antigen content of L. interrogans differs in an acutely infected versus a chronically infected animal.[19] The role of O antigen changes in the establishment or maintenance of acute or chronic infection, if any, is unknown.
# Habitat
Leptospira, both pathogenic and saprotrophic, can occupy diverse environments, habitats and life cycles; it generally recognized these bacteria are virtually ubiquitous in terms of geographic distribution (present everywhere except Antarctica).[20]
Most of Leptospira, however, are hydrophilic - high humidity and neutral (6.9-7.4) pH are essential for their survival in the environment, with stagnant water reservoirs - bogs, shallow lakes, ponds, puddles, etc - being natural placeholder for the bacteria.
# Nutrition
Leptospira are typically cultivated at 30 °C in Ellinghausen-McCullough-Johnson-Harris (EMJH) medium, which can be supplemented with 0.2-1% rabbit serum to enhance growth of fastidious strains.[21] Growth of pathogenic Leptospira in an artificial nutrient environment such as EMJH becomes noticeable in 4-7 days; growth of saprophytic strains occur within 2-3 days. The minimal growth temperature of pathogenic species is 13-15 °C. Because the minimal growth temperature of the saprophytes is 5-10 °C, the ability of Leptospira to grow at 13 °C can be used to distinguish saprophytic from pathogenic Leptospira species.[21] The optimal pH for growth of Leptospira is 7.2-7.6.
Leptospira are aerobes whose major carbon and energy source during in vitro growth is long-chain fatty acids, which are metabolized by beta-oxidation.[22][23] Fatty acids are provided in EMJH in the form of Tween.[21] Fatty acid molecules are bound by albumin in EMJH and are released slowly into the medium to prevent its toxic accumulation.
Like most bacteria, Leptospira require iron for growth.[24] L. interrogans and L. biflexa have the ability to acquire iron in different forms.[25] A TonB-dependent receptor required for utilization of the ferrous form of the iron has been identified in L. biflexa, and an ortholog of the receptor is encoded in the genome of L. interrogans. L. interrogans can also obtain iron from heme, which is bound to most of the iron in the human body. The HbpA hemin-binding protein, which may be involved in the uptake of hemin, has been identified on the surface of L. interrogans[26] Although other pathogenic species of Leptospira and L. biflexa lack HbpA, yet another hemin-binding protein, LipL41, may account for their ability to use hemin as a source of iron.[26] Although they do not secrete siderophores, L. biflexa and L. interrogans may be capable of obtaining iron from siderophores secreted by other microorganisms.[25]
# Genome
The genome of pathogenic Leptospira consists of two chromosomes. The size of the genomes of L. interrogans serovars Copenhageni and Lai is approximately 4.6 Mb.[27][28] However, the genome of L. borgpetersenii serovar Hardjo is only 3.9 Mb in size with a large number of pseudogenes, gene fragments, and insertion sequences relative to the genomes of L. interrogans.[29] L. borgpetersenii serovar Hardjo is usually transmitted by direct exposure to infected tissues, whereas L. interrogans is often acquired from water or soil contaminated by the urine of carrier animals harboring Leptospira in their kidneys. The high number of defective genes and insertion sequences in L. borgpetersenii Hardjo together with the poor survival outside of the host and difference in transmission patterns compared to L. interrogans suggest that L. borgpetersenii is undergoing insertion-sequence mediated genomic decay, with ongoing loss of genes necessary for survival outside of the host animal.[29] | https://www.wikidoc.org/index.php/Leptospira | |
829cc8b8e6dd2004590a91e1acbc3be0508e0523 | wikidoc | Letermovir | Letermovir
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# Overview
Letermovir is a antiviral drug that is FDA approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). Common adverse reactions include nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Letermovir is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT).
- The recommended dosage of letermovir is 480 mg administered orally or intravenously once daily. Initiate letermovir between Day 0 and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. Dosage of letermovir should be adjusted when co-administered with cyclosporine.
- Letermovir injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral letermovir as soon as they are able to take oral medications. Letermovir tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations.
- If oral or intravenous letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.
- If cyclosporine is initiated after starting letermovir, the next dose of letermovir should be decreased to 240 mg once daily.
- If cyclosporine is discontinued after starting letermovir, the next dose of letermovir should be increased to 480 mg once daily.
- If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of letermovir is needed.
- For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of letermovir is required based on renal impairment.
- There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make letermovir dosing recommendations.
- In patients with CLcr less than 50 mL/min receiving letermovir injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.
- No dosage adjustment of letermovir is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Letermovir is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
- Tablets
- Letermovir 240 mg tablet: yellow oval tablet with "591" on one side and Merck logo on the other side.
- Letermovir 480 mg tablet: pink oval, bi-convex tablet with "595" on one side and Merck logo on the other side.
- Injection
- Letermovir 240 mg/12 mL (20 mg/mL) injection: clear solution in a single-dose vial.
- Letermovir 480 mg/24 mL (20 mg/mL) injection: clear solution in a single-dose vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding letermovir 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 Letermovir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding letermovir Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Letermovir is contraindicated in patients receiving pimozide or ergot alkaloids:
- Pimozide: Concomitant administration of letermovir in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes.
- Ergot alkaloids: Concomitant administration of letermovir in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism.
- Letermovir is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of letermovir in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis.
# Warnings
- The concomitant use of letermovir and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (letermovir or concomitant drugs) or reduced therapeutic effect of letermovir or the concomitant drug.
- See TABLE 3 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during letermovir therapy; review concomitant medications during letermovir therapy; and monitor for adverse reactions associated with letermovir and concomitant medications.
# 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 safety of letermovir was evaluated in one Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with letermovir (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the letermovir arm compared to the placebo arm.
- The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving letermovir (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of letermovir subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of letermovir subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of letermovir and 92% of placebo subjects had events reported as mild or moderate in severity.
- The rate of adverse events occurring in at least 10% of subjects in the letermovir group and at a frequency at least 2% greater than placebo are outlined in Table 1.
- Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of letermovir subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of letermovir subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV letermovir after switching from oral letermovir, leading to treatment discontinuation.
Laboratory Abnormalities
- Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.
- The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the letermovir group and 18 days in the placebo group.
## Postmarketing Experience
There is limited information regarding Letermovir Postmarketing Experience in the drug label.
# Drug Interactions
- Potential for Other Drugs to Affect Letermovir
- Potential for Letermovir to Affect Other Drugs
- Established and Other Potentially Significant Drug Interactions
- Drugs without Clinically Significant Interactions with Letermovir
- Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters. Co-administration of letermovir with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations.
- Co-administration of letermovir with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A. Co-administration of letermovir with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
- Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of letermovir with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.
- The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.
- If dose adjustments of concomitant medications are made due to treatment with letermovir, doses should be readjusted after treatment with letermovir is completed.
- Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with letermovir or are predicted drug interactions that may occur with letermovir.
- No clinically significant interactions were observed in clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, posaconazole, ethinyl estradiol, and levonorgestrel.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- No adequate human data are available to establish whether letermovir poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
- Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).
- In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letermovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Letermovir during labor and delivery.
### Nursing Mothers
- It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.
- When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for letermovir and any potential adverse effects on the breastfed child from letermovir or from the underlying maternal condition.
- In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.
### Pediatric Use
- Safety and efficacy of letermovir in patients below 18 years of age have not been established.
### Geriatic Use
- Of the 373 subjects treated with letermovir in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of letermovir is required based on age.
### Gender
There is no FDA guidance on the use of Letermovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Letermovir with respect to specific racial populations.
### Renal Impairment
- For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of letermovir is required based on renal impairment. The safety of letermovir in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
- In patients with CLcr less than 50 mL/min receiving letermovir injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.
### Hepatic Impairment
- No dosage adjustment of letermovir is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Letermovir is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
### Females of Reproductive Potential and Males
- There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats.
### Immunocompromised Patients
There is no FDA guidance one the use of Letermovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Letermovir Tablets
- Administer with or without food.
- Swallow tablets whole.
- Letermovir Injection
- Administer by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
- Do not administer as an intravenous bolus injection.
- Letermovir injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). The preparation and administration instructions are the same for either dose.
- Letermovir vials are for single use only. Discard any unused portion.
- Letermovir must be diluted prior to intravenous (IV) use.
- Inspect vial contents for discoloration and particulate matter prior to dilution. Letermovir injection is a clear colorless solution. Do not use the vial if the solution is discolored or contains visible particles.
- Do not shake letermovir vial.
- Add one single-dose vial of letermovir injection into a 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with letermovir injection.
- Use compatible IV bags and infusion set materials. Letermovir injection is compatible with the following IV bags and infusion set materials. Letermovir injection is not recommended with any IV bags or infusion set materials not listed below (note that letermovir injection is not recommended for use with polyurethane-containing IV administration set tubing).
- IV Bags Materials:
- Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene)
- Infusion Sets Materials:
- PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS)
- Plasticizers:
- Diethylhexyl phthalate (DEHP), tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)
- Catheters:
- Radiopaque polyurethane
- Once diluted, the solution of letermovir is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed.
- The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion).
- Administer the entire contents of the intravenous bag by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
- The physical compatibility of letermovir injection with selected injectable drug products was evaluated in two commonly available diluents. Letermovir should not be co-administered through the same intravenous line (or cannula) with other drug products and diluent combinations except those listed below. Refer to the respective prescribing information of the co-administered drug(s) to confirm compatibility of simultaneous co-administration.
List of Compatible Drug Products when Letermovir and Drug Products are Prepared in 0.9% Sodium Chloride Injection, USP:
- Ampicillin sodium, ampicillin sodium/sulbactam sodium, anti-thymocyte globulin, caspofungin, daptomycin, fentanyl citrate, fluconazole, furosemide, human insulin, magnesium sulfate, methotrexate, micafungin.
List of Compatible Drug Products when Letermovir and Drug Products are Prepared in 5% Dextrose Injection, USP:
- Amphotericin B (lipid complex)1, anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium chloride, potassium phosphate, tacrolimus, telavancin, tigecycline.
- 1= Amphotericin B (lipid complex) is compatible with letermovir. However, Amphotericin B (liposomal) is incompatible.
- Letermovir injection is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.
### Monitoring
- Following the completion of letermovir prophylaxis, monitoring for CMV reactivation is recommended.
- Prophylaxis of clinically significant cytomegalovirus infection is indicative of efficacy.
- Serum creatinine levels: Closely in patients with CrCl less than 50 mL/min receiving IV formulation.
- Reactivation of cytomegalovirus.
# IV Compatibility
There is limited information regarding the compatibility of Letermovir and IV administrations.
# Overdosage
- There is no specific antidote for overdose with letermovir. In case of overdose, it is recommended that the patient be monitored for adverse reactions and appropriate symptomatic treatment be instituted.
- It is unknown whether dialysis will result in meaningful removal of letermovir from systemic circulation.
# Pharmacology
## Mechanism of Action
- Letermovir is an antiviral drug against CMV.
## Structure
## Pharmacodynamics
- In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
- The pharmacokinetic properties of letermovir are displayed in Table 4.
Pediatric Population
- The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.
Age, Gender, Race, and Weight
- Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.
Renal Impairment
- Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
- Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.
Hepatic Impairment
- Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B , score of 7-9) and severe (Child-Pugh Class C , score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
- Drug interaction studies were performed in healthy subjects with letermovir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions.
- In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data. Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be clinically relevant.
- Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.
- Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of letermovir with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition. Based on these results, co-administration of letermovir with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with letermovir, plasma concentrations of CYP2C8 substrates are predicted to be increased. Co-administration of letermovir reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of letermovir with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
- Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of letermovir with substrates of OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with letermovir in clinical studies. The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.
- Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of MRP2, OATP2B1, BSEP, OCT1, OCT2, or OAT1 in vitro.
- Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.
- The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).
- No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
In Cell Culture
- CMV mutants with reduced susceptibility to letermovir have been selected in cell culture and the resistance mutations map to UL56. Resistance-associated substitutions occur between amino acid positions pUL56 231 and 369 (V231A/L, V236L/M, E237D, L241P, T244K/R, L257I, F261C/L/S, Y321C, C325F/R/Y, M329T, R369G/M/S). EC50 values for virus expressing these substitutions are 13- to 5,870-fold higher than those for the wild-type reference virus.
In Clinical Studies
- In a Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom on-treatment samples were available for analysis. One subject had a letermovir resistance substitution, pUL56 V236M.
- In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 28 letermovir-treated subjects who had received at least one dose of study drug and experienced prophylaxis failure and for whom samples were available for analysis. Two subjects were identified as having a letermovir-resistance substitution, pUL56 V236M or C325W. These substitutions were identified from on-treatment samples. A virus from a third subject who experienced prophylaxis failure had a pUL56 E237G substitution at low frequency (<5%), and while pUL56 E237D was associated with resistance in cell culture, the clinical significance of this substitution at this frequency is unknown.
- Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (cidofovir, foscarnet, and ganciclovir). These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to letermovir.
## Nonclinical Toxicology
- Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.
- Carcinogenicity studies with letermovir have not been conducted.
- In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.
- In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD.
- Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD) was characterized by decreased testis weight, bilateral seminiferous tubular degeneration, decreased sperm count and motility, and resultant decreased male fertility. Male reproductive system toxicities were not observed in either a monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
# Clinical Studies
- To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of letermovir was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either letermovir at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of letermovir was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.
- Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received letermovir (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of letermovir was used at investigators' discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.
- At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).
Clinically Significant CMV Infection
- The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
- Efficacy results from Trial P001 are shown in Table 7.
- Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.
- Post-hoc analysis demonstrated that among letermovir-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.
Mortality
- The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant.
# How Supplied
- Each letermovir 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and Merck logo on the other side. Each letermovir 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and Merck logo on the other side.
- The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
- The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
- Letermovir is supplied as a sterile, clear solution for intravenous use of 240 mg (12 mL per vial) or 480 mg (24 mL per vial). The final solutions for infusion are obtained by dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
- The single dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).
## Storage
- Store letermovir tablets in the original package until use.
- Store letermovir tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- Store letermovir injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- Store in the original carton to protect from exposure to light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Inform patients that letermovir may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider.
- Inform patients that it is important not to miss or skip doses and to take letermovir for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of letermovir, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
- Advise patients to store letermovir tablets in the original package until use.
# Precautions with Alcohol
Alcohol-Letermovir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Prevymis
# Look-Alike Drug Names
There is limited information regarding Letermovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Letermovir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
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# Overview
Letermovir is a antiviral drug that is FDA approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Common adverse reactions include nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Letermovir is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).
- The recommended dosage of letermovir is 480 mg administered orally or intravenously once daily. Initiate letermovir between Day 0 and Day 28 post-transplantation (before or after engraftment), and continue through Day 100 post-transplantation. Dosage of letermovir should be adjusted when co-administered with cyclosporine.
- Letermovir injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy. Patients should be switched to oral letermovir as soon as they are able to take oral medications. Letermovir tablet and injection may be used interchangeably at the discretion of the physician, and no dosage adjustment is necessary when switching formulations.
- If oral or intravenous letermovir is co-administered with cyclosporine, the dosage of letermovir should be decreased to 240 mg once daily.
- If cyclosporine is initiated after starting letermovir, the next dose of letermovir should be decreased to 240 mg once daily.
- If cyclosporine is discontinued after starting letermovir, the next dose of letermovir should be increased to 480 mg once daily.
- If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of letermovir is needed.
- For patients with creatinine clearance (CLcr) greater than 10 mL/min, no dosage adjustment of letermovir is required based on renal impairment.
- There are insufficient data in patients with CLcr 10 mL/min or less or in patients on dialysis to make letermovir dosing recommendations.
- In patients with CLcr less than 50 mL/min receiving letermovir injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur. Closely monitor serum creatinine levels in these patients.
- No dosage adjustment of letermovir is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Letermovir is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
- Tablets
- Letermovir 240 mg tablet: yellow oval tablet with "591" on one side and Merck logo on the other side.
- Letermovir 480 mg tablet: pink oval, bi-convex tablet with "595" on one side and Merck logo on the other side.
- Injection
- Letermovir 240 mg/12 mL (20 mg/mL) injection: clear solution in a single-dose vial.
- Letermovir 480 mg/24 mL (20 mg/mL) injection: clear solution in a single-dose vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding letermovir 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 Letermovir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding letermovir Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding letermovir Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Letermovir is contraindicated in patients receiving pimozide or ergot alkaloids:
- Pimozide: Concomitant administration of letermovir in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes.
- Ergot alkaloids: Concomitant administration of letermovir in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism.
- Letermovir is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of letermovir in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis.
# Warnings
- The concomitant use of letermovir and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (letermovir or concomitant drugs) or reduced therapeutic effect of letermovir or the concomitant drug.
- See TABLE 3 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during letermovir therapy; review concomitant medications during letermovir therapy; and monitor for adverse reactions associated with letermovir and concomitant medications.
# 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 safety of letermovir was evaluated in one Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with letermovir (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the letermovir arm compared to the placebo arm.
- The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving letermovir (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of letermovir subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of letermovir subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of letermovir and 92% of placebo subjects had events reported as mild or moderate in severity.
- The rate of adverse events occurring in at least 10% of subjects in the letermovir group and at a frequency at least 2% greater than placebo are outlined in Table 1.
- Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of letermovir subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of letermovir subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV letermovir after switching from oral letermovir, leading to treatment discontinuation.
Laboratory Abnormalities
- Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in the table below.
- The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the letermovir group and 18 days in the placebo group.
## Postmarketing Experience
There is limited information regarding Letermovir Postmarketing Experience in the drug label.
# Drug Interactions
- Potential for Other Drugs to Affect Letermovir
- Potential for Letermovir to Affect Other Drugs
- Established and Other Potentially Significant Drug Interactions
- Drugs without Clinically Significant Interactions with Letermovir
- Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters. Co-administration of letermovir with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations.
- Co-administration of letermovir with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A. Co-administration of letermovir with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
- Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of letermovir with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.
- The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.
- If dose adjustments of concomitant medications are made due to treatment with letermovir, doses should be readjusted after treatment with letermovir is completed.
- Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with letermovir or are predicted drug interactions that may occur with letermovir.
- No clinically significant interactions were observed in clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, posaconazole, ethinyl estradiol, and levonorgestrel.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- No adequate human data are available to establish whether letermovir poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
- Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).
- In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Letermovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Letermovir during labor and delivery.
### Nursing Mothers
- It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.
- When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for letermovir and any potential adverse effects on the breastfed child from letermovir or from the underlying maternal condition.
- In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.
### Pediatric Use
- Safety and efficacy of letermovir in patients below 18 years of age have not been established.
### Geriatic Use
- Of the 373 subjects treated with letermovir in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of letermovir is required based on age.
### Gender
There is no FDA guidance on the use of Letermovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Letermovir with respect to specific racial populations.
### Renal Impairment
- For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of letermovir is required based on renal impairment. The safety of letermovir in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
- In patients with CLcr less than 50 mL/min receiving letermovir injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.
### Hepatic Impairment
- No dosage adjustment of letermovir is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Letermovir is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
### Females of Reproductive Potential and Males
- There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats.
### Immunocompromised Patients
There is no FDA guidance one the use of Letermovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Letermovir Tablets
- Administer with or without food.
- Swallow tablets whole.
- Letermovir Injection
- Administer by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
- Do not administer as an intravenous bolus injection.
- Letermovir injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). The preparation and administration instructions are the same for either dose.
- Letermovir vials are for single use only. Discard any unused portion.
- Letermovir must be diluted prior to intravenous (IV) use.
- Inspect vial contents for discoloration and particulate matter prior to dilution. Letermovir injection is a clear colorless solution. Do not use the vial if the solution is discolored or contains visible particles.
- Do not shake letermovir vial.
- Add one single-dose vial of letermovir injection into a 250 mL pre-filled IV bag containing either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and physically compatible with letermovir injection.
- Use compatible IV bags and infusion set materials. Letermovir injection is compatible with the following IV bags and infusion set materials. Letermovir injection is not recommended with any IV bags or infusion set materials not listed below (note that letermovir injection is not recommended for use with polyurethane-containing IV administration set tubing).
- IV Bags Materials:
- Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene)
- Infusion Sets Materials:
- PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS)
- Plasticizers:
- Diethylhexyl phthalate (DEHP), tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)
- Catheters:
- Radiopaque polyurethane
- Once diluted, the solution of letermovir is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed.
- The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F) (this time includes storage of the diluted solution in the intravenous bag through the duration of infusion).
- Administer the entire contents of the intravenous bag by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.
- The physical compatibility of letermovir injection with selected injectable drug products was evaluated in two commonly available diluents. Letermovir should not be co-administered through the same intravenous line (or cannula) with other drug products and diluent combinations except those listed below. Refer to the respective prescribing information of the co-administered drug(s) to confirm compatibility of simultaneous co-administration.
List of Compatible Drug Products when Letermovir and Drug Products are Prepared in 0.9% Sodium Chloride Injection, USP:
- Ampicillin sodium, ampicillin sodium/sulbactam sodium, anti-thymocyte globulin, caspofungin, daptomycin, fentanyl citrate, fluconazole, furosemide, human insulin, magnesium sulfate, methotrexate, micafungin.
List of Compatible Drug Products when Letermovir and Drug Products are Prepared in 5% Dextrose Injection, USP:
- Amphotericin B (lipid complex)1, anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium chloride, potassium phosphate, tacrolimus, telavancin, tigecycline.
- 1= Amphotericin B (lipid complex) is compatible with letermovir. However, Amphotericin B (liposomal) is incompatible.
- Letermovir injection is physically incompatible with amiodarone hydrochloride, amphotericin B (liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil hydrochloride, ondansetron, palonosetron.
### Monitoring
- Following the completion of letermovir prophylaxis, monitoring for CMV reactivation is recommended.
- Prophylaxis of clinically significant cytomegalovirus infection is indicative of efficacy.
- Serum creatinine levels: Closely in patients with CrCl less than 50 mL/min receiving IV formulation.
- Reactivation of cytomegalovirus.
# IV Compatibility
There is limited information regarding the compatibility of Letermovir and IV administrations.
# Overdosage
- There is no specific antidote for overdose with letermovir. In case of overdose, it is recommended that the patient be monitored for adverse reactions and appropriate symptomatic treatment be instituted.
- It is unknown whether dialysis will result in meaningful removal of letermovir from systemic circulation.
# Pharmacology
## Mechanism of Action
- Letermovir is an antiviral drug against CMV.
## Structure
## Pharmacodynamics
- In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
- The pharmacokinetic properties of letermovir are displayed in Table 4.
Pediatric Population
- The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.
Age, Gender, Race, and Weight
- Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.
Renal Impairment
- Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
- Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the literature in patients with severe renal impairment.
Hepatic Impairment
- Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
- Drug interaction studies were performed in healthy subjects with letermovir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions.
- In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data. Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be clinically relevant.
- Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro.
- Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of letermovir with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition. Based on these results, co-administration of letermovir with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates. Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with letermovir, plasma concentrations of CYP2C8 substrates are predicted to be increased. Co-administration of letermovir reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of letermovir with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
- Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of letermovir with substrates of OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with letermovir in clinical studies. The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.
- Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. Letermovir is not an inhibitor of MRP2, OATP2B1, BSEP, OCT1, OCT2, or OAT1 in vitro.
- Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.
- The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and gB4=3).
- No antagonism of the antiviral activity was seen when letermovir was combined with CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir).
In Cell Culture
- CMV mutants with reduced susceptibility to letermovir have been selected in cell culture and the resistance mutations map to UL56. Resistance-associated substitutions occur between amino acid positions pUL56 231 and 369 (V231A/L, V236L/M, E237D, L241P, T244K/R, L257I, F261C/L/S, Y321C, C325F/R/Y, M329T, R369G/M/S). EC50 values for virus expressing these substitutions are 13- to 5,870-fold higher than those for the wild-type reference virus.
In Clinical Studies
- In a Phase 2b trial evaluating letermovir or placebo in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom on-treatment samples were available for analysis. One subject had a letermovir resistance substitution, pUL56 V236M.
- In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 28 letermovir-treated subjects who had received at least one dose of study drug and experienced prophylaxis failure and for whom samples were available for analysis. Two subjects were identified as having a letermovir-resistance substitution, pUL56 V236M or C325W. These substitutions were identified from on-treatment samples. A virus from a third subject who experienced prophylaxis failure had a pUL56 E237G substitution at low frequency (<5%), and while pUL56 E237D was associated with resistance in cell culture, the clinical significance of this substitution at this frequency is unknown.
- Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (cidofovir, foscarnet, and ganciclovir). These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to letermovir.
## Nonclinical Toxicology
- Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse micronucleus study.
- Carcinogenicity studies with letermovir have not been conducted.
- In a fertility and early embryonic development study in rats, no effects of letermovir on female fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human exposure at the RHD.
- In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar to human exposure at the RHD.
- Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD) was characterized by decreased testis weight, bilateral seminiferous tubular degeneration, decreased sperm count and motility, and resultant decreased male fertility. Male reproductive system toxicities were not observed in either a monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day (approximately 3 times higher than human exposure at the RHD).
# Clinical Studies
- To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of letermovir was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either letermovir at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of letermovir was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-weekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-transplant.
- Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received letermovir (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of letermovir was used at investigators' discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or Latino.
- At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD) requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).
Clinically Significant CMV Infection
- The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
- Efficacy results from Trial P001 are shown in Table 7.
- Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1.
- Post-hoc analysis demonstrated that among letermovir-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-transplant.
Mortality
- The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant.
# How Supplied
- Each letermovir 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and Merck logo on the other side. Each letermovir 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and Merck logo on the other side.
- The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
- The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four (4) Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two (2) unit-dose 7-count blister cards for a total of 14 tablets.
- Letermovir is supplied as a sterile, clear solution for intravenous use of 240 mg (12 mL per vial) or 480 mg (24 mL per vial). The final solutions for infusion are obtained by dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
- The single dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).
## Storage
- Store letermovir tablets in the original package until use.
- Store letermovir tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- Store letermovir injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- Store in the original carton to protect from exposure to light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Inform patients that letermovir may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider.
- Inform patients that it is important not to miss or skip doses and to take letermovir for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of letermovir, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
- Advise patients to store letermovir tablets in the original package until use.
# Precautions with Alcohol
Alcohol-Letermovir interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Prevymis
# Look-Alike Drug Names
There is limited information regarding Letermovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Letermovir | |
1df817720d3f24ef0e210aa9f09c10a6992db3fe | wikidoc | Leukorrhea | Leukorrhea
# Overview
Leukorrhea (US) or leukorrhoea (Commonwealth) is a medical term that denotes a thick, whitish vaginal discharge. It results from inflammation or congestion of the vaginal mucosa. In cases where it is yellowish or gives off an odour, a doctor should be consulted since it could be a sign of an STD.
Leukorrhea is a sign that the vagina is healthy and keeping clean. It may sometimes occur before a girl has her first period, and is considered a sign of puberty.
# Causes
There are many causes of leukorrhea, the usual one being increased estrogen. The amount of discharge may increase due to vaginal infection or STDs, in which case it becomes more yellow and foul-smelling. Vaginal discharge is normal for a woman, and all women are different. Causes of change in discharge include infection, malignancy, and hormonal changes.
Leukorrhea may occur normally during pregnancy. This is caused by increased bloodflow to the vagina due to increased estrogen. Female infants may have leukorrhea for a short time after birth due to their in-uterine exposure to estrogen.
It is usually a non-pathological symptom secondary to inflammatory conditions of Vagina or cervix.
After birth leukorrhea accompanied by backache and foul-smelling lochia (post-partum vaginal discharge, containing blood, mucus, and placental tissue) may suggest involution (failure of the uterus to return to pre-pregnant size) due to infection. | Leukorrhea
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Leukorrhea (US) or leukorrhoea (Commonwealth) is a medical term that denotes a thick, whitish vaginal discharge. It results from inflammation or congestion of the vaginal mucosa. In cases where it is yellowish or gives off an odour, a doctor should be consulted since it could be a sign of an STD.
Leukorrhea is a sign that the vagina is healthy and keeping clean. It may sometimes occur before a girl has her first period, and is considered a sign of puberty.
# Causes
There are many causes of leukorrhea, the usual one being increased estrogen. The amount of discharge may increase due to vaginal infection or STDs, in which case it becomes more yellow and foul-smelling. Vaginal discharge is normal for a woman, and all women are different. Causes of change in discharge include infection, malignancy, and hormonal changes.
Leukorrhea may occur normally during pregnancy. This is caused by increased bloodflow to the vagina due to increased estrogen. Female infants may have leukorrhea for a short time after birth due to their in-uterine exposure to estrogen.
It is usually a non-pathological symptom secondary to inflammatory conditions of Vagina or cervix.
After birth leukorrhea accompanied by backache and foul-smelling lochia (post-partum vaginal discharge, containing blood, mucus, and placental tissue) may suggest involution (failure of the uterus to return to pre-pregnant size) due to infection.
# External links
- Overview at americanpregnancy.org
Template:Diseases of the pelvis, genitals and breasts
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Leucorrhea | |
2f9d9b470303bb7376f8f3d12ae84a1a5b78f42c | wikidoc | Leukocoria | Leukocoria
# Overview
Leukocoria refers to an abnormal white hue of the retina when viewed through routine medical ophthalmoscopy.
# Diagnosis
Usually, when a light is shone through the iris, the retina appears red to the observer. In leukocoria, the retina abnormally appears white. This may indicate congential cataracts, retrolental fibroplasia, corneal scarring, retinoblastoma, ocular toxocariasis, persistence of the tunica vasculosa lentis (PFV/PHPV), or Coats' disease, Norrie Disease, etc. Because of the potential life threatening nature of retinoblastoma, that condition is usually considered in the evaluation of leukocoria.
## Physical Examination
### Eyes
The term is also sometimes spelled leukokoria. In British English the usual spelling is leucocoria. | Leukocoria
# Overview
Leukocoria refers to an abnormal white hue of the retina when viewed through routine medical ophthalmoscopy.
# Diagnosis
Usually, when a light is shone through the iris, the retina appears red to the observer. In leukocoria, the retina abnormally appears white. This may indicate congential cataracts, retrolental fibroplasia, corneal scarring, retinoblastoma, ocular toxocariasis, persistence of the tunica vasculosa lentis (PFV/PHPV), or Coats' disease, Norrie Disease, etc. Because of the potential life threatening nature of retinoblastoma, that condition is usually considered in the evaluation of leukocoria.
## Physical Examination
### Eyes
The term is also sometimes spelled leukokoria.[2] In British English the usual spelling is leucocoria.[3] | https://www.wikidoc.org/index.php/Leukocoria | |
d3a9f2c065bc05568b6e0d971e8bcb29f3d347c0 | wikidoc | Leuprolide | Leuprolide
# 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
Leuprolide is a gonadatropin releasing hormone (GnRH) agonist that is FDA approved for the treatment of advanced prostate cancer. Common adverse reactions include malaise, fatigue, hot flashes/sweats, and testicular atrophy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ELIGARD® is administered subcutaneously and provides continuous release of leuprolide acetate over a one-, three-, four-, or six-month treatment period (TABLE 1). The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation.
- Once mixed, ELIGARD® should be discarded if not administered within 30 minutes.
- As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location chosen should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injection was administered in the upper- or mid-abdominal area. Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Leuprolide in adult patients.
### Non–Guideline-Supported Use
- Leuprolide 3.75 mg 1-month depot formulation.
- Leuprolide 1 mg (0.25 to 0.5 mg for those with lower body mass) subcutaneously either on day 1 of the menstrual cycle and continued each morning until the day of human chorionic gonadotropin (hCG) administration (flare protocol), or on day 21 of the prior cycle (down-regulation protocol).
- Leuprolide acetate, injected intramuscularly monthly at a dose of 7.5 mg.
- 3 monthly IM injections of either leuprolide depot 3.75 mg.
- Leuprolide IM (7.5 mg/month) or 22.5 mg every 3 months.
- Monthly IM injections of leuprolide 7.5 mg.
- Leuprolide acetate 0.5 mg daily for 24 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Leuprolide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Leuprolide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Leuprolide in pediatric patients.
# Contraindications
- Hypersensitivity
- ELIGARD® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD®. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature.
- Pregnancy
- ELIGARD may cause fetal harm when administered to a pregnant woman. Expected hormonal changes that occur with ELIGARD treatment increase the risk for pregnancy loss and fetal harm when administered to a pregnant women. ELIGARD 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, the patient should be apprised of the potential hazard to the fetus.
# Warnings
### Precautions
- Tumor Flare
- ELIGARD® 7.5 mg 22.5 mg 30 mg, like other GnRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. ELIGARD® 45 mg causes a transient increase in serum concentrations of testosterone during the first two weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction.
- Cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the palliative treatment of advanced prostate cancer using GnRH agonists.
- Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted.
- Laboratory Tests
- Response to ELIGARD® should be monitored by measuring serum concentrations of testosterone and prostate specific antigen periodically.
- In the majority of patients, testosterone levels increased above Baseline during the first week, declining thereafter to Baseline levels or below by the end of the second or third week. Castrate levels were generally reached within two to four weeks.
- Castrate testosterone levels were maintained for the duration of the treatment with ELIGARD® 7.5 mg. No increases to above the castrate level occurred in any of the patients.
- Castrate levels were generally maintained for the duration of treatment with ELIGARD® 22.5 mg.
- Once castrate levels were achieved with ELIGARD® 30 mg, most (86/89) patients remained suppressed throughout the study.
- Once castrate levels were achieved with ELIGARD® 45 mg, only one patient ( 50 ng/dL.
- Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.
- Drug/Laboratory Test Interactions: Therapy with leuprolide acetate results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.
- Hyperglycemia and Diabetes
- Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.
- Cardiovascular Diseases
- Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
# Adverse Reactions
## Clinical Trials Experience
- The safety of all ELIGARD® formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of ELIGARD® 7.5 mg was evaluated in 8 surgically castrated males (TABLE 4). ELIGARD®, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms.
- During the clinical trials, injection sites were closely monitored. Refer to TABLE 3 for a summary of reported injection site events.
- These localized adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.
- The following possibly or probably related systemic adverse events occurred during clinical trials with ELIGARD®, and were reported in > 2% of patients (TABLE 7). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.
- In addition, the following possibly or probably related systemic adverse events were reported by < 2% of the patients treated with ELIGARD® in these clinical studies.
Sweating, insomnia, syncope, rigors, weakness, lethargy
Flatulence, constipation, dyspepsia
Decreased red blood cell count, hematocrit and hemoglobin
Weight gain
Tremor, backache, joint pain, muscle atrophy, limb pain
Disturbance of smell and taste, depression, vertigo
Insomnia, depression, loss of libido*
Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated
Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size
Alopecia, clamminess, night sweats*, sweating increased*
Hypertension, hypotension
-*Expected pharmacological consequences of testosterone suppression.
- Changes in Bone Density
- Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.
## Postmarketing Experience
- During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
- Convulsions have also been reported in the postmarketing setting.
# Drug Interactions
- No pharmacokinetic drug-drug interaction studies were conducted with ELIGARD®.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- ELIGARD® is contraindicated in women who are or may become pregnant while receiving the drug. Expected hormonal changes that occur with ELIGARD® treatment increase the risk for pregnancy loss. 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 the fetus and the potential risk for pregnancy loss.
- In non-clinical studies in rats, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects of fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Leuprolide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Leuprolide during labor and delivery.
### Nursing Mothers
- ELIGARD® is not indicated for use in women . 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 Eligard, 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
- The safety and effectiveness of ELIGARD® in pediatric patients have not been established.
### Geriatic Use
- The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.
### Gender
There is no FDA guidance on the use of Leuprolide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Leuprolide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Leuprolide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Leuprolide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Leuprolide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Leuprolide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Leuprolide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Leuprolide in the drug label.
# Overdosage
- In clinical trials using daily subcutaneous injections of leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
# Pharmacology
## Mechanism of Action
- Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
- In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL). These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.
## Structure
- ELIGARD® is a sterile polymeric matrix formulation of leuprolide acetate, a GnRH agonist, for subcutaneous injection. It is designed to deliver leuprolide acetate at a controlled rate over a one-, three-, four- or six-month therapeutic period.
- Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:
- ELIGARD® is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. ELIGARD® is administered subcutaneously, where it forms a solid drug delivery depot.
- One syringe contains the ATRIGEL® Delivery System and the other contains leuprolide acetate. ATRIGEL® is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).
- Refer to TABLE 5 for the delivery system composition and constituted product formulation for each ELIGARD® product.
## Pharmacodynamics
- Following the first dose of ELIGARD®, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (≤ 50 ng/dL) within three weeks for all ELIGARD® concentrations.
- Continued monthly treatment with ELIGARD® 7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (FIGURE 11).
- One patient received less than a full dose of ELIGARD® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold. Once testosterone suppression was achieved, one patient ( 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (FIGURE 12).
- One patient withdrew from the ELIGARD® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (FIGURE 13).
- One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD® 45 mg study. Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient ( 50 ng/dL after achieving castrate levels) (FIGURE 14).
- Leuprolide acetate is not active when given orally.
## Pharmacokinetics
- Absorption
- ELIGARD® 7.5 mg
- The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 11. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL).
- ELIGARD® 22.5 mg
- The pharmacokinetics/pharmacodynamics observed during two injections every three months (ELIGARD® 22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 12. Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately 5 hours following the initial and second injections, respectively. After the initial increase following each injection, serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).
- ELIGARD® 30 mg
- The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (ELIGARD® 30 mg ) in 24 patients with advanced prostate cancer is shown in Figure 13. Mean serum leuprolide concentrations following the initial injection rose rapidly to 150 ng/mL (Cmax) at approximately 3.3 hours after injection. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.1 – 1.0 ng/mL).
- ELIGARD® 45 mg
- The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (ELIGARD® 45 mg) in 27 patients with advanced prostate cancer is shown in Figure 14. Mean serum leuprolide concentrations rose to 82 ng/mL and 102 ng/mL (Cmax) at approximately 4.5 hours following the initial and second injections, respectively. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).
- Distribution
- The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
- Metabolism
- In healthy male volunteers, a 1-mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 8.34 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
- No drug metabolism study was conducted with ELIGARD®. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite.
- Excretion
- No drug excretion study was conducted with ELIGARD®.
- Race
- In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to TABLE 6 for distribution of study patients by race.
- Renal and Hepatic Insufficiency
- The pharmacokinetics of ELIGARD® in hepatically and renally impaired patients have not been determined.
## Nonclinical Toxicology
- Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with ELIGARD®.
- Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with ELIGARD® 7.5 mg in bacterial systems. These studies provided no evidence of a mutagenic potential.
# Clinical Studies
- One open-label, multicenter study was conducted with each ELIGARD® formulation (7.5 mg, 22.5 mg, 30 mg, and 45 mg) in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of study drug (TABLE 7). These studies evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (FIGURES 15-18).
- During the AGL9904 study using ELIGARD® 7.5 mg, once testosterone suppression was achieved, no patients (0%) demonstrated breakthrough (concentration >50 ng/dL) at any time in the study.
- During the AGL9909 study using ELIGARD® 22.5 mg, once testosterone suppression was achieved, only one patient (< 1%) demonstrated breakthrough following the initial injection; that patient remained below the castrate threshold following the second injection.
- During the AGL0001 study using ELIGARD® 30 mg, once testosterone suppression was achieved, three patients (3%) demonstrated breakthrough. In the first of these patients, a single serum testosterone concentration of 53 ng/dL was reported on the day after the second injection. In this patient, castrate suppression was reported for all other timepoints. In the second patient, a serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to a maximum concentration of 147 ng/dL on the second day after the second injection. In this patient, castrate suppression was again reached on the seventh day after the second injection and was maintained thereafter. In the final patient, serum testosterone concentrations > 50 ng/dL were reported at 2 and at 8 hours after the second injection. Serum testosterone concentration rose to a maximum of 110 ng/dL on the third day after the second injection. In this patient, castrate suppression was again reached eighteen days after the second injection and was maintained until the final day of the study, when a single serum testosterone concentration of 55 ng/dL was reported.
- During the AGL0205 study using ELIGARD® 45 mg, once testosterone suppression was achieved, one patient (<1%) demonstrated breakthrough. This patient reached castrate suppression at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL. At Month 12 (Day 336), his testosterone was 210 ng/dL.
- Serum PSA decreased in all patients in all studies whose Baseline values were elevated above the normal limit. Refer to TABLE 8 for a summary of the effectiveness of ELIGARD® in reducing serum PSA values.
- Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms. Refer to TABLE 9 for a summary of these endpoints.
# How Supplied
- ELIGARD® is available in a single use kit of a two syringe-mixing system in the following strengths:
- ELIGARD® 7.5 mg – NDC 0024-0793-75
- ELIGARD® 22.5 mg – NDC 0024-0222-05
- ELIGARD® 30 mg – NDC 0024-0610-30
- ELIGARD® 45 mg – NDC 0024-0605-45
- Storage:
- Store at 2 – 8 °C (35.6 – 46.4 °F)
## Storage
There is limited information regarding Leuprolide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- As with other GnRH agonists, patients may experience hot flashes. During the first few weeks of treatment, patients may also experience increased bone pain, increased difficulty in urinating, and the onset or aggravation of weakness or paralysis. Patients should notify their doctor if they develop new or worsened symptoms after beginning ELIGARD® treatment. Patients should be told about the injection site related adverse reactions, such as transient burning/stinging, pain, bruising, and redness. These injection site reactions are usually mild and reversible. If they do not resolve, patients should tell their doctor. If the patient experiences an allergic reaction, they should contact their doctor immediately.
# Precautions with Alcohol
- Alcohol-Leuprolide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ELIGARD®
# Look-Alike Drug Names
There is limited information regarding Leuprolide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Leuprolide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Overview
Leuprolide is a gonadatropin releasing hormone (GnRH) agonist that is FDA approved for the treatment of advanced prostate cancer. Common adverse reactions include malaise, fatigue, hot flashes/sweats, and testicular atrophy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ELIGARD® is administered subcutaneously and provides continuous release of leuprolide acetate over a one-, three-, four-, or six-month treatment period (TABLE 1). The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation.
- Once mixed, ELIGARD® should be discarded if not administered within 30 minutes.
- As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location chosen should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injection was administered in the upper- or mid-abdominal area. Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Leuprolide in adult patients.
### Non–Guideline-Supported Use
- Leuprolide 3.75 mg 1-month depot formulation.[1]
- Leuprolide 1 mg (0.25 to 0.5 mg for those with lower body mass) subcutaneously either on day 1 of the menstrual cycle and continued each morning until the day of human chorionic gonadotropin (hCG) administration (flare protocol), or on day 21 of the prior cycle (down-regulation protocol).[2]
- Leuprolide acetate, injected intramuscularly monthly at a dose of 7.5 mg.[3]
- 3 monthly IM injections of either leuprolide depot 3.75 mg.[4]
- Leuprolide IM (7.5 mg/month) or 22.5 mg every 3 months.[5]
- Monthly IM injections of leuprolide 7.5 mg.[6]
- Leuprolide acetate 0.5 mg daily for 24 weeks.[7]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Leuprolide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Leuprolide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Leuprolide in pediatric patients.
# Contraindications
- Hypersensitivity
- ELIGARD® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs or any of the components of ELIGARD®. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature.
- Pregnancy
- ELIGARD may cause fetal harm when administered to a pregnant woman. Expected hormonal changes that occur with ELIGARD treatment increase the risk for pregnancy loss and fetal harm when administered to a pregnant women. ELIGARD 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, the patient should be apprised of the potential hazard to the fetus.
# Warnings
### Precautions
- Tumor Flare
- ELIGARD® 7.5 mg 22.5 mg 30 mg, like other GnRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. ELIGARD® 45 mg causes a transient increase in serum concentrations of testosterone during the first two weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction.
- Cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been observed in the palliative treatment of advanced prostate cancer using GnRH agonists.
- Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy. If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted.
- Laboratory Tests
- Response to ELIGARD® should be monitored by measuring serum concentrations of testosterone and prostate specific antigen periodically.
- In the majority of patients, testosterone levels increased above Baseline during the first week, declining thereafter to Baseline levels or below by the end of the second or third week. Castrate levels were generally reached within two to four weeks.
- Castrate testosterone levels were maintained for the duration of the treatment with ELIGARD® 7.5 mg. No increases to above the castrate level occurred in any of the patients.
- Castrate levels were generally maintained for the duration of treatment with ELIGARD® 22.5 mg.
- Once castrate levels were achieved with ELIGARD® 30 mg, most (86/89) patients remained suppressed throughout the study.
- Once castrate levels were achieved with ELIGARD® 45 mg, only one patient (< 1%) experienced a breakthrough, with testosterone levels > 50 ng/dL.
- Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.
- Drug/Laboratory Test Interactions: Therapy with leuprolide acetate results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.
- Hyperglycemia and Diabetes
- Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.
- Cardiovascular Diseases
- Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
# Adverse Reactions
## Clinical Trials Experience
- The safety of all ELIGARD® formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of ELIGARD® 7.5 mg was evaluated in 8 surgically castrated males (TABLE 4). ELIGARD®, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms.
- During the clinical trials, injection sites were closely monitored. Refer to TABLE 3 for a summary of reported injection site events.
- These localized adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.
- The following possibly or probably related systemic adverse events occurred during clinical trials with ELIGARD®, and were reported in > 2% of patients (TABLE 7). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related are excluded.
- In addition, the following possibly or probably related systemic adverse events were reported by < 2% of the patients treated with ELIGARD® in these clinical studies.
Sweating, insomnia, syncope, rigors, weakness, lethargy
Flatulence, constipation, dyspepsia
Decreased red blood cell count, hematocrit and hemoglobin
Weight gain
Tremor, backache, joint pain, muscle atrophy, limb pain
Disturbance of smell and taste, depression, vertigo
Insomnia, depression, loss of libido*
Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated
Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size
Alopecia, clamminess, night sweats*, sweating increased*
Hypertension, hypotension
-*Expected pharmacological consequences of testosterone suppression.
- Changes in Bone Density
- Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.
## Postmarketing Experience
- During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
- Convulsions have also been reported in the postmarketing setting.
# Drug Interactions
- No pharmacokinetic drug-drug interaction studies were conducted with ELIGARD®.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- ELIGARD® is contraindicated in women who are or may become pregnant while receiving the drug. Expected hormonal changes that occur with ELIGARD® treatment increase the risk for pregnancy loss. 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 the fetus and the potential risk for pregnancy loss.
- In non-clinical studies in rats, major fetal abnormalities were observed after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects of fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Leuprolide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Leuprolide during labor and delivery.
### Nursing Mothers
- ELIGARD® is not indicated for use in women [see INDICATIONS AND USAGE (1)]. 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 Eligard, 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
- The safety and effectiveness of ELIGARD® in pediatric patients have not been established.
### Geriatic Use
- The majority of the patients (approximately 70%) studied in the clinical trials were age 70 and older.
### Gender
There is no FDA guidance on the use of Leuprolide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Leuprolide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Leuprolide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Leuprolide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Leuprolide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Leuprolide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Leuprolide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Leuprolide in the drug label.
# Overdosage
- In clinical trials using daily subcutaneous injections of leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
# Pharmacology
## Mechanism of Action
- Leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular and ovarian steroidogenesis. This effect is reversible upon discontinuation of drug therapy.
- In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL). These decreases occur within two to four weeks after initiation of treatment. Long-term studies have shown that continuation of therapy with leuprolide acetate maintains testosterone below the castrate level for up to seven years.
## Structure
- ELIGARD® is a sterile polymeric matrix formulation of leuprolide acetate, a GnRH agonist, for subcutaneous injection. It is designed to deliver leuprolide acetate at a controlled rate over a one-, three-, four- or six-month therapeutic period.
- Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing hormone (GnRH) that, when given continuously, inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:
- ELIGARD® is prefilled and supplied in two separate, sterile syringes whose contents are mixed immediately prior to administration. The two syringes are joined and the single dose product is mixed until it is homogenous. ELIGARD® is administered subcutaneously, where it forms a solid drug delivery depot.
- One syringe contains the ATRIGEL® Delivery System and the other contains leuprolide acetate. ATRIGEL® is a polymeric (non-gelatin containing) delivery system consisting of a biodegradable poly (DL-lactide-co-glycolide) (PLGH or PLG) polymer formulation dissolved in a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).
- Refer to TABLE 5 for the delivery system composition and constituted product formulation for each ELIGARD® product.
## Pharmacodynamics
- Following the first dose of ELIGARD®, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold (≤ 50 ng/dL) within three weeks for all ELIGARD® concentrations.
- Continued monthly treatment with ELIGARD® 7.5 mg maintained castrate testosterone suppression throughout the study. No breakthrough of testosterone concentrations above castrate threshold (> 50 ng/dL) occurred at any time during the study once castrate suppression was achieved (FIGURE 11).
- One patient received less than a full dose of ELIGARD® 22.5 mg at baseline, never suppressed and withdrew from the study at Day 73. Of the 116 patients remaining in the study, 115 (99%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 35, 116 (100%) had serum testosterone levels below the castrate threshold. Once testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) following the initial injection; that patient remained below the castrate threshold following the second injection (FIGURE 12).
- One patient withdrew from the ELIGARD® 30 mg study at Day 14. Of the 89 patients remaining in the study, 85 (96%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). By Day 42, 89 (100%) of patients attained castrate testosterone suppression. Once castrate testosterone suppression was achieved, three patients (3%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (FIGURE 13).
- One patient at Day 1 and another patient at Day 29 were withdrawn from the ELIGARD® 45 mg study. Of the 109 patients remaining in the study, 108 (99.1%) had serum testosterone levels below the castrate threshold by Month 1 (Day 28). One patient did not achieve castrate suppression and was withdrawn from the study at Day 85. Once castrate testosterone suppression was achieved, one patient (< 1%) demonstrated breakthrough (concentrations > 50 ng/dL after achieving castrate levels) (FIGURE 14).
- Leuprolide acetate is not active when given orally.
## Pharmacokinetics
- Absorption
- ELIGARD® 7.5 mg
- The pharmacokinetics/pharmacodynamics observed during three once-monthly injections in 20 patients with advanced prostate cancer is shown in Figure 11. Mean serum leuprolide concentrations following the initial injection rose to 25.3 ng/mL (Cmax) at approximately 5 hours after injection. After the initial increase following each injection, serum concentrations remained relatively constant (0.28 – 2.00 ng/mL).
- ELIGARD® 22.5 mg
- The pharmacokinetics/pharmacodynamics observed during two injections every three months (ELIGARD® 22.5 mg) in 22 patients with advanced prostate cancer is shown in Figure 12. Mean serum leuprolide concentrations rose to 127 ng/mL and 107 ng/mL at approximately 5 hours following the initial and second injections, respectively. After the initial increase following each injection, serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).
- ELIGARD® 30 mg
- The pharmacokinetics/pharmacodynamics observed during injections administered initially and at four months (ELIGARD® 30 mg ) in 24 patients with advanced prostate cancer is shown in Figure 13. Mean serum leuprolide concentrations following the initial injection rose rapidly to 150 ng/mL (Cmax) at approximately 3.3 hours after injection. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.1 – 1.0 ng/mL).
- ELIGARD® 45 mg
- The pharmacokinetics/pharmacodynamics observed during injections administered initially and at six months (ELIGARD® 45 mg) in 27 patients with advanced prostate cancer is shown in Figure 14. Mean serum leuprolide concentrations rose to 82 ng/mL and 102 ng/mL (Cmax) at approximately 4.5 hours following the initial and second injections, respectively. After the initial increase following each injection, mean serum concentrations remained relatively constant (0.2 – 2.0 ng/mL).
- Distribution
- The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
- Metabolism
- In healthy male volunteers, a 1-mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 8.34 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
- No drug metabolism study was conducted with ELIGARD®. Upon administration with different leuprolide acetate formulations, the major metabolite of leuprolide acetate is a pentapeptide (M-1) metabolite.
- Excretion
- No drug excretion study was conducted with ELIGARD®.
- Race
- In patients studied, mean serum leuprolide concentrations were similar regardless of race. Refer to TABLE 6 for distribution of study patients by race.
- Renal and Hepatic Insufficiency
- The pharmacokinetics of ELIGARD® in hepatically and renally impaired patients have not been determined.
## Nonclinical Toxicology
- Two-year carcinogenicity studies were conducted with leuprolide acetate in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. No carcinogenicity studies have been conducted with ELIGARD®.
- Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems and with ELIGARD® 7.5 mg in bacterial systems. These studies provided no evidence of a mutagenic potential.
# Clinical Studies
- One open-label, multicenter study was conducted with each ELIGARD® formulation (7.5 mg, 22.5 mg, 30 mg, and 45 mg) in patients with Jewett stage A though D prostate cancer who were treated with at least a single injection of study drug (TABLE 7). These studies evaluated the achievement and maintenance of castrate serum testosterone suppression over the duration of therapy (FIGURES 15-18).
- During the AGL9904 study using ELIGARD® 7.5 mg, once testosterone suppression was achieved, no patients (0%) demonstrated breakthrough (concentration >50 ng/dL) at any time in the study.
- During the AGL9909 study using ELIGARD® 22.5 mg, once testosterone suppression was achieved, only one patient (< 1%) demonstrated breakthrough following the initial injection; that patient remained below the castrate threshold following the second injection.
- During the AGL0001 study using ELIGARD® 30 mg, once testosterone suppression was achieved, three patients (3%) demonstrated breakthrough. In the first of these patients, a single serum testosterone concentration of 53 ng/dL was reported on the day after the second injection. In this patient, castrate suppression was reported for all other timepoints. In the second patient, a serum testosterone concentration of 66 ng/dL was reported immediately prior to the second injection. This rose to a maximum concentration of 147 ng/dL on the second day after the second injection. In this patient, castrate suppression was again reached on the seventh day after the second injection and was maintained thereafter. In the final patient, serum testosterone concentrations > 50 ng/dL were reported at 2 and at 8 hours after the second injection. Serum testosterone concentration rose to a maximum of 110 ng/dL on the third day after the second injection. In this patient, castrate suppression was again reached eighteen days after the second injection and was maintained until the final day of the study, when a single serum testosterone concentration of 55 ng/dL was reported.
- During the AGL0205 study using ELIGARD® 45 mg, once testosterone suppression was achieved, one patient (<1%) demonstrated breakthrough. This patient reached castrate suppression at Day 21 and remained suppressed until Day 308 when his testosterone level rose to 112 ng/dL. At Month 12 (Day 336), his testosterone was 210 ng/dL.
- Serum PSA decreased in all patients in all studies whose Baseline values were elevated above the normal limit. Refer to TABLE 8 for a summary of the effectiveness of ELIGARD® in reducing serum PSA values.
- Other secondary efficacy endpoints evaluated included WHO performance status, bone pain, urinary pain and urinary signs and symptoms. Refer to TABLE 9 for a summary of these endpoints.
# How Supplied
- ELIGARD® is available in a single use kit of a two syringe-mixing system in the following strengths:
- ELIGARD® 7.5 mg – NDC 0024-0793-75
- ELIGARD® 22.5 mg – NDC 0024-0222-05
- ELIGARD® 30 mg – NDC 0024-0610-30
- ELIGARD® 45 mg – NDC 0024-0605-45
- Storage:
- Store at 2 – 8 °C (35.6 – 46.4 °F)
## Storage
There is limited information regarding Leuprolide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- As with other GnRH agonists, patients may experience hot flashes. During the first few weeks of treatment, patients may also experience increased bone pain, increased difficulty in urinating, and the onset or aggravation of weakness or paralysis. Patients should notify their doctor if they develop new or worsened symptoms after beginning ELIGARD® treatment. Patients should be told about the injection site related adverse reactions, such as transient burning/stinging, pain, bruising, and redness. These injection site reactions are usually mild and reversible. If they do not resolve, patients should tell their doctor. If the patient experiences an allergic reaction, they should contact their doctor immediately.
# Precautions with Alcohol
- Alcohol-Leuprolide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ELIGARD®[8]
# Look-Alike Drug Names
There is limited information regarding Leuprolide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Leuprolide | |
b2c0f6875c9f266dca7f7e1df27309c334f7fa18 | wikidoc | Penbutolol | Penbutolol
# 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
Penbutolol is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include nausea, dizziness, headache and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The usual starting and maintenance dose of penbutolol, used alone or in combination with other antihypertensive agents, such as thiazide-type diuretics, is 20 mg given once daily.
- Doses of 40 mg and 80 mg have been well-tolerated but have not been shown to give a greater antihypertensive effect. The full effect of a 20- or 40-mg dose is seen by the end of 2 weeks. A dose of 10 mg also lowers blood pressure, but the full effect is not seen for 4 to 6 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Penbutolol in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 40 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Penbutolol 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 Penbutolol in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Penbutolol in pediatric patients.
# Contraindications
- Cardiogenic shock
- Sinus bradycardia
- Second degree heart block
- Third degree heart block
- Bronchial asthma
- Hypersensitivity to penbutolol
# Warnings
- Sympathetic stimulation may be essential for supporting circulatory function in patients with heart failure, and its inhibition by ß-adrenergic receptor blockade may precipitate more severe failure. Although ß-blockers should be avoided in overt congestive heart failure, penbutolol can, if necessary, be used with caution in patients with a history of cardiac failure who are well compensated, on treatment with vasodilators, digitalis and/or diuretics. Both digitalis and penbutolol slow AV conduction. Beta-adrenergic receptor antagonists do not inhibit the inotropic action of digitalis on heart muscle. If cardiac failure persists, treatment with penbutolol should be discontinued.
- Continued depression of the myocardium with ß-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first evidence of heart failure, patients receiving penbutolol should be given appropriate treatment, and the response should be closely observed. If cardiac failure continues despite adequate intervention with appropriate drugs, penbutolol should be withdrawn (gradually, if possible).
- Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with ß-blocking agents; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing penbutolol, particularly in patients with ischemic heart disease, the dosage should be reduced gradually over a period of 1 to 2 weeks and the patient should be monitored carefully. If angina becomes more pronounced or acute coronary insufficiency develops, administration of penbutolol should be reinstated promptly, at least on a temporary basis, and appropriate measures should be taken for the management of unstable angina. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may not be recognized, it may not be prudent to discontinue penbutolol abruptly, even in patients who are being treated only for hypertension.
- Penbutolol is contraindicated in bronchial asthma. In general, patients with bronchospastic diseases should not receive ß-blockers. Penbutolol should be administered with caution because it may block bronchodilation produced by endogenous catecholamine stimulation of ß-2 receptors.
- Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
- Beta-adrenergic receptor blockade may prevent the appearance of signs and symptoms of acute hypoglycemia, such as tachycardia and blood pressure changes. This is especially important in patients with labile diabetes. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of hypoglycemic drugs. Beta-adrenergic blockade may also impair the homeostatic response to hypoglycemia; in that event, the spontaneous recovery from hypoglycemia may be delayed during treatment with ß-adrenergic receptor antagonists.
- Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of ß-adrenergic receptor blockers that might precipitate a thyroid storm.
# Adverse Reactions
## Clinical Trials Experience
- Penbutolol is usually well tolerated in properly selected patients. Most adverse effects observed during clinical trials have been mild and reversible.
- Table 1 lists the adverse reactions reported from 4 controlled studies conducted in the United States involving once-a-day administration of penbutolol (at doses ranging from 10 to 120 mg) as monotherapy or in combination with hydrochlorothiazide. Penbutolol doses above 40 mg/day are not, however, recommended. The table includes only those events where the prevalence rate in the penbutolol group was at least 1.5%, or where the reaction is of particular interest.
Over a dose range from 10 to 40 mg, once a day, fatigue, nausea, and sexual impotence occurred at a greater frequency as the dose was increased.
- In a double-blind clinical trial comparing In a double-blind clinical trial comparing penbutolol (40 mg and greater once a day) and propranolol (40 mg or more twice a day), heart rates of less than 60 beats/min. were recorded at least once in 25% of the patients in the group receiving penbutolol and in 37% of the patients in the propranolol group. Corresponding figures for heart rates of less than 50 beats/min. were 1.2% and 6% respectively. No symptoms associated with bradycardia were reported.
- Discontinuations of penbutolol because of adverse reactions have ranged between 2.4% and 6.9% of patients in double-blind, parallel, controlled clinical trials, as compared to 1.8% to 4.1% in the corresponding control groups that were given placebo. The frequency and severity of adverse reactions have not increased during long-term administration of penbutolol. The prevalence of adverse reactions reported from 4 controlled clinical trials (referred to in the table above) as reasons for discontinuation of therapy by>0.5% of the penbutolol group is listed in the table below.
- In addition, certain adverse effects not listed above have been reported with other ß-blocking agents and should also be considered as potential adverse effects of penbutolol.
- Central Nervous System: Reversible mental depression progressing tocatatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics).
- Cardiovascular: Intensification of AV block.
- Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.
- Hematologic: Agranulocytosis, nonthrombocytopenic and thrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis.
- Miscellaneous: Reversible alopecia and Peyronie’s disease. The oculomucocutaneous syndrome associated with the ß-blocker practolol has not been reported with penbutolol during investigational use and extensive foreign clinical experience.
## Postmarketing Experience
There is limited information regarding Penbutolol Postmarketing Experience in the drug label.
# Drug Interactions
- Penbutalol has been used in combination with hydrochlorothiazide in at least 100 patients without unexpected adverse reactions.
- Penbutolol increases the volume of distribution of lidocaine in normal subjects. This could result in a requirement for higher loading doses of lidocaine.
- Cimetidine has no effect on the clearance of penbutolol. The major metabolite of penbutolol is a glucuronide, and it has been shown that cimetidine does not inhibit glucuronidation.
- Synergistic hypotensive effects, bradycardia, and arrhythmias have been reported in some patients receiving ß-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen.
- Generally, penbutatol should not be used in patients receiving catecholamine-depleting drugs.
- Digoxin: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
- Anesthesia: Care should be taken when using anesthetic agents that depress the myocardium, such as ether, cyclopropane, and trichloroethylene, and it is prudent to use the lowest possible dose of penbutolol. Penbutolol, like other beta-blockers, is a competitive inhibitor of beta-receptor agonists, and its effect on the heart can be reversed by cautious administration of such agents (eg, dobutamine or isoproterenol). Manifestations of excessive vagal tone (eg, profound bradycardia, hypotension) may be corrected with atropine 1 to 3 mg IV in divided doses.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratology studies in rats and rabbits revealed no teratogenic effects related to treatment with penbutolol at oral doses up to 200 mg/kg/day (250 times the MRHD). In rabbits, a slight increase in the intrauterine fetal mortality and a reduced 24-hour offspring survival rate were observed in the groups treated with 125 mg/kg/day (156 times the MRHD) but not in the groups treated with 0.2 and 5 mg (0.25 to 6 times the MRHD).
- There are no adequate and well-controlled studies in pregnant women. Penbutatol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In a perinatal and postnatal study in rats, the pup body weight and pup survival rate were reduced at the highest dose level of 160 mg/kg/day (200 times the MRHD).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Penbutolol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Penbutolol during labor and delivery.
### Nursing Mothers
- It is not known whether penbutatol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when penbutatol is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of penbutatol in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of penbutatol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.
- 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 Penbutolol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Penbutolol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Penbutolol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Penbutolol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Penbutolol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Penbutolol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Penbutolol in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Penbutolol and IV administrations.
# Overdosage
- There is no actual experience with penbutatol overdose. The signs and symptoms that would be expected with overdosage of beeta-adrenergic receptor antagonists are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. In addition to discontinuation of penbutatol, gastric emptying, and close observation of the patient, the following measures might be considered as appropriate:
- Excessive bradycardia: Administer atropine sulfate to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride may be administered cautiously; larger than usual doses may be needed. In refractory cases, the use of a transvenous cardiac pacemaker may be necessary.
- Hypotension: Sympathomimetic drug therapy, such as dopamine, dobutamine, or levarterenol, may be considered if hypotension persists despite correction of bradycardia. In refractory cases, administration of glucagon hydrochloride has been reported to be useful.
- Bronchospasm: A beta-2-agonist or Isoproterenol hydrochloride may be administered. Additional therapy with aminophylline may be considered.
- Acute Cardiac Failure: Institute conventional therapy immediately. Intravenous administration of dobutamine and glucagon hydrochloride has been reported to be useful.
- Heart Block (Second or Third Degree): Isoproterenol hydrochloride or a transvenous cardiac pacemaker may be used.
# Pharmacology
## Mechanism of Action
- The mechanisms of the antihypertensive actions of beta-receptor antagonists have not been established. However, factors that may be involved are:
- Competitive antagonism of catecholamines at peripheral adrenergic receptor sites (especially cardiac) that leads to decreased cardiac output.
- A central nervous system (CNS) action that results in a decrease in tonic sympathetic neural outflow to the periphery.
- A reduction of renin secretion through blockade of beta-receptors involved in release of renin from the kidneys.
## Structure
- Penbutolol sulfate is a synthetic beta-receptor antagonist for oral administration. The chemical name of penbutolol sulfate is (S)-1-tert-butylamino-3-(o-cyclopentylphenoxy)-2-propanol sulfate. It is provided as the levorotatory isomer. The empirical formula for penbutolol sulfate is C36H60N2O8S. Its molecular weight is 680.94. A dose of 20 mg is equivalent to 29.4 µmol. The structural formula is as follows:
- Penbutolol is a white, odorless, crystalline powder. Penbutatol is available as tablets for oral administration. Each tablet contains 20 mg of penbutolol sulfate. It also contains corn starch, D&C Yellow No. 10, lactose, magnesium stearate, povidone, silicon dioxide, talc, titanium dioxide, synthetic black iron oxide, hypromellose, simethicone and other inactive ingredients.
## Pharmacodynamics
- Penbutolol is a beta-1, beta-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol.
- Penbutolol antagonizes the heart rate effects of exercise and infused isoproterenol. The beta-blocking potency of penbutolol is approximately 4 times that of propranolol. An oral dose of less than 10 mg will reduce exercise-induced tachycardia to one-half its usual level; maximum antagonism follows doses of 10 to 20 mg. The peak effect is between 1.5 and 3 hours after oral administration. The duration of effect exceeds 20 hours during a once-daily dosing regimen. During chronic administration of penbutolol, the duration of antihypertensive effects permits a once-daily dosage schedule.
- Acute hemodynamic effects of penbutolol have been studied following single intravenous doses between 0.1 and 4 mg. The cardiovascular responses included significant reductions in heart rate, left ventricular maximum dP/dt, cardiac output, stroke volume index, stroke work, and stroke work index. Systolic blood pressure and mean arterial pressure were reduced, and total peripheral resistance was increased.
- Chronic administration of penbutolol to hypertensive patients results in the hemodynamic pattern typical of beta-adrenergic blocking drugs: a reduction in cardiac index, heart rate, systolic blood pressure and diastolic blood pressure, and the product of heart rate and mean arterial pressure both at rest and with all levels of exercise, without significant change in total peripheral resistance. Penbutolol causes a reduction in left ventricular contractility. Penbutolol decreases glomerular filtration rate, but not significantly.
- Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic blood pressures and diastolic blood pressure. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in caucasians than blacks.
- Penbutolol decreases plasma renin activity in normal subjects and in patients with essential and renovascular hypertension.
- Penbutolol dose dependently increases the RR and QT intervals. There is no influence on the PR]], QRS, or QT c (corrected) intervals.
## Pharmacokinetics
- Following oral administration, penbutolol is rapidly and completely absorbed. Peak plasma concentrations of penbutolol occur between 2 and 3 hours after oral administration and are proportional to single and multiple doses between 10 and 40 mg once a day. The average plasma elimination half-life of penbutolol is approximately 5 hours in normal subjects. There is no significant difference in the plasma half-life of penbutolol in healthy elderly persons or patients on renal dialysis. Twelve to 24 hours after oral administration of doses up to 120 mg, plasma concentrations of parent drug are 0% to 10% of the peak level. No accumulation of penbutolol is observed in hypertensive patients after 8 days of therapy at doses of 40 mg daily or 20 mg twice a day. Penbutolol is approximately 80% to 98% bound to plasma proteins.
- The metabolism of penbutolol in humans involves conjugation and oxidation. The metabolites are excreted principally in the urine. When radiolabeled penbutolol was administered to humans, approximately 90% of the radioactivity was excreted in the urine. Approximately 1/6 of the dose of penbutolol was recovered as penbutolol conjugate while the remaining fraction was not identified. Conjugated penbutolol has a plasma elimination half-life of approximately 20 hours in healthy persons, 25 hours in healthy elderly persons, and 100 hours in patients on renal dialysis. Thus, accumulation of penbutolol conjugate may be expected upon multiple-dosing in renal insufficiency. An oxidative metabolite of penbutolol, 4-hydroxy penbutolol, has been identified in small quantities in plasma and urine. It is 1/8 to 1/15 times as active as the parent compound in blocking isoproterenol-induced ß-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs.
## Nonclinical Toxicology
- Studies in rats indicated that the combination of penbutolol, triamterene, and hydrochlorothiazide (up to 40, 50 and 25 mg/kg respectively) increased the incidence and severity of renal tubular dilation and regeneration when compared to that in rats treated only with triamterene and hydrochlorothiazide. Dogs administered the same doses of triamterene and hydrochlorothiazide alone and in combination with penbutolol had an increase in serum alkaline phosphatase and serum alanine transferase, but there were no gross or microscopic abnormalities observed. No significant toxicologic findings were observed in rats and dogs treated with a combination of penbutolol and hydrochlorothiazide.
# Clinical Studies
- Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic blood pressures and diastolic blood pressure. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in caucasians than blacks.
# How Supplied
- Penbutolol sulfate 20 mg tablets are capsule-shaped, film-coated, yellow tablets scored on both sides and imprinted in black with “SP 22” on one side. They are supplied as follows: Bottles of 100 (NDC 52244-450-10)
## Storage
- Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F).
- Keep tightly closed and protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
- In one study, the combination of penbutolol and alcohol increased the number of errors in the eye-hand psychomotor function test.
# Brand Names
- Levatol
# Look-Alike Drug Names
There is limited information regarding Penbutolol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Penbutolol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2], Sheng Shi, M.D. [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.
# Overview
Penbutolol is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include nausea, dizziness, headache and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The usual starting and maintenance dose of penbutolol, used alone or in combination with other antihypertensive agents, such as thiazide-type diuretics, is 20 mg given once daily.
- Doses of 40 mg and 80 mg have been well-tolerated but have not been shown to give a greater antihypertensive effect. The full effect of a 20- or 40-mg dose is seen by the end of 2 weeks. A dose of 10 mg also lowers blood pressure, but the full effect is not seen for 4 to 6 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Penbutolol in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 40 mg/day.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Penbutolol 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 Penbutolol in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Penbutolol in pediatric patients.
# Contraindications
- Cardiogenic shock
- Sinus bradycardia
- Second degree heart block
- Third degree heart block
- Bronchial asthma
- Hypersensitivity to penbutolol
# Warnings
- Sympathetic stimulation may be essential for supporting circulatory function in patients with heart failure, and its inhibition by ß-adrenergic receptor blockade may precipitate more severe failure. Although ß-blockers should be avoided in overt congestive heart failure, penbutolol can, if necessary, be used with caution in patients with a history of cardiac failure who are well compensated, on treatment with vasodilators, digitalis and/or diuretics. Both digitalis and penbutolol slow AV conduction. Beta-adrenergic receptor antagonists do not inhibit the inotropic action of digitalis on heart muscle. If cardiac failure persists, treatment with penbutolol should be discontinued.
- Continued depression of the myocardium with ß-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first evidence of heart failure, patients receiving penbutolol should be given appropriate treatment, and the response should be closely observed. If cardiac failure continues despite adequate intervention with appropriate drugs, penbutolol should be withdrawn (gradually, if possible).
- Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with ß-blocking agents; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing penbutolol, particularly in patients with ischemic heart disease, the dosage should be reduced gradually over a period of 1 to 2 weeks and the patient should be monitored carefully. If angina becomes more pronounced or acute coronary insufficiency develops, administration of penbutolol should be reinstated promptly, at least on a temporary basis, and appropriate measures should be taken for the management of unstable angina. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may not be recognized, it may not be prudent to discontinue penbutolol abruptly, even in patients who are being treated only for hypertension.
- Penbutolol is contraindicated in bronchial asthma. In general, patients with bronchospastic diseases should not receive ß-blockers. Penbutolol should be administered with caution because it may block bronchodilation produced by endogenous catecholamine stimulation of ß-2 receptors.
- Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
- Beta-adrenergic receptor blockade may prevent the appearance of signs and symptoms of acute hypoglycemia, such as tachycardia and blood pressure changes. This is especially important in patients with labile diabetes. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of hypoglycemic drugs. Beta-adrenergic blockade may also impair the homeostatic response to hypoglycemia; in that event, the spontaneous recovery from hypoglycemia may be delayed during treatment with ß-adrenergic receptor antagonists.
- Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of ß-adrenergic receptor blockers that might precipitate a thyroid storm.
# Adverse Reactions
## Clinical Trials Experience
- Penbutolol is usually well tolerated in properly selected patients. Most adverse effects observed during clinical trials have been mild and reversible.
- Table 1 lists the adverse reactions reported from 4 controlled studies conducted in the United States involving once-a-day administration of penbutolol (at doses ranging from 10 to 120 mg) as monotherapy or in combination with hydrochlorothiazide. Penbutolol doses above 40 mg/day are not, however, recommended. The table includes only those events where the prevalence rate in the penbutolol group was at least 1.5%, or where the reaction is of particular interest.
Over a dose range from 10 to 40 mg, once a day, fatigue, nausea, and sexual impotence occurred at a greater frequency as the dose was increased.
- In a double-blind clinical trial comparing In a double-blind clinical trial comparing penbutolol (40 mg and greater once a day) and propranolol (40 mg or more twice a day), heart rates of less than 60 beats/min. were recorded at least once in 25% of the patients in the group receiving penbutolol and in 37% of the patients in the propranolol group. Corresponding figures for heart rates of less than 50 beats/min. were 1.2% and 6% respectively. No symptoms associated with bradycardia were reported.
- Discontinuations of penbutolol because of adverse reactions have ranged between 2.4% and 6.9% of patients in double-blind, parallel, controlled clinical trials, as compared to 1.8% to 4.1% in the corresponding control groups that were given placebo. The frequency and severity of adverse reactions have not increased during long-term administration of penbutolol. The prevalence of adverse reactions reported from 4 controlled clinical trials (referred to in the table above) as reasons for discontinuation of therapy by>0.5% of the penbutolol group is listed in the table below.
- In addition, certain adverse effects not listed above have been reported with other ß-blocking agents and should also be considered as potential adverse effects of penbutolol.
- Central Nervous System: Reversible mental depression progressing tocatatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics).
- Cardiovascular: Intensification of AV block.
- Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.
- Hematologic: Agranulocytosis, nonthrombocytopenic and thrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis.
- Miscellaneous: Reversible alopecia and Peyronie’s disease. The oculomucocutaneous syndrome associated with the ß-blocker practolol has not been reported with penbutolol during investigational use and extensive foreign clinical experience.
## Postmarketing Experience
There is limited information regarding Penbutolol Postmarketing Experience in the drug label.
# Drug Interactions
- Penbutalol has been used in combination with hydrochlorothiazide in at least 100 patients without unexpected adverse reactions.
- Penbutolol increases the volume of distribution of lidocaine in normal subjects. This could result in a requirement for higher loading doses of lidocaine.
- Cimetidine has no effect on the clearance of penbutolol. The major metabolite of penbutolol is a glucuronide, and it has been shown that cimetidine does not inhibit glucuronidation.
- Synergistic hypotensive effects, bradycardia, and arrhythmias have been reported in some patients receiving ß-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen.
- Generally, penbutatol should not be used in patients receiving catecholamine-depleting drugs.
- Digoxin: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
- Anesthesia: Care should be taken when using anesthetic agents that depress the myocardium, such as ether, cyclopropane, and trichloroethylene, and it is prudent to use the lowest possible dose of penbutolol. Penbutolol, like other beta-blockers, is a competitive inhibitor of beta-receptor agonists, and its effect on the heart can be reversed by cautious administration of such agents (eg, dobutamine or isoproterenol). Manifestations of excessive vagal tone (eg, profound bradycardia, hypotension) may be corrected with atropine 1 to 3 mg IV in divided doses.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratology studies in rats and rabbits revealed no teratogenic effects related to treatment with penbutolol at oral doses up to 200 mg/kg/day (250 times the MRHD). In rabbits, a slight increase in the intrauterine fetal mortality and a reduced 24-hour offspring survival rate were observed in the groups treated with 125 mg/kg/day (156 times the MRHD) but not in the groups treated with 0.2 and 5 mg (0.25 to 6 times the MRHD).
- There are no adequate and well-controlled studies in pregnant women. Penbutatol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In a perinatal and postnatal study in rats, the pup body weight and pup survival rate were reduced at the highest dose level of 160 mg/kg/day (200 times the MRHD).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Penbutolol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Penbutolol during labor and delivery.
### Nursing Mothers
- It is not known whether penbutatol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when penbutatol is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of penbutatol in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of penbutatol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.
- 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 Penbutolol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Penbutolol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Penbutolol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Penbutolol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Penbutolol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Penbutolol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Penbutolol in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Penbutolol and IV administrations.
# Overdosage
- There is no actual experience with penbutatol overdose. The signs and symptoms that would be expected with overdosage of beeta-adrenergic receptor antagonists are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. In addition to discontinuation of penbutatol, gastric emptying, and close observation of the patient, the following measures might be considered as appropriate:
- Excessive bradycardia: Administer atropine sulfate to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride may be administered cautiously; larger than usual doses may be needed. In refractory cases, the use of a transvenous cardiac pacemaker may be necessary.
- Hypotension: Sympathomimetic drug therapy, such as dopamine, dobutamine, or levarterenol, may be considered if hypotension persists despite correction of bradycardia. In refractory cases, administration of glucagon hydrochloride has been reported to be useful.
- Bronchospasm: A beta-2-agonist or Isoproterenol hydrochloride may be administered. Additional therapy with aminophylline may be considered.
- Acute Cardiac Failure: Institute conventional therapy immediately. Intravenous administration of dobutamine and glucagon hydrochloride has been reported to be useful.
- Heart Block (Second or Third Degree): Isoproterenol hydrochloride or a transvenous cardiac pacemaker may be used.
# Pharmacology
## Mechanism of Action
- The mechanisms of the antihypertensive actions of beta-receptor antagonists have not been established. However, factors that may be involved are:
- Competitive antagonism of catecholamines at peripheral adrenergic receptor sites (especially cardiac) that leads to decreased cardiac output.
- A central nervous system (CNS) action that results in a decrease in tonic sympathetic neural outflow to the periphery.
- A reduction of renin secretion through blockade of beta-receptors involved in release of renin from the kidneys.
## Structure
- Penbutolol sulfate is a synthetic beta-receptor antagonist for oral administration. The chemical name of penbutolol sulfate is (S)-1-tert-butylamino-3-(o-cyclopentylphenoxy)-2-propanol sulfate. It is provided as the levorotatory isomer. The empirical formula for penbutolol sulfate is C36H60N2O8S. Its molecular weight is 680.94. A dose of 20 mg is equivalent to 29.4 µmol. The structural formula is as follows:
- Penbutolol is a white, odorless, crystalline powder. Penbutatol is available as tablets for oral administration. Each tablet contains 20 mg of penbutolol sulfate. It also contains corn starch, D&C Yellow No. 10, lactose, magnesium stearate, povidone, silicon dioxide, talc, titanium dioxide, synthetic black iron oxide, hypromellose, simethicone and other inactive ingredients.
## Pharmacodynamics
- Penbutolol is a beta-1, beta-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol.
- Penbutolol antagonizes the heart rate effects of exercise and infused isoproterenol. The beta-blocking potency of penbutolol is approximately 4 times that of propranolol. An oral dose of less than 10 mg will reduce exercise-induced tachycardia to one-half its usual level; maximum antagonism follows doses of 10 to 20 mg. The peak effect is between 1.5 and 3 hours after oral administration. The duration of effect exceeds 20 hours during a once-daily dosing regimen. During chronic administration of penbutolol, the duration of antihypertensive effects permits a once-daily dosage schedule.
- Acute hemodynamic effects of penbutolol have been studied following single intravenous doses between 0.1 and 4 mg. The cardiovascular responses included significant reductions in heart rate, left ventricular maximum dP/dt, cardiac output, stroke volume index, stroke work, and stroke work index. Systolic blood pressure and mean arterial pressure were reduced, and total peripheral resistance was increased.
- Chronic administration of penbutolol to hypertensive patients results in the hemodynamic pattern typical of beta-adrenergic blocking drugs: a reduction in cardiac index, heart rate, systolic blood pressure and diastolic blood pressure, and the product of heart rate and mean arterial pressure both at rest and with all levels of exercise, without significant change in total peripheral resistance. Penbutolol causes a reduction in left ventricular contractility. Penbutolol decreases glomerular filtration rate, but not significantly.
- Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic blood pressures and diastolic blood pressure. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in caucasians than blacks.
- Penbutolol decreases plasma renin activity in normal subjects and in patients with essential and renovascular hypertension.
- Penbutolol dose dependently increases the RR and QT intervals. There is no influence on the PR]], QRS, or QT c (corrected) intervals.
## Pharmacokinetics
- Following oral administration, penbutolol is rapidly and completely absorbed. Peak plasma concentrations of penbutolol occur between 2 and 3 hours after oral administration and are proportional to single and multiple doses between 10 and 40 mg once a day. The average plasma elimination half-life of penbutolol is approximately 5 hours in normal subjects. There is no significant difference in the plasma half-life of penbutolol in healthy elderly persons or patients on renal dialysis. Twelve to 24 hours after oral administration of doses up to 120 mg, plasma concentrations of parent drug are 0% to 10% of the peak level. No accumulation of penbutolol is observed in hypertensive patients after 8 days of therapy at doses of 40 mg daily or 20 mg twice a day. Penbutolol is approximately 80% to 98% bound to plasma proteins.
- The metabolism of penbutolol in humans involves conjugation and oxidation. The metabolites are excreted principally in the urine. When radiolabeled penbutolol was administered to humans, approximately 90% of the radioactivity was excreted in the urine. Approximately 1/6 of the dose of penbutolol was recovered as penbutolol conjugate while the remaining fraction was not identified. Conjugated penbutolol has a plasma elimination half-life of approximately 20 hours in healthy persons, 25 hours in healthy elderly persons, and 100 hours in patients on renal dialysis. Thus, accumulation of penbutolol conjugate may be expected upon multiple-dosing in renal insufficiency. An oxidative metabolite of penbutolol, 4-hydroxy penbutolol, has been identified in small quantities in plasma and urine. It is 1/8 to 1/15 times as active as the parent compound in blocking isoproterenol-induced ß-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs.
## Nonclinical Toxicology
- Studies in rats indicated that the combination of penbutolol, triamterene, and hydrochlorothiazide (up to 40, 50 and 25 mg/kg respectively) increased the incidence and severity of renal tubular dilation and regeneration when compared to that in rats treated only with triamterene and hydrochlorothiazide. Dogs administered the same doses of triamterene and hydrochlorothiazide alone and in combination with penbutolol had an increase in serum alkaline phosphatase and serum alanine transferase, but there were no gross or microscopic abnormalities observed. No significant toxicologic findings were observed in rats and dogs treated with a combination of penbutolol and hydrochlorothiazide.
# Clinical Studies
- Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic blood pressures and diastolic blood pressure. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in caucasians than blacks.
# How Supplied
- Penbutolol sulfate 20 mg tablets are capsule-shaped, film-coated, yellow tablets scored on both sides and imprinted in black with “SP 22” on one side. They are supplied as follows: Bottles of 100 (NDC 52244-450-10)
## Storage
- Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F).
- Keep tightly closed and protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
(Patient Counseling Information)
# Precautions with Alcohol
- In one study, the combination of penbutolol and alcohol increased the number of errors in the eye-hand psychomotor function test.
# Brand Names
- Levatol
# Look-Alike Drug Names
There is limited information regarding Penbutolol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Levatol | |
7ebeed8eb04e04899c08b22732753a249a990fc7 | wikidoc | Vardenafil | Vardenafil
# 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
Vardenafil is a Phosphodiesterase 5 Inhibitor that is FDA approved for the treatment of treatment of erectile dysfunction. Common adverse reactions include flushing, dizziness, headache, rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Erectile Dysfunction
- General Dose Information
- Recommended starting dosage: 10 mg PO approximately 60 minutes before sexual activity.
- The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and side effects.
- The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.
- Use with Food
- Vardenafil can be taken with or without food.
- Use in Specific Populations
- Geriatrics: A starting dose of 5 mg Vardenafil should be considered in patients ≥ 65 years of age.
- Hepatic Impairment
- For patients with moderate hepatic impairment (Child-Pugh B)
- Starting dosage: 5 mg
- Maximum dosage: ≤ 10 mg.
- Do not use Vardenafil in patients with severe hepatic impairment (Child-Pugh C).
- Renal Impairment: Do not use Vardenafil in patients on renal dialysis.
- Concomitant Medications
- Nitrates: Concomitant use with nitrates and nitric oxide donors in any form is contraindicated.
- CYP3A4 Inhibitors: The dosage of Vardenafil may require adjustment in patients receiving potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, and clarithromycin as well as in other patients receiving moderate CYP3A4 inhibitors such as erythromycin.
- For ritonavir, a single dose of 2.5 mg Vardenafil should not be exceeded in a 72-hour period.
- For indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily,
- For itraconazole: 400 mg daily
- For clarithromycin: ≤ 2.5 mg PO qd.
- For ketoconazole: 200 mg/day
- For itraconazole: 200 mg/day
- For erythromycin: ≤5 mg PO qd
- Alpha-Blockers: In those patients who are stable on alpha-blocker therapy, phosphodiesterase type 5 (PDE5) inhibitors should be initiated at the lowest recommended starting dose. Concomitant treatment should be initiated only if the patient is stable on his alpha-blocker therapy. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a phosphodiesterase (PDE5) inhibitor including vardenafil. In those patients who are stable on alpha-blocker therapy, Vardenafil should be initiated at a dose of 5 mg (2.5 mg when used concomitantly with certain CYP3A4 inhibitors).
- A time interval between dosing should be considered when Vardenafil is prescribed concomitantly with alpha-blocker therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vardenafil in adult patients.
### Non–Guideline-Supported Use
### Benign prostatic hyperplasia - Lower urinary tract symptoms
- Dosing information
- 10 mg/day ,
### Pulmonary hypertension
- Dosing information
- 5 mg PO qd for the first 4 weeks, then 5 mg PO bid ,
### Secondary Raynaud's phenomenon
- Dosing information
- 10 mg PO bid
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Vardenafil is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vardenafil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vardenafil in pediatric patients.
# Contraindications
## Nitrates
- Administration of Vardenafil with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including Vardenafil, may potentiate the hypotensive effects of nitrates. A suitable time interval following dosing of Vardenafil for the safe administration of nitrates or nitric oxide donors has not been determined.
# Warnings
- The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment.
- Before prescribing Vardenafil, it is important to note the following:
## Cardiovascular Effects
### General
- Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including Vardenafil, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status.
- There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of less than 90 mmHg); uncontrolled hypertension (greater than 170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.
### Left Ventricular Outflow Obstruction
- Patients with left ventricular outflow obstruction, (for example, aortic stenosis and idiopathic hypertrophic sub aortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.
### Blood Pressure Effects
- Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic). While this normally would be expected to be of little consequence in most patients, prior to prescribing Vardenafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.
## Potential for Drug Interactions with Potent or Moderate CYP3A4 Inhibitors
- Concomitant administration with potent CYP3A4 inhibitors (such as ritonavir, indinavir, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil. Dosage adjustment is necessary when Vardenafil is administered with certain CYP3A4 inhibitors .
Long-term safety information is not available on the concomitant administration of vardenafil with HIV protease inhibitors.
## Risk of Priapism
- There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including vardenafil. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
- Vardenafil should be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
## Effects on the Eye
- Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Vardenafil, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
- Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including Vardenafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Vardenafil, for this uncommon condition.
- Vardenafil has not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.
## Sudden Hearing Loss
- Physicians should advise patients to stop taking all PDE5 inhibitors, including Vardenafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
## Alpha-Blockers
- Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Vardenafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Consideration should be given to the following:
- Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
- In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose.
- In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.
- Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.
## Congenital or Acquired QT Prolongation
- In a study of the effect of Vardenafil on QT interval in 59 healthy males , therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QTc interval. A postmarketing study evaluating the effect of combining Vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone. These observations should be considered in clinical decisions when prescribing Vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.
- Patients taking Class 1A (for example. quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using Vardenafil.
## Hepatic Impairment
- Dosage adjustment is necessary in patients with moderate hepatic impairment (Child-Pugh B). Do not use Vardenafil in patients with severe (Child-Pugh C) hepatic impairment.
## Renal Impairment
- Do not use Vardenafil in patients on renal dialysis, as vardenafil has not been evaluated in this population.
## Combination with Other Erectile Dysfunction Therapies
- The safety and efficacy of Vardenafil used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
## Effects on Bleeding
- In humans, vardenafil alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin. Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore Vardenafil should be administered to these patients after careful benefit-risk assessment.
## Sexually Transmitted Disease
- The use of Vardenafil offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.
# 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.
- Vardenafil was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year.
In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for Vardenafil compared to 1.1% for placebo.
When Vardenafil was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1).
- Back pain was reported in 2.0% of patients treated with Vardenafil and 1.7% of patients on placebo.
Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of Vardenafil.
All Vardenafil Studies: Vardenafil film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18–89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.
In the placebo-controlled clinical trials for Vardenafil film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo.
- The following section identifies additional, less frequent adverse reactions (less than 2%) reported during the clinical development of Vardenafil film-coated tablets and vardenafil orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:
Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain
Auditory: tinnitus, vertigo
Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension
Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophagea reflux disease, gastritis, vomiting, increase in transaminases
Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia
Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure
Respiratory: dyspnea, sinus congestion
Skin and appendages: erythema, rash
Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis
Urogenital: increase in erection, priapism
## Postmarketing Experience
The following adverse reactions have been identified during post approval use of Vardenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.
Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil.
Neurologic: Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil.
Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors
# Drug Interactions
## Potential for Pharmacodynamic Interactions with Vardenafil
Nitrates: Concomitant use of Vardenafil and nitrates and nitric oxide donors is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of Vardenafil in healthy middle-aged subjects. These effects were not observed when Vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of Vardenafil and nitrates is contraindicated.
Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Vardenafil and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin.
Antihypertensives: Vardenafil may add to the blood pressure lowering effects of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.
Alcohol: Vardenafil (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.
## Effect of Other Drugs on Vardenafil
### In vitro studies
- Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance.
### In vivo studies
- Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (Cmax) when co-administered with Vardenafil (5 mg) in healthy volunteers. A 5-mg Vardenafil dose should not be exceeded in a 24-hour period when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in Cmax and AUC, a single 2.5 mg dose of Vardenafil should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily.
- Indinavir (800 mg t.i.d.) co-administered with Vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg Vardenafil dose in a 24-hour period when used in combination with indinavir.
- Ritonavir (600 mg b.i.d.) co-administered with Vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg Vardenafil dose in a 72-hour period when used in combination with ritonavir.
### Moderate CYP3A4 inhibitors
- Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with Vardenafil 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of Vardenafil in a 24-hour period when used in combination with erythromycin.
Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.
### Other Drug Interactions
- No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (Cmax) of vardenafil when co-administered with 20 mg Vardenafil in healthy volunteers.
## Effects of Vardenafil on Other Drugs
### In vitro studies
- Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki greater than 100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg vardenafil dose.
### In vivo studie
Nifedipine:Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of Vardenafil when taken in combination. In these patients whose hypertension was controlled with nifedipine, Vardenafil 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.
Ritonavir and Indinavir: Upon concomitant administration of 5 mg of Vardenafil with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Vardenafil with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.
Aspirin: Vardenafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Vardenafil is not indicated for use in women. There are no studies of Vardenafil use in pregnant women. No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the maximum recommended human dose (MRHD) of 20 mg.
- In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day. Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk. The number of living pups born to rats exposed pre- and postnatally was reduced at 60 mg/kg/day. Based on the results of the pre- and postnatal study, the developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vardenafil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vardenafil during labor and delivery.
### Nursing Mothers
- Vardenafil is not indicated for use in women. It is not known if vardenafil is excreted in human breast milk.
Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.
### Pediatric Use
- Vardenafil is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population.
### Geriatic Use
- Elderly males 65 years of age and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean Cmax and AUC were 34% and 52% higher, respectively. Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of Vardenafil 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg Vardenafil should be considered in patients ≥65 years of age.
### Gender
There is no FDA guidance on the use of Vardenafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vardenafil with respect to specific racial populations.
### Renal Impairment
- Do not use Vardenafil in patients on renal dialysis as vardenafil has not been evaluated in such patients.
No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. In male volunteers with CLcr = 50-80 ml/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30-50 mL/min or CLcr less than 30 mL/min, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with CLcr greater than 80 mL/min.
### Hepatic Impairment
Dosage adjustment is necessary in patients with moderate hepatic impairment.
Do not use Vardenafil in patients with severe hepatic impairment (Child-Pugh C). Vardenafil has not been evaluated in this patient population.
A starting dose of 5 mg is recommended in patients with moderate hepatic impairment (Child-Pugh B) and the maximum dose should not exceed 10 mg. In volunteers with moderate hepatic impairment, the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects.
- In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. No dosage adjustment is necessary in patients with mild hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vardenafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vardenafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Vardenafil contains no information regarding drug monitoring.
# IV Compatibility
FDA Package Insert for Vardenafil contains no information regarding IV compatibility.
# Overdosage
- The maximum dose of Vardenafil for which human data are available is a single 120 mg dose administered to healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.” Single doses up to 80 mg vardenafil and multiple doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing serious adverse side effects.
When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed. No muscle or neurological toxicity was identified.
In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.
# Pharmacology
## Mechanism of Action
- Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.
In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).
## Structure
- Vardenafil is administered orally for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Vardenafil HCl is designated chemically as piperazine, 1-3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo5,1-f 1,2,4-triazin-2-yl)-4-ethoxyphenylsulfonyl-4-ethyl-, monohydrochloride and has the following structural formula:
- Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.
Vardenafil is formulated as orange, round, film-coated tablets with “BAYER” cross debossed on one side and “2.5”, “5”, “10”, and “20” on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
## Pharmacodynamics
## Effects on Blood Pressure
- In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents.
## Effects on Blood Pressure and Heart Rate when Vardenafil is Combined with Nitrates
- A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with Vardenafil 20 mg at various times before NTG administration. Vardenafil 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when Vardenafil 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when Vardenafil 20 mg was dosed 24 hours before NTG. (See Figure 1.)
- Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated.
## Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment
- Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment, consisting of alfuzosin, tamsulosin or terazosin.
Study 1: This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For blood pressure (BP) results see Table 2. One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of less than 85 mmHg. A decrease in standing SBP of greater than 30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP less than 85 mmHg and one patient had a decrease in SBP of greater than 30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.
- Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours are shown in Figure 2. Blood pressure effects (standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours, are shown in Figure 3.
- Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1)
- Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1)
- Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23) on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks. The design was a randomized, double blind, two-period cross-over study. Vardenafil or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For BP results see Table 3. One patient experienced a decrease from baseline in standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood pressure values (standing SBP less than 85 mmHg or decrease from baseline in standing SBP of greater than 30 mmHg). Three patients reported dizziness following vardenafil 20 mg. There were no cases of syncope.
- Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4.
- Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg (Stage 1), vardenafil 20 mg (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 2)
Study 3: This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a randomized, double blind, 3-period cross-over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo. For BP results see Table 4.
- One patient experienced decreases from baseline in standing systolic blood pressure >30 mm Hg after administration of vardenafil 5 mg film-coated tablet and vardenafil 10 mg film-coated tablet. No instances of standing systolic blood pressure <85 mm Hg were observed during this study. Four patients, one dosed with placebo, two dosed with vardenafil 5 mg film-coated tablets and one dosed with vardenafil 10 mg film-coated tablets, reported dizziness. Blood pressure effects (standing SBP) in normotensive men on a stable dose of alfuzosin 10 mg following administration of vardenafil 5 mg, vardenafil 10 mg, or placebo separated by 4 hours, are shown in Figure 5.
Blood pressure effects in normotensive men after forced titration with alpha-blockers:
- Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy normotensive volunteers (age range, 45-74 years) were performed after forced titration of the alpha-blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects receiving tamsulosin. Instances of outlier blood pressure values (defined as standing SBP less than 85 mmHg and/or a decrease from baseline of standing SBP greater than 30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP <85 mmHg given vardenafil and terazosin to achieve simultaneous Tmax led to early termination of that arm of the study. In most (7/8) of these subjects, instances of standing SBP <85 mmHg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil and terazosin were given to achieve simultaneous Tmax than when dosing was administered to separate Tmax by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and vardenafil. Seven subjects experienced dizziness mainly occurring with simultaneous Tmaxadministration of tamsulosin. There were no cases of syncope.
## Effects on Cardiac Electrophysiology
- The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males (81% White, 12% Black, 7% Hispanic) aged 45-60 years. The QT interval was measured at one hour post dose because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of Vardenafil (four times the highest recommended dose) was chosen because this dose yields plasma concentrations covering those observed upon co-administration of a low-dose of Vardenafil (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with vardenafil. Table 6 summarizes the effect on mean uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia and a linear individual correction method) at one hour post-dose. No single correction method is known to be more valid than the other. In this study, the mean increase in heart rate associated with a 10 mg dose of Vardenafil compared to placebo was 5 beats/minute and with an 80 mg dose of Vardenafil the mean increase was 6 beats/minute.
- Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced similar increases in QTc interval. This study, however, was not designed to make direct statistical comparisons between the drug or the dose levels. The clinical impact of these QTc changes is unknown.
- In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg Vardenafil resulted in a placebo-subtracted mean change from baseline of QTcF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When Vardenafil 10mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11). The clinical impact of these QT changes is unknown.
## Effects on Exercise Treadmill Test in Patients with Coronary Artery Disease (CAD):
- In two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively, vardenafil did not alter the total treadmill exercise time compared to placebo. The patient population included men aged 40-80 years with stable exercise-induced angina documented by at least one of the following: 1) prior history of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear perfusion study.
- Results of these studies showed that Vardenafil did not alter the total treadmill exercise time compared to placebo (10 mg Vardenafil vs. placebo: 433±109 and 426±105 seconds, respectively; 20 mg Vardenafil vs. placebo: 414±114 and 411±124 seconds, respectively). The total time to angina was not altered by Vardenafil when compared to placebo (10 mg Vardenafil vs. placebo: 291±123 and 292±110 seconds; 20 mg Vardenafil vs. placebo: 354±137 and 347±143 seconds, respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both the 10 mg and the 20 mg Vardenafil groups (10 mg Vardenafil vs. placebo: 380±108 and 334±108 seconds; 20 mg Vardenafil vs. placebo: 364±101 and 366±105 seconds, respectively).
## Effects on Eye
- Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration. In a single dose study in 25 normal males, Vardenafil 40 mg, twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings.
- In another double-blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo to 52 males. Thirty-two (32) males (62%) of the patients completed the trial. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. The trial was designed to detect changes in retinal function that might occur in more than 10% of patients. Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia (objects appear blue).
## Effects on Sperm Motility/Morphology
- There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in healthy volunteers.
## Pharmacokinetics
- The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range.
## Absorption
- Mean vardenafil plasma concentrations measured after the administration of a single oral dose of 20 mg to healthy male volunteers are depicted in Figure 8.
- Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasma concentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in Cmax by 18%-50%.
## Distribution
- The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.
- Following a single oral dose of 20 mg vardenafil in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.
## Metabolism
- Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.
## Excretion
- The total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite (M1) is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).
## Pharmacokinetics in Specific Populations
### Pediatrics
- Vardenafil is not indicated for use in pediatric patients. Vardenafil trials were not conducted in the pediatric population.
### Geriatric
- In a healthy volunteer study of elderly males (≥65 years) and younger males (18–45 years), mean Cmax and AUC were 34% and 52% higher, respectively, in the elderly males.
### Hepatic Impairment
- In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.
### Renal Impairment
- In male volunteers with CLcr = 50–80 mL/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30–50 mL/min or CLcr80 mL/min). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
### Carcinogenesis
- Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were approximately 400- and 170-fold for male and female rats, respectively, and 21- and 37-fold for male and female mice, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg.
### Mutagenesis
- Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V79 cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivomouse micronucleus test.
### Impairment of Fertility
- Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28 days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.
# Clinical Studies
- Vardenafil was evaluated in four major double-blind, randomized, placebo-controlled, fixed-dose, parallel design, multicenter trials in 2431 men aged 20-83 (mean age 57 years; 78% White, 7% Black, 2% Asian, 3% Hispanic and 10% Other/Unknown). The doses of Vardenafil in these studies were 5 mg, 10 mg, and 20 mg. Two of these trials were conducted in the general erectile dysfunction (ED) population and two in special ED populations (one in patients with diabetes mellitus and one in post-prostatectomy patients). Vardenafil was dosed without regard to meals on an as needed basis in men with ED, many of whom had multiple other medical conditions. The primary endpoints were assessed at 3 months.
- Primary efficacy assessment in all four major trials was by means of the Erectile Function (EF) Domain score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3).
- In all four fixed-dose efficacy trials, Vardenafil showed clinically meaningful and statistically significant improvement in the EF Domain, SEP2, and SEP3 scores compared to placebo. The mean baseline EF Domain score in these trials was 11.8 (scores range from 0-30 where lower scores represent more severe disease). Vardenafil (5 mg, 10 mg, and 20 mg) was effective in all age categories (<45, 45 to <65, and ≥65 years) and was also effective regardless of race (White, Black, Other).
## Trials in a General Erectile Dysfunction Population
- In the major North American fixed-dose trial, 762 patients (mean age 57, range 20-83 years; 79% White, 13% Black, 4% Hispanic, 2% Asian and 2% Other) were evaluated. The mean baseline EF Domain scores were 13, 13, 13, 14 for the Vardenafil 5 mg, 10 mg, 20 mg and placebo groups, respectively. There was significant improvement (p <0.0001) at 3 months with Vardenafil (EF Domain scores of 18, 21, 21, for the 5 mg, 10 mg, and 20 mg dose groups, respectively) compared to the placebo group (EF Domain score of 15). The European trial (total N=803) confirmed these results. The improvement in mean score was maintained at all doses at 6 months in the North American trial.
- In the North American trial, Vardenafil significantly improved the rates of achieving an erection sufficient for penetration (SEP2) at doses of 5 mg, 10 mg, and 20 mg compared to placebo (65%, 75%, and 80%, respectively, compared to a 52% response in the placebo group at 3 months; p <0.0001). The European trial confirmed these results.
- Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (51% on 5 mg, 64% on 10 mg, and 65% on 20 mg, respectively, compared to 32% on placebo; p <0.0001) at 3 months in the North American trial. The European trial showed comparable efficacy. This improvement in mean score was maintained at all doses at 6 months in the North American trial.
## Trial in Patients with ED and Diabetes Mellitus
- Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose (10 and 20 mg Vardenafil), double-blind, placebo-controlled trial of patients with diabetes mellitus (n=439; mean age 57 years, range 33-81; 80% White, 9% Black, 8% Hispanic, and 3% Other).
- Significant improvements in the EF Domain were shown in this study (EF Domain scores of 17 on 10 mg Vardenafil and 19 on 20 mg Vardenafil compared to 13 on placebo; p <0.0001).
- Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (61% on 10 mg and 64% on 20 mg Vardenafil compared to 36% on placebo; p <0.0001).
- Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (49% on 10 mg, 54% on 20 mg Vardenafil compared to 23% on placebo; p <0.0001).
## Trial in Patients with ED after Radical Prostatectomy
- Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose (10 and 20 mg Vardenafil), double-blind, placebo-controlled trial in post-prostatectomy patients (n=427, mean age 60, range 44-77 years; 93% White, 5% Black, 2% Other).
- Significant improvements in the EF Domain were shown in this study (EF Domain scores of 15 on 10 mg Vardenafil and 15 on 20 mg Vardenafil compared to 9 on placebo; p <0.0001).
- Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (47% on 10 mg and 48% on 20 mg Vardenafil compared to 22% on placebo; p <0.0001).
- Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (37% on 10 mg, 34% on 20 mg Vardenafil compared to 10% on placebo; p<0.0001).
# How Supplied
- Vardenafil (vardenafil HCl) is formulated as orange, film-coated round tablets with debossed “BAYER” cross on one side and “2.5”, “5”, “10”, and “20” on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively.
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
“See FDA-approved patient labeling (Patient Information)”
Nitrates
- Physicians should discuss with patients the contraindication of Vardenafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of Vardenafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Cardiovascular
- Physicians should discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.
Concomitant Use with Drugs which Lower Blood Pressure
- Physicians should inform their patients that in some patients concomitant use of PDE5 inhibitors, including Vardenafil, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Patients prescribed Vardenafil who are taking alpha-blockers should be started on the lowest recommended starting dose of Vardenafil. Patients should be advised of the possible occurrence of symptoms related to postural hypotension and appropriate countermeasures. Patients should be advised to contact the prescribing physician if other anti-hypertensive drugs or new medications that may interact with Vardenafil are prescribed by another healthcare provider.
Recommended Administration
- Physicians should discuss with patients the appropriate use of Vardenafil and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking Vardenafil. Vardenafil should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of Vardenafil especially regarding the maximum daily dose. Patients should be advised to contact their healthcare provider for dose modification if they are not satisfied with the quality of their sexual performance with Vardenafil or in the case of an unwanted effect.
Priapism
- Physicians should inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for Vardenafil and this class of compounds. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Drug Interactions
- Patients should be advised to contact the prescribing physician if new medications that may interact with Vardenafil are prescribed by another healthcare provider.
Sudden Loss of Vision
- Physicians should advise patients to stop use of all PDE5 inhibitors, including Vardenafil, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including Vardenafil, for this uncommon condition.
Sudden Hearing Loss
- Physicians should advise patients to stop taking PDE5 inhibitors, including Vardenafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
Sexually Transmitted Disease
- The use of Vardenafil offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.
Dose Adjustment
- Inform patients that the recommended starting dose of Vardenafil is 10 mg. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and tolerability. The maximum recommended dosing frequency is one tablet per day.
FDA-approved patient labeling
Vardenafil® (Luh-VEE-Trah)
(vardenafil HCl) Tablets
- Read the Patient Information about Vardenafil before you start taking it and again each time you get a refill. There may be new information. You may also find it helpful to share this information with your partner. This leaflet does not take the place of talking with your doctor. You and your doctor should talk about Vardenafil when you start taking it and at regular checkups. If you do not understand the information, or have questions, talk with your doctor or pharmacist.
### WHAT IMPORTANT INFORMATION SHOULD YOU KNOW ABOUT Vardenafil?
Vardenafil can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. With a sudden drop in blood pressure, you could get dizzy, faint, or have a heart attack or stroke.
Do not take Vardenafil if you:
- Take any medicines called “nitrates” (often used to control chest pain, also known as angina).
- Use recreational drugs called “poppers” like amyl nitrate and butyl nitrate.
(See "Who Should Not Take Vardenafil?")
- Tell all your healthcare providers that you take Vardenafil. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took Vardenafil.
### WHAT IS Vardenafil?
- Vardenafil is a prescription medicine taken by mouth for the treatment of erectile dysfunction (ED) in men.
- ED is a condition where the penis does not harden and expand when a man is sexually excited, or when he cannot keep an erection. A man who has trouble getting or keeping an erection should see his doctor for help if the condition bothers him. Vardenafil may help a man with ED get and keep an erection when he is sexually excited.
### Vardenafil does not:
- Cure ED
- Increase a man’s sexual desire
- Protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your doctor about ways to guard against sexually transmitted diseases.
- Serve as a male form of birth control.
- Vardenafil is only for men with ED. Vardenafil is not for women or children. Vardenafil must be used only under a doctor’s care.
### HOW DOES Vardenafil WORK?
- When a man is sexually stimulated, his body’s normal physical response is to increase blood flow to his penis. This results in an erection. Vardenafil helps increase blood flow to the penis and may help men with ED get and keep an erection satisfactory for sexual activity. Once a man has completed sexual activity, blood flow to his penis decreases, and his erection goes away.
### WHO CAN TAKE Vardenafil?
- Talk to your doctor to decide if Vardenafil is right for you.
- Vardenafil has been shown to be effective in men over the age of 18 years who have erectile dysfunction, including men with diabetes or who have undergone prostatectomy.
### WHO SHOULD NOT TAKE Vardenafil?
- Do not take Vardenafil if you:
- Take any medicines called “nitrates” (See “What important information should you know about Vardenafil?”). Nitrates are commonly used to treat angina. Angina is a symptom of heart disease and can cause pain in your chest, jaw, or down your arm.
- Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide mononitrate. Some recreational drugs called “poppers” also contain nitrates, such as amyl nitrate and butyl nitrate. Do not use Vardenafil if you are using these drugs. Ask your doctor or pharmacist if you are not sure if any of your medicines are nitrates.
- Have been told by your healthcare provider to not have sexual activity because of health problems. Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease.
### WHAT SHOULD YOU DISCUSS WITH YOUR DOCTOR BEFORE TAKING Vardenafil?
- Before taking Vardenafil, tell your doctor about all your medical problems, including if you:
1.Have heart problems such as angina, heart failure, irregular heartbeats, or have had a heart attack. Ask your doctor if it is safe for you to have sexual activity.
2.Have low blood pressure or have high blood pressure that is not controlled.
3.Have had a stroke.
4.Have had a seizure.
5.Or any family members have a rare heart condition known as prolongation of the QT interval (long QT syndrome).
6.Have liver problems.
7.Have kidney problems and require dialysis.
8.Have retinitis pigmentosa, a rare genetic (runs in families) eye disease
9.Have ever had severe vision loss, or if you have an eye condition called non-arteritic anterior ischemic optic neuropathy (NAION).
10.Have stomach ulcers.
11.Have a bleeding problem.
12.Have a deformed penis shape or Peyronie’s disease.
13.Have had an erection that lasted more than 4 hours.
14.Have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia.
15.Have hearing problems.
### CAN OTHER MEDICATIONS AFFECT Vardenafil?
- Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Vardenafil and other medicines may affect each other. Always check with your doctor before starting or stopping any medicines. Especially tell your doctor if you take any of the following:
- Medicines called nitrates (see “What important information should you know about Vardenafil?”).
- Ketoconazole or itraconazole (such as Nizoral® or Sporanox®).
- Ritonavir (Norvir®) or indinavir sulfate (Crixivan®) saquinavir (Fortavase® or Invirase®) or atazanavir (Reyataz®).
- Erythromycin or clarithromycin.
- Medicines called alpha-blockers. These include Hytrin® (terazosin HCl), Flomax® (tamsulosin HCl), Cardura® (doxazosin mesylate), Minipress® (prazosin HCl), Rapaflo® (silodosin) or Uroxatral® (alfuzosin HCl). Alpha-blockers are sometimes prescribed for prostate problems or high blood pressure. In some patients the use of PDE5 inhibitor drugs, including Vardenafil, with alpha-blockers can lower blood pressure significantly leading to fainting. You should contact the prescribing physician if alpha-blockers or other drugs that lower blood pressure are prescribed by another healthcare provider.
- Medicines that treat abnormal heartbeat. These include quinidine, procainamide, amiodarone and sotalol.
- Other medicines or treatments for ED.
### HOW SHOULD YOU TAKE Vardenafil
Take Vardenafil exactly as your doctor prescribes. Do not take more than one Vardenafil a day. Doses should be taken at least 24 hours apart. Some men can only take a low dose of Vardenafil because of medical conditions or medicines they take. Your doctor will prescribe the dose that is right for you.
- If you are older than 65 or have liver problems, your doctor may start you on a lower dose of Vardenafil.
- If you have prostate problems or high blood pressure, for which you take medicines called alpha-blockers, your doctor may start you on a lower dose of Vardenafil.
- If you are taking certain other medicines your doctor may prescribe a lower starting dose and limit you to one dose of Vardenafil in a 72-hour (3 days) period.
Take 1 Vardenafil tablet about 1 hour (60 minutes) before sexual activity. Some form of sexual stimulation is needed for an erection to happen with Vardenafil. Vardenafil may be taken with or without meals.
Do not change your dose of Vardenafil without talking to your doctor. Your doctor may lower your dose or raise your dose, depending on how your body reacts to Vardenafil.
Call your doctor or emergency room immediately if you accidentally took more Vardenafil than prescribed.
### WHAT ARE THE POSSIBLE SIDE EFFECTS OF Vardenafil?
The most common side effects with Vardenafil are headache, flushing, stuffy or runny nose, indigestion, upset stomach, dizziness or back pain. These side effects usually go away after a few hours. Call your doctor if you get a side effect that bothers you or one that will not go away.
Vardenafil may uncommonly cause:
- An erection that won’t go away (priapism). If you get an erection that lasts more than 4 hours, get medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to your penis including the inability to have erections.
- Color vision changes, such as seeing a blue tinge to objects or having difficulty telling the difference between the colors blue and green.
In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including Vardenafil) reported a sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including Vardenafil, and call a doctor right away.
Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including Vardenafil. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking Vardenafil and contact a doctor right away.
These are not all the side effects of Vardenafil. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
### HOW SHOULD Vardenafil BE STORED?
Store Vardenafil at room temperature between 59–86° F (15–30° C).
Keep Vardenafil and all medicines out of the reach of children.
### GENERAL INFORMATION ABOUT Vardenafil
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Vardenafil for a condition for which it was not prescribed. Do not give Vardenafil to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about Vardenafil. If you would like more information, talk with your healthcare provider. You can ask your doctor or pharmacist for information about Vardenafil that is written for health professionals.
For more information you can also visit www.Vardenafil.com, or call 1-866-Vardenafil.
### WHAT ARE THE INGREDIENTS OF Vardenafil?
Active Ingredient: vardenafil hydrochloride
Inactive Ingredients: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Products cited in Vardenafil USPI
Norvir (ritonavir) is a trademark of Abbott Laboratories
Crixivan (indinavir sulfate) is a trademark of Merck & Co., Inc.
Invirase or Fortavase (saquinavir mesylate) is a trademark of Roche Laboratories Inc.
Reyataz (atazanavir sulfate) is a trademark of Bristol-Myers Squibb Company
Nizoral (ketoconazole) is a trademark of Johnson & Johnson
Sporanox (itraconazole) is a trademark of Johnson & Johnson
Hytrin (terazosin HCl) is a trademark of Abbott Laboratories
Flomax (tamsulosin HCl) is a trademark of Yamanouchi Pharmaceutical Co., Ltd.
Cardura (doxazosin mesylate) is a trademark of Pfizer Inc.
Minipress (prazosin HCl) is a trademark of Pfizer Inc.
Rapaflo (silodosin) is a trademark of Watson Pharma Inc.
Uroxatral (alfuzosin HCl) is a trademark of Sanofi-Synthelabo
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
Distributed by:
GlaxoSmithKline
Research Triangle Park
NC 27709
Vardenafil is a registered trademark of Bayer Pharma AG and is used under license by GlaxoSmithKline.
Rx Only
# Precautions with Alcohol
Alcohol-Vardenafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Levitra
- Staxyn
# Look-Alike Drug Names
There is limited information about the look-alike names.
# Drug Shortage Status
# Price | Vardenafil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3]
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# Overview
Vardenafil is a Phosphodiesterase 5 Inhibitor that is FDA approved for the treatment of treatment of erectile dysfunction. Common adverse reactions include flushing, dizziness, headache, rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Erectile Dysfunction
- General Dose Information
- Recommended starting dosage: 10 mg PO approximately 60 minutes before sexual activity.
- The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and side effects.
- The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.
- Use with Food
- Vardenafil can be taken with or without food.
- Use in Specific Populations
- Geriatrics: A starting dose of 5 mg Vardenafil should be considered in patients ≥ 65 years of age.
- Hepatic Impairment
- For patients with moderate hepatic impairment (Child-Pugh B)
- Starting dosage: 5 mg
- Maximum dosage: ≤ 10 mg.
- Do not use Vardenafil in patients with severe hepatic impairment (Child-Pugh C).
- Renal Impairment: Do not use Vardenafil in patients on renal dialysis.
- Concomitant Medications
- Nitrates: Concomitant use with nitrates and nitric oxide donors in any form is contraindicated.
- CYP3A4 Inhibitors: The dosage of Vardenafil may require adjustment in patients receiving potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, and clarithromycin as well as in other patients receiving moderate CYP3A4 inhibitors such as erythromycin.
- For ritonavir, a single dose of 2.5 mg Vardenafil should not be exceeded in a 72-hour period.
- For indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily,
- For itraconazole: 400 mg daily
- For clarithromycin: ≤ 2.5 mg PO qd.
- For ketoconazole: 200 mg/day
- For itraconazole: 200 mg/day
- For erythromycin: ≤5 mg PO qd
- Alpha-Blockers: In those patients who are stable on alpha-blocker therapy, phosphodiesterase type 5 (PDE5) inhibitors should be initiated at the lowest recommended starting dose. Concomitant treatment should be initiated only if the patient is stable on his alpha-blocker therapy. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a phosphodiesterase (PDE5) inhibitor including vardenafil. In those patients who are stable on alpha-blocker therapy, Vardenafil should be initiated at a dose of 5 mg (2.5 mg when used concomitantly with certain CYP3A4 inhibitors).
- A time interval between dosing should be considered when Vardenafil is prescribed concomitantly with alpha-blocker therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vardenafil in adult patients.
### Non–Guideline-Supported Use
### Benign prostatic hyperplasia - Lower urinary tract symptoms
- Dosing information
- 10 mg/day [1], [2]
### Pulmonary hypertension
- Dosing information
- 5 mg PO qd for the first 4 weeks, then 5 mg PO bid [3], [4]
### Secondary Raynaud's phenomenon
- Dosing information
- 10 mg PO bid [5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Vardenafil is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vardenafil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vardenafil in pediatric patients.
# Contraindications
## Nitrates
- Administration of Vardenafil with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including Vardenafil, may potentiate the hypotensive effects of nitrates. A suitable time interval following dosing of Vardenafil for the safe administration of nitrates or nitric oxide donors has not been determined.
# Warnings
- The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment.
- Before prescribing Vardenafil, it is important to note the following:
## Cardiovascular Effects
### General
- Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including Vardenafil, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status.
- There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of less than 90 mmHg); uncontrolled hypertension (greater than 170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.
### Left Ventricular Outflow Obstruction
- Patients with left ventricular outflow obstruction, (for example, aortic stenosis and idiopathic hypertrophic sub aortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.
### Blood Pressure Effects
- Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic). While this normally would be expected to be of little consequence in most patients, prior to prescribing Vardenafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.
## Potential for Drug Interactions with Potent or Moderate CYP3A4 Inhibitors
- Concomitant administration with potent CYP3A4 inhibitors (such as ritonavir, indinavir, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil. Dosage adjustment is necessary when Vardenafil is administered with certain CYP3A4 inhibitors .
Long-term safety information is not available on the concomitant administration of vardenafil with HIV protease inhibitors.
## Risk of Priapism
- There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including vardenafil. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
- Vardenafil should be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
## Effects on the Eye
- Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Vardenafil, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
- Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including Vardenafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Vardenafil, for this uncommon condition.
- Vardenafil has not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.
## Sudden Hearing Loss
- Physicians should advise patients to stop taking all PDE5 inhibitors, including Vardenafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
## Alpha-Blockers
- Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Vardenafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Consideration should be given to the following:
- Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
- In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose.
- In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.
- Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.
## Congenital or Acquired QT Prolongation
- In a study of the effect of Vardenafil on QT interval in 59 healthy males [see Clinical Pharmacology (12.2)], therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QTc interval. A postmarketing study evaluating the effect of combining Vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone. These observations should be considered in clinical decisions when prescribing Vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.
- Patients taking Class 1A (for example. quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using Vardenafil.
## Hepatic Impairment
- Dosage adjustment is necessary in patients with moderate hepatic impairment (Child-Pugh B). Do not use Vardenafil in patients with severe (Child-Pugh C) hepatic impairment.
## Renal Impairment
- Do not use Vardenafil in patients on renal dialysis, as vardenafil has not been evaluated in this population.
## Combination with Other Erectile Dysfunction Therapies
- The safety and efficacy of Vardenafil used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
## Effects on Bleeding
- In humans, vardenafil alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin. Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore Vardenafil should be administered to these patients after careful benefit-risk assessment.
## Sexually Transmitted Disease
- The use of Vardenafil offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.
# 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.
- Vardenafil was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year.
In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for Vardenafil compared to 1.1% for placebo.
When Vardenafil was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1).
- Back pain was reported in 2.0% of patients treated with Vardenafil and 1.7% of patients on placebo.
Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of Vardenafil.
All Vardenafil Studies: Vardenafil film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18–89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.
In the placebo-controlled clinical trials for Vardenafil film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo.
- The following section identifies additional, less frequent adverse reactions (less than 2%) reported during the clinical development of Vardenafil film-coated tablets and vardenafil orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:
Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain
Auditory: tinnitus, vertigo
Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension
Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophagea reflux disease, gastritis, vomiting, increase in transaminases
Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia
Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure
Respiratory: dyspnea, sinus congestion
Skin and appendages: erythema, rash
Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis
Urogenital: increase in erection, priapism
## Postmarketing Experience
The following adverse reactions have been identified during post approval use of Vardenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.
Ophthalmologic: Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil.
Neurologic: Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil.
Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors
# Drug Interactions
## Potential for Pharmacodynamic Interactions with Vardenafil
Nitrates: Concomitant use of Vardenafil and nitrates and nitric oxide donors is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of Vardenafil in healthy middle-aged subjects. These effects were not observed when Vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of Vardenafil and nitrates is contraindicated.
Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Vardenafil and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin.
Antihypertensives: Vardenafil may add to the blood pressure lowering effects of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.
Alcohol: Vardenafil (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.
## Effect of Other Drugs on Vardenafil
### In vitro studies
- Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance.
### In vivo studies
- Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (Cmax) when co-administered with Vardenafil (5 mg) in healthy volunteers. A 5-mg Vardenafil dose should not be exceeded in a 24-hour period when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in Cmax and AUC, a single 2.5 mg dose of Vardenafil should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily.
- Indinavir (800 mg t.i.d.) co-administered with Vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg Vardenafil dose in a 24-hour period when used in combination with indinavir.
- Ritonavir (600 mg b.i.d.) co-administered with Vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg Vardenafil dose in a 72-hour period when used in combination with ritonavir.
### Moderate CYP3A4 inhibitors
- Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with Vardenafil 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of Vardenafil in a 24-hour period when used in combination with erythromycin.
Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.
### Other Drug Interactions
- No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (Cmax) of vardenafil when co-administered with 20 mg Vardenafil in healthy volunteers.
## Effects of Vardenafil on Other Drugs
### In vitro studies
- Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki greater than 100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg vardenafil dose.
### In vivo studie
Nifedipine:Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of Vardenafil when taken in combination. In these patients whose hypertension was controlled with nifedipine, Vardenafil 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.
Ritonavir and Indinavir: Upon concomitant administration of 5 mg of Vardenafil with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Vardenafil with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.
Aspirin: Vardenafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Vardenafil is not indicated for use in women. There are no studies of Vardenafil use in pregnant women. No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the maximum recommended human dose (MRHD) of 20 mg.
- In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day. Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk. The number of living pups born to rats exposed pre- and postnatally was reduced at 60 mg/kg/day. Based on the results of the pre- and postnatal study, the developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vardenafil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vardenafil during labor and delivery.
### Nursing Mothers
- Vardenafil is not indicated for use in women. It is not known if vardenafil is excreted in human breast milk.
Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.
### Pediatric Use
- Vardenafil is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population.
### Geriatic Use
- Elderly males 65 years of age and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean Cmax and AUC were 34% and 52% higher, respectively. Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of Vardenafil 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg Vardenafil should be considered in patients ≥65 years of age.
### Gender
There is no FDA guidance on the use of Vardenafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vardenafil with respect to specific racial populations.
### Renal Impairment
- Do not use Vardenafil in patients on renal dialysis as vardenafil has not been evaluated in such patients.
No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. In male volunteers with CLcr = 50-80 ml/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30-50 mL/min or CLcr less than 30 mL/min, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with CLcr greater than 80 mL/min.
### Hepatic Impairment
Dosage adjustment is necessary in patients with moderate hepatic impairment.
Do not use Vardenafil in patients with severe hepatic impairment (Child-Pugh C). Vardenafil has not been evaluated in this patient population.
A starting dose of 5 mg is recommended in patients with moderate hepatic impairment (Child-Pugh B) and the maximum dose should not exceed 10 mg. In volunteers with moderate hepatic impairment, the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects.
- In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. No dosage adjustment is necessary in patients with mild hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vardenafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vardenafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Vardenafil contains no information regarding drug monitoring.
# IV Compatibility
FDA Package Insert for Vardenafil contains no information regarding IV compatibility.
# Overdosage
- The maximum dose of Vardenafil for which human data are available is a single 120 mg dose administered to healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.” Single doses up to 80 mg vardenafil and multiple doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing serious adverse side effects.
When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed. No muscle or neurological toxicity was identified.
In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.
# Pharmacology
## Mechanism of Action
- Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.
In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).
## Structure
- Vardenafil is administered orally for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Vardenafil HCl is designated chemically as piperazine, 1-3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo5,1-f 1,2,4-triazin-2-yl)-4-ethoxyphenylsulfonyl-4-ethyl-, monohydrochloride and has the following structural formula:
- Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.
Vardenafil is formulated as orange, round, film-coated tablets with “BAYER” cross debossed on one side and “2.5”, “5”, “10”, and “20” on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
## Pharmacodynamics
## Effects on Blood Pressure
- In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents.
## Effects on Blood Pressure and Heart Rate when Vardenafil is Combined with Nitrates
- A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with Vardenafil 20 mg at various times before NTG administration. Vardenafil 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when Vardenafil 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when Vardenafil 20 mg was dosed 24 hours before NTG. (See Figure 1.)
- Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated.
## Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment
- Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment, consisting of alfuzosin, tamsulosin or terazosin.
Study 1: This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For blood pressure (BP) results see Table 2. One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of less than 85 mmHg. A decrease in standing SBP of greater than 30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP less than 85 mmHg and one patient had a decrease in SBP of greater than 30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.
- Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours are shown in Figure 2. Blood pressure effects (standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours, are shown in Figure 3.
- Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1)
- Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1)
- Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23) on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks. The design was a randomized, double blind, two-period cross-over study. Vardenafil or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For BP results see Table 3. One patient experienced a decrease from baseline in standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood pressure values (standing SBP less than 85 mmHg or decrease from baseline in standing SBP of greater than 30 mmHg). Three patients reported dizziness following vardenafil 20 mg. There were no cases of syncope.
- Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4.
- Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg (Stage 1), vardenafil 20 mg (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 2)
Study 3: This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a randomized, double blind, 3-period cross-over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo. For BP results see Table 4.
- One patient experienced decreases from baseline in standing systolic blood pressure >30 mm Hg after administration of vardenafil 5 mg film-coated tablet and vardenafil 10 mg film-coated tablet. No instances of standing systolic blood pressure <85 mm Hg were observed during this study. Four patients, one dosed with placebo, two dosed with vardenafil 5 mg film-coated tablets and one dosed with vardenafil 10 mg film-coated tablets, reported dizziness. Blood pressure effects (standing SBP) in normotensive men on a stable dose of alfuzosin 10 mg following administration of vardenafil 5 mg, vardenafil 10 mg, or placebo separated by 4 hours, are shown in Figure 5.
Blood pressure effects in normotensive men after forced titration with alpha-blockers:
- Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy normotensive volunteers (age range, 45-74 years) were performed after forced titration of the alpha-blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects receiving tamsulosin. Instances of outlier blood pressure values (defined as standing SBP less than 85 mmHg and/or a decrease from baseline of standing SBP greater than 30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP <85 mmHg given vardenafil and terazosin to achieve simultaneous Tmax led to early termination of that arm of the study. In most (7/8) of these subjects, instances of standing SBP <85 mmHg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil and terazosin were given to achieve simultaneous Tmax than when dosing was administered to separate Tmax by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and vardenafil. Seven subjects experienced dizziness mainly occurring with simultaneous Tmaxadministration of tamsulosin. There were no cases of syncope.
## Effects on Cardiac Electrophysiology
- The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males (81% White, 12% Black, 7% Hispanic) aged 45-60 years. The QT interval was measured at one hour post dose because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of Vardenafil (four times the highest recommended dose) was chosen because this dose yields plasma concentrations covering those observed upon co-administration of a low-dose of Vardenafil (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with vardenafil. Table 6 summarizes the effect on mean uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia and a linear individual correction method) at one hour post-dose. No single correction method is known to be more valid than the other. In this study, the mean increase in heart rate associated with a 10 mg dose of Vardenafil compared to placebo was 5 beats/minute and with an 80 mg dose of Vardenafil the mean increase was 6 beats/minute.
- Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced similar increases in QTc interval. This study, however, was not designed to make direct statistical comparisons between the drug or the dose levels. The clinical impact of these QTc changes is unknown.
- In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg Vardenafil resulted in a placebo-subtracted mean change from baseline of QTcF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When Vardenafil 10mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11). The clinical impact of these QT changes is unknown.
## Effects on Exercise Treadmill Test in Patients with Coronary Artery Disease (CAD):
- In two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively, vardenafil did not alter the total treadmill exercise time compared to placebo. The patient population included men aged 40-80 years with stable exercise-induced angina documented by at least one of the following: 1) prior history of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear perfusion study.
- Results of these studies showed that Vardenafil did not alter the total treadmill exercise time compared to placebo (10 mg Vardenafil vs. placebo: 433±109 and 426±105 seconds, respectively; 20 mg Vardenafil vs. placebo: 414±114 and 411±124 seconds, respectively). The total time to angina was not altered by Vardenafil when compared to placebo (10 mg Vardenafil vs. placebo: 291±123 and 292±110 seconds; 20 mg Vardenafil vs. placebo: 354±137 and 347±143 seconds, respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both the 10 mg and the 20 mg Vardenafil groups (10 mg Vardenafil vs. placebo: 380±108 and 334±108 seconds; 20 mg Vardenafil vs. placebo: 364±101 and 366±105 seconds, respectively).
## Effects on Eye
- Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration. In a single dose study in 25 normal males, Vardenafil 40 mg, twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings.
- In another double-blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo to 52 males. Thirty-two (32) males (62%) of the patients completed the trial. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. The trial was designed to detect changes in retinal function that might occur in more than 10% of patients. Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia (objects appear blue).
## Effects on Sperm Motility/Morphology
- There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in healthy volunteers.
## Pharmacokinetics
- The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range.
## Absorption
- Mean vardenafil plasma concentrations measured after the administration of a single oral dose of 20 mg to healthy male volunteers are depicted in Figure 8.
- Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasma concentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in Cmax by 18%-50%.
## Distribution
- The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.
- Following a single oral dose of 20 mg vardenafil in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.
## Metabolism
- Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.
## Excretion
- The total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite (M1) is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).
## Pharmacokinetics in Specific Populations
### Pediatrics
- Vardenafil is not indicated for use in pediatric patients. Vardenafil trials were not conducted in the pediatric population.
### Geriatric
- In a healthy volunteer study of elderly males (≥65 years) and younger males (18–45 years), mean Cmax and AUC were 34% and 52% higher, respectively, in the elderly males.
### Hepatic Impairment
- In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.
### Renal Impairment
- In male volunteers with CLcr = 50–80 mL/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30–50 mL/min or CLcr<30 mL/min renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with CLcr>80 mL/min). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
### Carcinogenesis
- Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were approximately 400- and 170-fold for male and female rats, respectively, and 21- and 37-fold for male and female mice, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg.
### Mutagenesis
- Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V79 cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivomouse micronucleus test.
### Impairment of Fertility
- Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28 days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.
# Clinical Studies
- Vardenafil was evaluated in four major double-blind, randomized, placebo-controlled, fixed-dose, parallel design, multicenter trials in 2431 men aged 20-83 (mean age 57 years; 78% White, 7% Black, 2% Asian, 3% Hispanic and 10% Other/Unknown). The doses of Vardenafil in these studies were 5 mg, 10 mg, and 20 mg. Two of these trials were conducted in the general erectile dysfunction (ED) population and two in special ED populations (one in patients with diabetes mellitus and one in post-prostatectomy patients). Vardenafil was dosed without regard to meals on an as needed basis in men with ED, many of whom had multiple other medical conditions. The primary endpoints were assessed at 3 months.
- Primary efficacy assessment in all four major trials was by means of the Erectile Function (EF) Domain score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3).
- In all four fixed-dose efficacy trials, Vardenafil showed clinically meaningful and statistically significant improvement in the EF Domain, SEP2, and SEP3 scores compared to placebo. The mean baseline EF Domain score in these trials was 11.8 (scores range from 0-30 where lower scores represent more severe disease). Vardenafil (5 mg, 10 mg, and 20 mg) was effective in all age categories (<45, 45 to <65, and ≥65 years) and was also effective regardless of race (White, Black, Other).
## Trials in a General Erectile Dysfunction Population
- In the major North American fixed-dose trial, 762 patients (mean age 57, range 20-83 years; 79% White, 13% Black, 4% Hispanic, 2% Asian and 2% Other) were evaluated. The mean baseline EF Domain scores were 13, 13, 13, 14 for the Vardenafil 5 mg, 10 mg, 20 mg and placebo groups, respectively. There was significant improvement (p <0.0001) at 3 months with Vardenafil (EF Domain scores of 18, 21, 21, for the 5 mg, 10 mg, and 20 mg dose groups, respectively) compared to the placebo group (EF Domain score of 15). The European trial (total N=803) confirmed these results. The improvement in mean score was maintained at all doses at 6 months in the North American trial.
- In the North American trial, Vardenafil significantly improved the rates of achieving an erection sufficient for penetration (SEP2) at doses of 5 mg, 10 mg, and 20 mg compared to placebo (65%, 75%, and 80%, respectively, compared to a 52% response in the placebo group at 3 months; p <0.0001). The European trial confirmed these results.
- Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (51% on 5 mg, 64% on 10 mg, and 65% on 20 mg, respectively, compared to 32% on placebo; p <0.0001) at 3 months in the North American trial. The European trial showed comparable efficacy. This improvement in mean score was maintained at all doses at 6 months in the North American trial.
## Trial in Patients with ED and Diabetes Mellitus
- Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose (10 and 20 mg Vardenafil), double-blind, placebo-controlled trial of patients with diabetes mellitus (n=439; mean age 57 years, range 33-81; 80% White, 9% Black, 8% Hispanic, and 3% Other).
- Significant improvements in the EF Domain were shown in this study (EF Domain scores of 17 on 10 mg Vardenafil and 19 on 20 mg Vardenafil compared to 13 on placebo; p <0.0001).
- Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (61% on 10 mg and 64% on 20 mg Vardenafil compared to 36% on placebo; p <0.0001).
- Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (49% on 10 mg, 54% on 20 mg Vardenafil compared to 23% on placebo; p <0.0001).
## Trial in Patients with ED after Radical Prostatectomy
- Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose (10 and 20 mg Vardenafil), double-blind, placebo-controlled trial in post-prostatectomy patients (n=427, mean age 60, range 44-77 years; 93% White, 5% Black, 2% Other).
- Significant improvements in the EF Domain were shown in this study (EF Domain scores of 15 on 10 mg Vardenafil and 15 on 20 mg Vardenafil compared to 9 on placebo; p <0.0001).
- Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (47% on 10 mg and 48% on 20 mg Vardenafil compared to 22% on placebo; p <0.0001).
- Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (37% on 10 mg, 34% on 20 mg Vardenafil compared to 10% on placebo; p<0.0001).
# How Supplied
- Vardenafil (vardenafil HCl) is formulated as orange, film-coated round tablets with debossed “BAYER” cross on one side and “2.5”, “5”, “10”, and “20” on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively.
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
“See FDA-approved patient labeling (Patient Information)”
Nitrates
- Physicians should discuss with patients the contraindication of Vardenafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of Vardenafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Cardiovascular
- Physicians should discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.
Concomitant Use with Drugs which Lower Blood Pressure
- Physicians should inform their patients that in some patients concomitant use of PDE5 inhibitors, including Vardenafil, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Patients prescribed Vardenafil who are taking alpha-blockers should be started on the lowest recommended starting dose of Vardenafil. Patients should be advised of the possible occurrence of symptoms related to postural hypotension and appropriate countermeasures. Patients should be advised to contact the prescribing physician if other anti-hypertensive drugs or new medications that may interact with Vardenafil are prescribed by another healthcare provider.
Recommended Administration
- Physicians should discuss with patients the appropriate use of Vardenafil and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking Vardenafil. Vardenafil should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of Vardenafil especially regarding the maximum daily dose. Patients should be advised to contact their healthcare provider for dose modification if they are not satisfied with the quality of their sexual performance with Vardenafil or in the case of an unwanted effect.
Priapism
- Physicians should inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for Vardenafil and this class of compounds. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Drug Interactions
- Patients should be advised to contact the prescribing physician if new medications that may interact with Vardenafil are prescribed by another healthcare provider.
Sudden Loss of Vision
- Physicians should advise patients to stop use of all PDE5 inhibitors, including Vardenafil, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including Vardenafil, for this uncommon condition.
Sudden Hearing Loss
- Physicians should advise patients to stop taking PDE5 inhibitors, including Vardenafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
Sexually Transmitted Disease
- The use of Vardenafil offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.
Dose Adjustment
- Inform patients that the recommended starting dose of Vardenafil is 10 mg. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and tolerability. The maximum recommended dosing frequency is one tablet per day.
FDA-approved patient labeling
Vardenafil® (Luh-VEE-Trah)
(vardenafil HCl) Tablets
- Read the Patient Information about Vardenafil before you start taking it and again each time you get a refill. There may be new information. You may also find it helpful to share this information with your partner. This leaflet does not take the place of talking with your doctor. You and your doctor should talk about Vardenafil when you start taking it and at regular checkups. If you do not understand the information, or have questions, talk with your doctor or pharmacist.
### WHAT IMPORTANT INFORMATION SHOULD YOU KNOW ABOUT Vardenafil?
Vardenafil can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. With a sudden drop in blood pressure, you could get dizzy, faint, or have a heart attack or stroke.
Do not take Vardenafil if you:
- Take any medicines called “nitrates” (often used to control chest pain, also known as angina).
- Use recreational drugs called “poppers” like amyl nitrate and butyl nitrate.
(See "Who Should Not Take Vardenafil?")
- Tell all your healthcare providers that you take Vardenafil. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took Vardenafil.
### WHAT IS Vardenafil?
- Vardenafil is a prescription medicine taken by mouth for the treatment of erectile dysfunction (ED) in men.
- ED is a condition where the penis does not harden and expand when a man is sexually excited, or when he cannot keep an erection. A man who has trouble getting or keeping an erection should see his doctor for help if the condition bothers him. Vardenafil may help a man with ED get and keep an erection when he is sexually excited.
### Vardenafil does not:
- Cure ED
- Increase a man’s sexual desire
- Protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your doctor about ways to guard against sexually transmitted diseases.
- Serve as a male form of birth control.
- Vardenafil is only for men with ED. Vardenafil is not for women or children. Vardenafil must be used only under a doctor’s care.
### HOW DOES Vardenafil WORK?
- When a man is sexually stimulated, his body’s normal physical response is to increase blood flow to his penis. This results in an erection. Vardenafil helps increase blood flow to the penis and may help men with ED get and keep an erection satisfactory for sexual activity. Once a man has completed sexual activity, blood flow to his penis decreases, and his erection goes away.
### WHO CAN TAKE Vardenafil?
- Talk to your doctor to decide if Vardenafil is right for you.
- Vardenafil has been shown to be effective in men over the age of 18 years who have erectile dysfunction, including men with diabetes or who have undergone prostatectomy.
### WHO SHOULD NOT TAKE Vardenafil?
- Do not take Vardenafil if you:
- Take any medicines called “nitrates” (See “What important information should you know about Vardenafil?”). Nitrates are commonly used to treat angina. Angina is a symptom of heart disease and can cause pain in your chest, jaw, or down your arm.
- Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide mononitrate. Some recreational drugs called “poppers” also contain nitrates, such as amyl nitrate and butyl nitrate. Do not use Vardenafil if you are using these drugs. Ask your doctor or pharmacist if you are not sure if any of your medicines are nitrates.
- Have been told by your healthcare provider to not have sexual activity because of health problems. Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease.
### WHAT SHOULD YOU DISCUSS WITH YOUR DOCTOR BEFORE TAKING Vardenafil?
- Before taking Vardenafil, tell your doctor about all your medical problems, including if you:
1.Have heart problems such as angina, heart failure, irregular heartbeats, or have had a heart attack. Ask your doctor if it is safe for you to have sexual activity.
2.Have low blood pressure or have high blood pressure that is not controlled.
3.Have had a stroke.
4.Have had a seizure.
5.Or any family members have a rare heart condition known as prolongation of the QT interval (long QT syndrome).
6.Have liver problems.
7.Have kidney problems and require dialysis.
8.Have retinitis pigmentosa, a rare genetic (runs in families) eye disease
9.Have ever had severe vision loss, or if you have an eye condition called non-arteritic anterior ischemic optic neuropathy (NAION).
10.Have stomach ulcers.
11.Have a bleeding problem.
12.Have a deformed penis shape or Peyronie’s disease.
13.Have had an erection that lasted more than 4 hours.
14.Have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia.
15.Have hearing problems.
### CAN OTHER MEDICATIONS AFFECT Vardenafil?
- Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Vardenafil and other medicines may affect each other. Always check with your doctor before starting or stopping any medicines. Especially tell your doctor if you take any of the following:
- Medicines called nitrates (see “What important information should you know about Vardenafil?”).
- Ketoconazole or itraconazole (such as Nizoral® or Sporanox®).
- Ritonavir (Norvir®) or indinavir sulfate (Crixivan®) saquinavir (Fortavase® or Invirase®) or atazanavir (Reyataz®).
- Erythromycin or clarithromycin.
- Medicines called alpha-blockers. These include Hytrin® (terazosin HCl), Flomax® (tamsulosin HCl), Cardura® (doxazosin mesylate), Minipress® (prazosin HCl), Rapaflo® (silodosin) or Uroxatral® (alfuzosin HCl). Alpha-blockers are sometimes prescribed for prostate problems or high blood pressure. In some patients the use of PDE5 inhibitor drugs, including Vardenafil, with alpha-blockers can lower blood pressure significantly leading to fainting. You should contact the prescribing physician if alpha-blockers or other drugs that lower blood pressure are prescribed by another healthcare provider.
- Medicines that treat abnormal heartbeat. These include quinidine, procainamide, amiodarone and sotalol.
- Other medicines or treatments for ED.
### HOW SHOULD YOU TAKE Vardenafil
Take Vardenafil exactly as your doctor prescribes. Do not take more than one Vardenafil a day. Doses should be taken at least 24 hours apart. Some men can only take a low dose of Vardenafil because of medical conditions or medicines they take. Your doctor will prescribe the dose that is right for you.
- If you are older than 65 or have liver problems, your doctor may start you on a lower dose of Vardenafil.
- If you have prostate problems or high blood pressure, for which you take medicines called alpha-blockers, your doctor may start you on a lower dose of Vardenafil.
- If you are taking certain other medicines your doctor may prescribe a lower starting dose and limit you to one dose of Vardenafil in a 72-hour (3 days) period.
Take 1 Vardenafil tablet about 1 hour (60 minutes) before sexual activity. Some form of sexual stimulation is needed for an erection to happen with Vardenafil. Vardenafil may be taken with or without meals.
Do not change your dose of Vardenafil without talking to your doctor. Your doctor may lower your dose or raise your dose, depending on how your body reacts to Vardenafil.
Call your doctor or emergency room immediately if you accidentally took more Vardenafil than prescribed.
### WHAT ARE THE POSSIBLE SIDE EFFECTS OF Vardenafil?
The most common side effects with Vardenafil are headache, flushing, stuffy or runny nose, indigestion, upset stomach, dizziness or back pain. These side effects usually go away after a few hours. Call your doctor if you get a side effect that bothers you or one that will not go away.
Vardenafil may uncommonly cause:
- An erection that won’t go away (priapism). If you get an erection that lasts more than 4 hours, get medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to your penis including the inability to have erections.
- Color vision changes, such as seeing a blue tinge to objects or having difficulty telling the difference between the colors blue and green.
In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including Vardenafil) reported a sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including Vardenafil, and call a doctor right away.
Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including Vardenafil. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking Vardenafil and contact a doctor right away.
These are not all the side effects of Vardenafil. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
### HOW SHOULD Vardenafil BE STORED?
Store Vardenafil at room temperature between 59–86° F (15–30° C).
Keep Vardenafil and all medicines out of the reach of children.
### GENERAL INFORMATION ABOUT Vardenafil
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Vardenafil for a condition for which it was not prescribed. Do not give Vardenafil to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about Vardenafil. If you would like more information, talk with your healthcare provider. You can ask your doctor or pharmacist for information about Vardenafil that is written for health professionals.
For more information you can also visit www.Vardenafil.com, or call 1-866-Vardenafil.
### WHAT ARE THE INGREDIENTS OF Vardenafil?
Active Ingredient: vardenafil hydrochloride
Inactive Ingredients: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Products cited in Vardenafil USPI
Norvir (ritonavir) is a trademark of Abbott Laboratories
Crixivan (indinavir sulfate) is a trademark of Merck & Co., Inc.
Invirase or Fortavase (saquinavir mesylate) is a trademark of Roche Laboratories Inc.
Reyataz (atazanavir sulfate) is a trademark of Bristol-Myers Squibb Company
Nizoral (ketoconazole) is a trademark of Johnson & Johnson
Sporanox (itraconazole) is a trademark of Johnson & Johnson
Hytrin (terazosin HCl) is a trademark of Abbott Laboratories
Flomax (tamsulosin HCl) is a trademark of Yamanouchi Pharmaceutical Co., Ltd.
Cardura (doxazosin mesylate) is a trademark of Pfizer Inc.
Minipress (prazosin HCl) is a trademark of Pfizer Inc.
Rapaflo (silodosin) is a trademark of Watson Pharma Inc.
Uroxatral (alfuzosin HCl) is a trademark of Sanofi-Synthelabo
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
Distributed by:
GlaxoSmithKline
Research Triangle Park
NC 27709
Vardenafil is a registered trademark of Bayer Pharma AG and is used under license by GlaxoSmithKline.
Rx Only
# Precautions with Alcohol
Alcohol-Vardenafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Levitra
- Staxyn
# Look-Alike Drug Names
There is limited information about the look-alike names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Levitra | |
19f40d810ad62b41c3132a94331972c15e875c56 | wikidoc | Lewis acid | Lewis acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A Lewis acid (LA) can accept a pair of electrons and form a coordinate covalent bond. The Lewis acid and Lewis base theory, named after the American chemist Gilbert Lewis, is one of several acid-base reaction theories. Therefore the term acid, it self, is ambiguous; it should always be clarified as being a Lewis acid or a Brønsted-Lowry acid.
An electrophile or electron acceptor is a Lewis acid. A Lewis acid usually has a low-energy LUMO, which interacts with the HOMO of the Lewis base. Unlike a Brønsted-Lowry acid, which always transfers a hydrogen ion (H+), a Lewis acid can be any electrophile (including H+). Although all Brønsted-Lowry acids are Lewis acids, in common usage the term Lewis acid is often reserved for those Lewis acids which are not Brønsted-Lowry acids.
The reactivity of Lewis acids can be judged from the Hard-Soft Acid-Base concept. There is no universally valid description of Lewis acid strength, because Lewis acid strength depends on the specific Lewis base. One model has predicted Lewis acid strength based on a computational model of gas-phase affinity for fluoride, and out of a selection of common isolable Lewis acids they found that SbF5 had the strongest fluoride affinity. Fluoride is a "hard" Lewis base; chloride and "softer" Lewis bases are very difficult to study because of limitations of the computational methods, and Lewis acidity in solution suffers from the same restriction.
Some common Lewis acids include aluminium chloride, iron(III) chloride, boron trifluoride, niobium pentachloride and the lanthanide triflates such as ytterbium(III) triflate.
Lewis acids may be corrosive. Zinc chloride, which is corrosive, particularly towards cellulose (paper and cotton), is a notable example of Lewis acidity itself causing a corrosive effect. As water is Lewis basic, common Lewis acids react rapidly with water to give hydrates, which are Brønsted acidic. Thus, solutions of many common Lewis acids are also Brønsted acidic. Hydrates have strong chemical bonding between the Lewis acid and water, and it is usually not possible to "dry" them, i.e. the hydrate forms a separate chemical compound. For example, attempted drying of a metal chloride gives vapors of hydrogen chloride and metal oxychloride.
# Ate complexes
An ate complex is a salt formed by reaction of a Lewis acid with a base whereby the central atom increases its valence . Often in chemical nomenclature the phrase ate is suffixed to the element in question. For example, the ate complex of a boron compound is called a borate. Thus trimethylborane and methyllithium react to form the ate compound Me4B-Li+. This concept was introduced by Georg Wittig in 1958 . Similarly Lewis bases form onium salts. | Lewis acid
Template:POV-check
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A Lewis acid (LA) can accept a pair of electrons and form a coordinate covalent bond. The Lewis acid and Lewis base theory, named after the American chemist Gilbert Lewis, is one of several acid-base reaction theories. Therefore the term acid, it self, is ambiguous; it should always be clarified as being a Lewis acid or a Brønsted-Lowry acid.
An electrophile or electron acceptor is a Lewis acid. A Lewis acid usually has a low-energy LUMO, which interacts with the HOMO of the Lewis base. Unlike a Brønsted-Lowry acid, which always transfers a hydrogen ion (H+), a Lewis acid can be any electrophile (including H+). Although all Brønsted-Lowry acids are Lewis acids, in common usage the term Lewis acid is often reserved for those Lewis acids which are not Brønsted-Lowry acids.
The reactivity of Lewis acids can be judged from the Hard-Soft Acid-Base concept. There is no universally valid description of Lewis acid strength, because Lewis acid strength depends on the specific Lewis base. One model [1] has predicted Lewis acid strength based on a computational model of gas-phase affinity for fluoride, and out of a selection of common isolable Lewis acids they found that SbF5 had the strongest fluoride affinity. Fluoride is a "hard" Lewis base; chloride and "softer" Lewis bases are very difficult to study because of limitations of the computational methods, and Lewis acidity in solution suffers from the same restriction.[2]
Some common Lewis acids include aluminium chloride, iron(III) chloride, boron trifluoride, niobium pentachloride and the lanthanide triflates such as ytterbium(III) triflate.
Lewis acids may be corrosive. Zinc chloride, which is corrosive, particularly towards cellulose (paper and cotton), is a notable example of Lewis acidity itself causing a corrosive effect. As water is Lewis basic, common Lewis acids react rapidly with water to give hydrates, which are Brønsted acidic. Thus, solutions of many common Lewis acids are also Brønsted acidic. Hydrates have strong chemical bonding between the Lewis acid and water, and it is usually not possible to "dry" them, i.e. the hydrate forms a separate chemical compound. For example, attempted drying of a metal chloride gives vapors of hydrogen chloride and metal oxychloride.
# Ate complexes
An ate complex is a salt formed by reaction of a Lewis acid with a base whereby the central atom increases its valence [3]. Often in chemical nomenclature the phrase ate is suffixed to the element in question. For example, the ate complex of a boron compound is called a borate. Thus trimethylborane and methyllithium react to form the ate compound Me4B-Li+. This concept was introduced by Georg Wittig in 1958 [4]. Similarly Lewis bases form onium salts. | https://www.wikidoc.org/index.php/Lewis_acid | |
0e25daa2da9e7385296103f74913dc854faebd50 | wikidoc | Prevalence | Prevalence
# Overview
Prevalence is a measure of disease frequency which counts the total number of existing cases of disease within a population during a specified period of time. As it is a proportion, prevalence is often expressed in term of a percentage within a population.
# Epidemiologic Usage
- Prevalence rates for specific diseases are calculated from periodic health examination surveys that government agencies conduct. Annual changes in prevalence as reported in this booklet only reflect changes in the population; rates do not change until there’s a new survey. Changes in rates can only be evaluated with data from new surveys.
## Types of Prevalence
- Point prevalence measures the proportion of a population that is diseased at a single point in time. It is viewed as a "snapshot" of disease frequency associated to a specific time period.
- Period prevalence measures the proportion of a population that is diseased during a specified duration of time. Period prevalence differs from point prevalence in that it counts the number of cases that were present at the start of the defined time period and accounts for the number that develop over time. It is viewed more as a serious of snapshots of disease frequency associated to a string of time versus a single time point.
- Lifetime prevalence (LTP) is the number of individuals in a statistical population that at some point in their life (up to the time of assessment) have experienced a "case" (e.g., a disorder), compared to the total number of individuals (i.e. it is expressed as a ratio or percentage). Often, a 12-month prevalence (or some other type of "period prevalence") is used in conjunction with lifetime prevalence. There is also point prevalence, the prevalence of disorder at a more specific (a month or less) point in time. There is also a related figure lifetime morbid risk - the theoretical prevalance at any point in life for anyone, regardless of time of assessment. (example: Synopsis of article on "How Prevalent Is Schizophrenia?" from Public Library of Science)
# Critical Considerations
- Prevalence utilizes two key assumptions:
- The numerator (number of existing cases of disease) accounts for all currently living cases 'regardless of disease onset.
- The denominator (number in total population) accounts for everyone in the population studied. This includes sick, healthy, at-risk and non-at-risk.
- Prevalence, as a value, is a proportional measurement and can only between zero to one or 0-100%.
# Relationship to Incidence
- P/(1-P) = IR - D (where: P is prevalence, IR is incidence rate, and D is duration of time) | Prevalence
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-In-Chief: Kristin Feeney, B.S.
# Overview
Prevalence is a measure of disease frequency which counts the total number of existing cases of disease within a population during a specified period of time. As it is a proportion, prevalence is often expressed in term of a percentage within a population.
# Epidemiologic Usage
- Prevalence rates for specific diseases are calculated from periodic health examination surveys that government agencies conduct. Annual changes in prevalence as reported in this booklet only reflect changes in the population; rates do not change until there’s a new survey. Changes in rates can only be evaluated with data from new surveys. [1]
## Types of Prevalence
- Point prevalence measures the proportion of a population that is diseased at a single point in time. It is viewed as a "snapshot" of disease frequency associated to a specific time period.
- Period prevalence measures the proportion of a population that is diseased during a specified duration of time. Period prevalence differs from point prevalence in that it counts the number of cases that were present at the start of the defined time period and accounts for the number that develop over time. It is viewed more as a serious of snapshots of disease frequency associated to a string of time versus a single time point.
- Lifetime prevalence (LTP) is the number of individuals in a statistical population that at some point in their life (up to the time of assessment) have experienced a "case" (e.g., a disorder), compared to the total number of individuals (i.e. it is expressed as a ratio or percentage). Often, a 12-month prevalence (or some other type of "period prevalence") is used in conjunction with lifetime prevalence. There is also point prevalence, the prevalence of disorder at a more specific (a month or less) point in time. There is also a related figure lifetime morbid risk - the theoretical prevalance at any point in life for anyone, regardless of time of assessment. (example: Synopsis of article on "How Prevalent Is Schizophrenia?" from Public Library of Science)
# Critical Considerations
- Prevalence utilizes two key assumptions:
- The numerator (number of existing cases of disease) accounts for all currently living cases 'regardless of disease onset.
- The denominator (number in total population) accounts for everyone in the population studied. This includes sick, healthy, at-risk and non-at-risk.
- Prevalence, as a value, is a proportional measurement and can only between zero to one or 0-100%.
# Relationship to Incidence
- P/(1-P) = IR * D (where: P is prevalence, IR is incidence rate, and D is duration of time) | https://www.wikidoc.org/index.php/Lifetime_prevalence | |
32d7217e1092a2812fda3eb4cb9a644c976f8423 | wikidoc | Scattering | Scattering
Scattering is a general physical process whereby some forms of radiation, such as light, sound or moving particles, for example, are forced to deviate from a straight trajectory by one or more localized non-uniformities in the medium through which it passes. In conventional use, this also includes deviation of reflected radiation from the angle predicted by the law of reflection. Reflections that undergo scattering are often called diffuse reflections and unscattered reflections are called specular (mirror-like) reflections.
The types of non-uniformities that can cause scattering, sometimes known as scatterers or scattering centers, are too numerous to list, but a small sample includes particles, bubbles, droplets, density fluctuations in fluids, defects in crystalline solids, surface roughness, cells in organisms, and textile fibers in clothing. The effects of such features on the path of almost any type of propagating wave or moving particle can be described in the framework of scattering theory.
# Elastic and inelastic scattering
In physical descriptions of scattering, physicists commonly distinguish between two broad types, elastic and inelastic. Elastic scattering involves no (or a very small) loss or gain of energy by the radiation, whereas inelastic scattering does involve some change in the energy of the radiation. These terms derive from the kinetic theory of the collision of solid bodies, which can often be used to model scattering processes.
If the radiation is substantially or completely extinguished by the interaction (losing a significant proportion of its energy), the process is known as absorption. In some contexts, absorption is considered to be merely an extreme form of inelastic scattering. Generally speaking, in classical physics absorption and scattering tend to be treated as different phenomena, while in quantum physics absorption is treated as a form of scattering via the S-matrix. To be precise, absorption cannot occur without some degree of scattering, and scattering is rarely completely elastic, but on a macroscopic scale it is common for "absorption" and "scattering" to take place without any appreciable contribution from the other process, so treating them separately is often convenient.
# Single and multiple scattering
When radiation is only scattered by one localized scattering center, this is called single scattering. It is very common that scattering centers are grouped together, and in those cases the radiation may scatter many times, which is known as multiple scattering. The main difference between the effects of single and multiple scattering is that single scattering can usually be treated as a random phenomenon and multiple scattering is usually more deterministic. Since the location of a single often microscopic scattering center is not usually well known relative to the path of the radiation, the outcome, which tends to depend strongly on the exact incoming trajectory, appears random to an observer. This type of scattering would be exemplified by an electron being fired at an atomic nucleus. In that case, the atom's exact position relative to the path of the electron is unknown and would be immeasurable, so the exact direction of the electron after the collision is unknown, plus the quantum-mechanical nature of this particular interaction also makes the interaction random. Single scattering is therefore often described by probability distributions.
With multiple scattering, the randomness of the interaction tends to be averaged out by the large number of scattering events, so that the final path of the radiation appears to be a deterministic distribution of intensity as the radiation is spread out. This is exemplified by a light beam passing through thick fog. Multiple scattering is highly analogous to diffusion, and the terms multiple scattering and diffusion are interchangeable in many contexts. Optical elements designed to produce multiple scattering are thus known as diffusers.
Not all single scattering is random, however, as a well-controlled laser beam can be exactly positioned to scatter off a microscopic particle with a deterministic outcome. Such situations are encountered in radar scattering as well, where the targets tend to be macroscopic objects such as people or aircraft.
Similarly, multiple scattering can sometimes have somewhat random outcomes, particularly with coherent radiation. The random fluctuations in the multiply-scattered intensity of coherent radiation are called speckles. Speckle also occurs if multiple parts of a coherent wave scatter from different centers. In certain rare circumstances, multiple scattering may only involve small number of interactions such that the randomness is not completely averaged out. These systems are considered to be some of the most difficult to model accurately.
The description of scattering and the distinction between single and multiple scattering are often highly involved with wave-particle duality.
Major research problems in scattering often involve predicting how various systems will scatter radiation, which can almost always be solved given sufficient computing power and knowledge of the system. A widely studied but more difficult challenge is the inverse scattering problem, in which the goal is to observe scattered radiation and use that observation to determine properties of either the scatterer or the radiation before scattering. In general, the inverse is not unique; several different types of scattering centers can usually give rise to the same pattern of scattered radiation, so the problem is not solvable in the general case. Fortunately, there are ways to extract some useful, albeit incomplete, information about the scatterer, and these techniques are widely used for sensing and metrology applications (Colton & Kress 1998).
Some areas where scattering and scattering theory are significant include radar sensing, medical ultrasound, semiconductor wafer inspection, polymerization process monitoring, acoustic tiling, free-space communications, and computer-generated imagery.
# Electromagnetic scattering
Electromagnetic (EM) waves are one of the best known and most commonly encountered forms of radiation that undergo scattering. Scattering of light and radio waves (especially in radar) is particularly important. Several different aspects of electromagnetic scattering are distinct enough to have conventional names. Major forms of elastic light scattering (involving negligible energy transfer) are Rayleigh scattering and Mie scattering. Inelastic EM scattering effects include Brillouin scattering, Raman scattering,
inelastic X-ray scattering and Compton scattering.
Light scattering is one of the two major physical processes that contribute to the visible appearance of most objects, the other being absorption. Surfaces described as white owe their appearance almost completely to the scattering of light by the surface of the object. The absence of surface scattering leads to a shiny or glossy appearance. Light scattering can also give color to some objects, usually shades of blue (as with the sky, the human iris, and the feathers of some birds (Prum et al. 1998), but resonant light scattering in nanoparticles can produce different highly saturated and vibrant hues, especially when surface plasmon resonance is involved (Roqué et al. 2006).
Rayleigh scattering is a process in which electromagnetic radiation (including light) is scattered by a small spherical volume of variant refractive index, such as a particle, bubble, droplet, or even a density fluctuation. This effect was first modeled successfully by Lord Rayleigh, from whom it gets its name. In order for Rayleigh's model to apply, the sphere must be much smaller in diameter than the wavelength (λ) of the scattered wave; typically the upper limit is taken to be about 1/10 the wavelength. In this size regime, the exact shape of the scattering center is usually not very significant and can often be treated as a sphere of equivalent volume. The inherent scattering that radiation undergoes passing through a pure gas is due to microscopic density fluctuations as the gas molecules move around, which are normally small enough in scale for Rayleigh's model to apply. This scattering mechanism is the primary cause of the blue color of the Earth's sky on a clear day, as the shorter blue wavelengths of sunlight passing overhead are more strongly scattered than the longer red wavelengths according to Rayleigh's famous 1/λ 4 relation. Along with absorption, such scattering is a major cause of the attenuation of radiation by the atmosphere. The degree of scattering varies as a function of the ratio of the particle diameter to the wavelength of the radiation, along with many other factors including polarization, angle, and coherence.
For larger diameters, the problem of electromagnetic scattering by spheres was first solved by Gustav Mie, and scattering by spheres larger than the Rayleigh range is therefore usually known as Mie scattering. In the Mie regime, the shape of the scattering center becomes much more significant and the theory only applies well to spheres and, with some modification, spheroids and ellipsoids. Closed-form solutions for scattering by certain other simple shapes exist, but no general closed-form solution is known for arbitrary shapes.
Both Mie and Rayleigh scattering are considered elastic scattering processes, in which the energy (and thus wavelength and frequency) of the light is not substantially changed. However, electromagnetic radiation scattered by moving scattering centers does undergo a Doppler shift, which can be detected and used to measure the velocity of the scattering center/s in forms of techniques such as LIDAR and radar. This shift involves a slight change in energy.
At values of the ratio of particle diameter to wavelength more than about 10, the laws of geometric optics are mostly sufficient to describe the interaction of light with the particle, and at this point the interaction is not usually described as scattering.
For modeling of scattering in cases where the Rayleigh and Mie models do not apply such as irregularly shaped particles, there are many numerical methods that can be used. The most common are finite-element methods which solve Maxwell's equations to find the distribution of the scattered electromagnetic field. Sophisticated software packages exist which allow the user to specify the refractive index or indices of the scattering feature in space, creating a 2- or sometimes 3-dimensional model of the structure. For relatively large and complex structures, these models usually require substantial execution times on a computer.
Another special type of EM scattering is coherent backscattering. This is a relatively obscure phenomenon that occurs when coherent radiation
(such as a laser beam) propagates through a medium which has a large number of scattering centers, so that the waves are
scattered many times while traveling through it. A thick cloud is a typical example of this sort of multiple-scattering medium. The effect produces a very large peak in the scattering intensity in the direction from the which the wave travels—effectively, the light scatters preferentially back the way it came. For incoherent radiation, the scattering typically reaches a local maximum in the backward direction, but the coherent backscatter peak is two times higher than the level would have been if the light were incoherent. It is very difficult to detect and measure for two reasons. The first is fairly obvious, that it is difficult to measure the direct backscatter without blocking the beam, but there are methods for overcoming this problem. The second is that the peak is usually extremely sharp around the backward direction, so that a very high level of angular resolution is needed for the detector to see the peak without averaging its intensity out over the surrounding angles where the intensity can undergo large dips. At angles other than the backscatter direction, the light intensity is subject to numerous essentially random fluctuations called speckles.
This is one of the most robust interference phenomena that survives
multiple scattering, and it is regarded as an aspect of a quantum mechanical phenomenon known as weak
localization (Akkermans et al. 1986). In weak
localization, interference of the direct and reverse paths leads
to a net reduction of light transport in the forward direction. This phenomenon is typical of any coherent wave which is multiple scattered. It is typically discussed for light waves, for which it is
similar to the weak localization phenomenon for electrons in
disordered (semi)conductors and often seen as the precursor to
Anderson (or strong) localization of light. Weak localization of light can
be detected since it is manifested as an enhancement of light
intensity in the backscattering direction. This substantial
enhancement is called the cone of coherent
backscattering .
Coherent backscattering has its origin in the interference between
direct and reverse paths in the backscattering direction.
When a multiply scattering medium is illuminated by a laser beam,
the scattered intensity results from the interference between the
amplitudes associated with the various scattering paths; for a
disordered medium, the interference terms are washed out when
averaged over many sample configurations, except in a narrow
angular range around exact backscattering where the average
intensity is enhanced. This phenomenon, is the result of many sinusoidal
two-waves interference patterns which add up.
The cone is the Fourier transform of the spatial distribution of
the intensity of the scattered light on the sample surface, when
the latter is illuminated by a point-like source.
The enhanced backscattering relies on the constructive
interference between reverse paths. One can make an analogy with a
Young's interference experiment, where two diffracting slits would
be positioned in place of the "input" and "output" scatterers.
# Scattering in particle physics
In particle physics, scattering refers to deflection of subatomic particles, a process central to many experiments. In scattering experiments, a target of some material is bombarded with a beam of particles (typically electrons, protons, or neutrons) and the number of particles emerging in various directions is measured. This distribution reveals information about the interaction that takes place between the target and the scattered particle.
Depending on the type of interaction between beam-particle and target, the scattering process is called elastic, inelastic or deeply inelastic. In an elastic scattering process the incident and target particles are left intact and only their momenta may be changed. In an inelastic scattering process the target particle is excited. For example if a nucleus is bombarded by neutrons, it may be excited to some nuclear resonance. In deep inelastic scattering the target (and sometimes the incident particle) is destroyed and completely new particles may be created.
A famous scattering experiment of alpha particles off gold nuclei performed by Ernest Rutherford revealed the basic structure of the atom - a tiny nucleus surrounded by electrons. See Rutherford scattering. Scattering has also been done off of nucleons and quarks.
Mathematically, scientists describe scattering by an impact parameter (which describes how close the incident particle would come to the target if it moved in a straight line) and an angle of deflection (which describes the angle at which the particle emerges relative to its original direction). The distribution of deflection angles is described by a function known as the differential cross section, which (roughly) relates a direction in space in which some particles emerge to the amount of the incoming beam (in area) those particles came from.
In more complicated cases of scattering, such as deep inelastic scattering of electrons and protons,
so-called form factors have to be multiplied to the scattering formulae, describing the internal structure of the proton.
The abstract mathematics of scattering is developed as scattering theory.
See also S-matrix. | Scattering
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Scattering is a general physical process whereby some forms of radiation, such as light, sound or moving particles, for example, are forced to deviate from a straight trajectory by one or more localized non-uniformities in the medium through which it passes. In conventional use, this also includes deviation of reflected radiation from the angle predicted by the law of reflection. Reflections that undergo scattering are often called diffuse reflections and unscattered reflections are called specular (mirror-like) reflections.
The types of non-uniformities that can cause scattering, sometimes known as scatterers or scattering centers, are too numerous to list, but a small sample includes particles, bubbles, droplets, density fluctuations in fluids, defects in crystalline solids, surface roughness, cells in organisms, and textile fibers in clothing. The effects of such features on the path of almost any type of propagating wave or moving particle can be described in the framework of scattering theory.
# Elastic and inelastic scattering
In physical descriptions of scattering, physicists commonly distinguish between two broad types, elastic and inelastic. Elastic scattering involves no (or a very small) loss or gain of energy by the radiation, whereas inelastic scattering does involve some change in the energy of the radiation. These terms derive from the kinetic theory of the collision of solid bodies, which can often be used to model scattering processes.
If the radiation is substantially or completely extinguished by the interaction (losing a significant proportion of its energy), the process is known as absorption. In some contexts, absorption is considered to be merely an extreme form of inelastic scattering. Generally speaking, in classical physics absorption and scattering tend to be treated as different phenomena, while in quantum physics absorption is treated as a form of scattering via the S-matrix. To be precise, absorption cannot occur without some degree of scattering, and scattering is rarely completely elastic, but on a macroscopic scale it is common for "absorption" and "scattering" to take place without any appreciable contribution from the other process, so treating them separately is often convenient.
# Single and multiple scattering
When radiation is only scattered by one localized scattering center, this is called single scattering. It is very common that scattering centers are grouped together, and in those cases the radiation may scatter many times, which is known as multiple scattering. The main difference between the effects of single and multiple scattering is that single scattering can usually be treated as a random phenomenon and multiple scattering is usually more deterministic. Since the location of a single often microscopic scattering center is not usually well known relative to the path of the radiation, the outcome, which tends to depend strongly on the exact incoming trajectory, appears random to an observer. This type of scattering would be exemplified by an electron being fired at an atomic nucleus. In that case, the atom's exact position relative to the path of the electron is unknown and would be immeasurable, so the exact direction of the electron after the collision is unknown, plus the quantum-mechanical nature of this particular interaction also makes the interaction random. Single scattering is therefore often described by probability distributions.
With multiple scattering, the randomness of the interaction tends to be averaged out by the large number of scattering events, so that the final path of the radiation appears to be a deterministic distribution of intensity as the radiation is spread out. This is exemplified by a light beam passing through thick fog. Multiple scattering is highly analogous to diffusion, and the terms multiple scattering and diffusion are interchangeable in many contexts. Optical elements designed to produce multiple scattering are thus known as diffusers.
Not all single scattering is random, however, as a well-controlled laser beam can be exactly positioned to scatter off a microscopic particle with a deterministic outcome. Such situations are encountered in radar scattering as well, where the targets tend to be macroscopic objects such as people or aircraft.
Similarly, multiple scattering can sometimes have somewhat random outcomes, particularly with coherent radiation. The random fluctuations in the multiply-scattered intensity of coherent radiation are called speckles. Speckle also occurs if multiple parts of a coherent wave scatter from different centers. In certain rare circumstances, multiple scattering may only involve small number of interactions such that the randomness is not completely averaged out. These systems are considered to be some of the most difficult to model accurately.
The description of scattering and the distinction between single and multiple scattering are often highly involved with wave-particle duality.
Major research problems in scattering often involve predicting how various systems will scatter radiation, which can almost always be solved given sufficient computing power and knowledge of the system. A widely studied but more difficult challenge is the inverse scattering problem, in which the goal is to observe scattered radiation and use that observation to determine properties of either the scatterer or the radiation before scattering. In general, the inverse is not unique; several different types of scattering centers can usually give rise to the same pattern of scattered radiation, so the problem is not solvable in the general case. Fortunately, there are ways to extract some useful, albeit incomplete, information about the scatterer, and these techniques are widely used for sensing and metrology applications (Colton & Kress 1998).
Some areas where scattering and scattering theory are significant include radar sensing, medical ultrasound, semiconductor wafer inspection, polymerization process monitoring, acoustic tiling, free-space communications, and computer-generated imagery.
# Electromagnetic scattering
Electromagnetic (EM) waves are one of the best known and most commonly encountered forms of radiation that undergo scattering. Scattering of light and radio waves (especially in radar) is particularly important. Several different aspects of electromagnetic scattering are distinct enough to have conventional names. Major forms of elastic light scattering (involving negligible energy transfer) are Rayleigh scattering and Mie scattering. Inelastic EM scattering effects include Brillouin scattering, Raman scattering,
inelastic X-ray scattering and Compton scattering.
Light scattering is one of the two major physical processes that contribute to the visible appearance of most objects, the other being absorption. Surfaces described as white owe their appearance almost completely to the scattering of light by the surface of the object. The absence of surface scattering leads to a shiny or glossy appearance. Light scattering can also give color to some objects, usually shades of blue (as with the sky, the human iris, and the feathers of some birds (Prum et al. 1998), but resonant light scattering in nanoparticles can produce different highly saturated and vibrant hues, especially when surface plasmon resonance is involved (Roqué et al. 2006).
Rayleigh scattering is a process in which electromagnetic radiation (including light) is scattered by a small spherical volume of variant refractive index, such as a particle, bubble, droplet, or even a density fluctuation. This effect was first modeled successfully by Lord Rayleigh, from whom it gets its name. In order for Rayleigh's model to apply, the sphere must be much smaller in diameter than the wavelength (λ) of the scattered wave; typically the upper limit is taken to be about 1/10 the wavelength. In this size regime, the exact shape of the scattering center is usually not very significant and can often be treated as a sphere of equivalent volume. The inherent scattering that radiation undergoes passing through a pure gas is due to microscopic density fluctuations as the gas molecules move around, which are normally small enough in scale for Rayleigh's model to apply. This scattering mechanism is the primary cause of the blue color of the Earth's sky on a clear day, as the shorter blue wavelengths of sunlight passing overhead are more strongly scattered than the longer red wavelengths according to Rayleigh's famous 1/λ 4 relation. Along with absorption, such scattering is a major cause of the attenuation of radiation by the atmosphere. The degree of scattering varies as a function of the ratio of the particle diameter to the wavelength of the radiation, along with many other factors including polarization, angle, and coherence.
For larger diameters, the problem of electromagnetic scattering by spheres was first solved by Gustav Mie, and scattering by spheres larger than the Rayleigh range is therefore usually known as Mie scattering. In the Mie regime, the shape of the scattering center becomes much more significant and the theory only applies well to spheres and, with some modification, spheroids and ellipsoids. Closed-form solutions for scattering by certain other simple shapes exist, but no general closed-form solution is known for arbitrary shapes.
Both Mie and Rayleigh scattering are considered elastic scattering processes, in which the energy (and thus wavelength and frequency) of the light is not substantially changed. However, electromagnetic radiation scattered by moving scattering centers does undergo a Doppler shift, which can be detected and used to measure the velocity of the scattering center/s in forms of techniques such as LIDAR and radar. This shift involves a slight change in energy.
At values of the ratio of particle diameter to wavelength more than about 10, the laws of geometric optics are mostly sufficient to describe the interaction of light with the particle, and at this point the interaction is not usually described as scattering.
For modeling of scattering in cases where the Rayleigh and Mie models do not apply such as irregularly shaped particles, there are many numerical methods that can be used. The most common are finite-element methods which solve Maxwell's equations to find the distribution of the scattered electromagnetic field. Sophisticated software packages exist which allow the user to specify the refractive index or indices of the scattering feature in space, creating a 2- or sometimes 3-dimensional model of the structure. For relatively large and complex structures, these models usually require substantial execution times on a computer.
Another special type of EM scattering is coherent backscattering. This is a relatively obscure phenomenon that occurs when coherent radiation
(such as a laser beam) propagates through a medium which has a large number of scattering centers, so that the waves are
scattered many times while traveling through it. A thick cloud is a typical example of this sort of multiple-scattering medium. The effect produces a very large peak in the scattering intensity in the direction from the which the wave travels—effectively, the light scatters preferentially back the way it came. For incoherent radiation, the scattering typically reaches a local maximum in the backward direction, but the coherent backscatter peak is two times higher than the level would have been if the light were incoherent. It is very difficult to detect and measure for two reasons. The first is fairly obvious, that it is difficult to measure the direct backscatter without blocking the beam, but there are methods for overcoming this problem. The second is that the peak is usually extremely sharp around the backward direction, so that a very high level of angular resolution is needed for the detector to see the peak without averaging its intensity out over the surrounding angles where the intensity can undergo large dips. At angles other than the backscatter direction, the light intensity is subject to numerous essentially random fluctuations called speckles.
This is one of the most robust interference phenomena that survives
multiple scattering, and it is regarded as an aspect of a quantum mechanical phenomenon known as weak
localization (Akkermans et al. 1986). In weak
localization, interference of the direct and reverse paths leads
to a net reduction of light transport in the forward direction. This phenomenon is typical of any coherent wave which is multiple scattered. It is typically discussed for light waves, for which it is
similar to the weak localization phenomenon for electrons in
disordered (semi)conductors and often seen as the precursor to
Anderson (or strong) localization of light. Weak localization of light can
be detected since it is manifested as an enhancement of light
intensity in the backscattering direction. This substantial
enhancement is called the cone of coherent
backscattering .
Coherent backscattering has its origin in the interference between
direct and reverse paths in the backscattering direction.
When a multiply scattering medium is illuminated by a laser beam,
the scattered intensity results from the interference between the
amplitudes associated with the various scattering paths; for a
disordered medium, the interference terms are washed out when
averaged over many sample configurations, except in a narrow
angular range around exact backscattering where the average
intensity is enhanced. This phenomenon, is the result of many sinusoidal
two-waves interference patterns which add up.
The cone is the Fourier transform of the spatial distribution of
the intensity of the scattered light on the sample surface, when
the latter is illuminated by a point-like source.
The enhanced backscattering relies on the constructive
interference between reverse paths. One can make an analogy with a
Young's interference experiment, where two diffracting slits would
be positioned in place of the "input" and "output" scatterers.
# Scattering in particle physics
In particle physics, scattering refers to deflection of subatomic particles, a process central to many experiments. In scattering experiments, a target of some material is bombarded with a beam of particles (typically electrons, protons, or neutrons) and the number of particles emerging in various directions is measured. This distribution reveals information about the interaction that takes place between the target and the scattered particle.
Depending on the type of interaction between beam-particle and target, the scattering process is called elastic, inelastic or deeply inelastic. In an elastic scattering process the incident and target particles are left intact and only their momenta may be changed. In an inelastic scattering process the target particle is excited. For example if a nucleus is bombarded by neutrons, it may be excited to some nuclear resonance. In deep inelastic scattering the target (and sometimes the incident particle) is destroyed and completely new particles may be created.
A famous scattering experiment of alpha particles off gold nuclei performed by Ernest Rutherford revealed the basic structure of the atom - a tiny nucleus surrounded by electrons. See Rutherford scattering. Scattering has also been done off of nucleons and quarks.
Mathematically, scientists describe scattering by an impact parameter (which describes how close the incident particle would come to the target if it moved in a straight line) and an angle of deflection (which describes the angle at which the particle emerges relative to its original direction). The distribution of deflection angles is described by a function known as the differential cross section, which (roughly) relates a direction in space in which some particles emerge to the amount of the incoming beam (in area) those particles came from.
In more complicated cases of scattering, such as deep inelastic scattering of electrons and protons,
so-called form factors have to be multiplied to the scattering formulae, describing the internal structure of the proton.
The abstract mathematics of scattering is developed as scattering theory.
See also S-matrix. | https://www.wikidoc.org/index.php/Light_scattering | |
d3e3feb0bcfc949c61dd271a1df525a73cc4c8ee | wikidoc | Lipid raft | Lipid raft
# Overview
A lipid raft is a cholesterol-enriched microdomain in cell membranes. Since 1972, it has been believed that, in cell membranes, phospholipids and membrane proteins are ubiquitously distributed according to a fluid mosaic model. However, in 1988, Kai Simons at the European Molecular Biology Laboratory (EMBL) in Germany and Gerrit van Meer from the University of Utrecht, Netherlands suggested the novel idea that there exist microdomains, which are enriched with many kinds of lipids such as cholesterol, glycolipids, and sphingolipids, present in cell membranes. This was the first time these microdomains were called "lipid rafts". The original concept of rafts was used as an explanation for the transport of cholesterol from the trans Golgi network to the plasma membrane. The idea was more formally developed in 1997 by Simons and Ikonen.
# Properties of lipid rafts
Rietveld & Simons related lipid rafts in model membranes to the immiscibility of ordered (Lo phase) and disordered Ld or Lα phase) liquid phases. The cause of this immiscibility is uncertain, but the immiscibility is thought to minimize the free energy between the two phases.
By one early definition of lipid rafts, lipid rafts differ from the rest of the plasma membrane. In fact, researchers have hypothesized that the lipid rafts can be extracted from a plasma membrane. The extraction would take advantage of lipid raft resistance to non-ionic detergents, such as Triton X-100 or Brij-98 at low temperatures (e.g., 4°C). When such a detergent is added to cells, the fluid membrane will dissolve while the lipid rafts may remain intact and could be extracted.
Because of their composition and detergent resistance, lipid rafts are also called detergent-insoluble glycolipid-enriched complexes (GEMs) or DIGs or Detergent Resistant Membranes (DRMs). However the validity of the detergent resistance methodology of membranes has recently been called into question due to ambiguities in the lipids and proteins recovered and the observation that they can also cause solid areas to form where there were none previously.
# Examples
Certain proteins associated with cellular signaling processes have been shown to associate with lipid rafts. Proteins that have shown association to the lipid rafts include glycosylphosphatidylinositol (GPI)-anchored proteins, doubly-acylated tyrosine kinases of the Src family, and transmembrane proteins. This association can at least be partially contributed to the acylated, saturated tails of both the tyrosine kinases and the GPI-anchored proteins, which matches the properties of sphingolipids more so than the rest of the membrane (Simons & Ikonen, 1997). While these proteins tend to continuously be present in lipid rafts, there are others that associate with lipid rafts only when the protein is activated. Some examples of these include, but are not limited to, B cell receptors (BCRs), T cell receptors (TCRs), PAG, and an enzyme called CD39.
Other proteins are excluded from rafts, such as transferrin-receptor and a member of the Ras family. Typically the inclusion or exclusion of proteins is determined by whether or not they are found in membrane fragments extracted using Triton - the DRM definition of a raft.
Researchers have tested the presence and importance of lipid rafts in cellular signaling by first understanding the initial signaling processes, and then disrupting the lipid rafts at which point they observe any changes in cellular function. Lipid rafts are typically disrupted by removing the cholesterol from the membrane, using systems such as cyclodextrin.
In normal B cells, when the cell encounters an antigen, the BCR shifts into a lipid raft domain and then relays a signal that causes the cell to proliferate into plasma cells and produce antibodies. However, when the cholesterol was depleted from B lymphocytes, presumably destroying lipid rafts, the BCRs were no longer able to relay the signal that they had encountered an antigen, and no antibodies were produced. In a similar fashion, when rafts were depleted in T lymphocytes, the TCRs lost their ability to relay signals due to antigen attachment as well. Lipid raft depletion also affected the function of CD39 an enzyme that plays a role in platelet aggregation.
Rafts have been implicated in a number of other processes and systems both physiological and pathological. These include cell signalling, molecular trafficking, the function of the immune, vasular, digestive and reproductive systems. The pathogenesis of diseases such as HIV (viral), Salmonella (bacterial) and malaria (eukaryotic) has been linked to the role of rafts. Typically this involves the 'hi-jacking' of the host cell raft function by the pathogen for it's own purposes, e.g. to gain access to the interior of a host cell.
# Visualization of lipid rafts
Due to their size being below the classical diffraction limit of the light microscope, lipid rafts have proved difficult to visualize directly. Despite this, fluorescence microscopy is used extensively in the field. For example, fluorophores conjugated to cholera-toxin B-subunit, which binds to the raft constituent ganglioside GM1 is used extensively. Also used are lipophilic membrane dyes which either partition between rafts and the bulk membrane, or change their fluorescent properties in response to membrane phase. Laurdan is one of the prime examples of such a dye. Rafts may also be labeled by genetic expression of fluorescent fusion proteins such as Lck-GFP.
To combat the problems of small size and dynamic nature, single particle and molecule tracking using cooled, sensitive CCD cameras and total internal reflection (TIRF) microscopy is coming to prominence. This allows information of the diffusivity of particles in the membrane to be extracted as well as revealing membrane corrals, barriers and sites of confinement. The Kusumi lab are some of the leaders in this field of raft study.
Other optical techniques are also used: Fluorescence Correlation and Cross-Correlation Spectroscopy (FCS/FCCS) can be used to gain information of fluorophore mobility in the membrane, Fluorescence Resonance Energy Transfer (FRET) can detect when fluorophores are in close proximity and optical tweezer techniques can give information on membrane viscosity.
Also used are atomic force microscopy (AFM), Scanning Ion Conductance Microscopy (SICM), Nuclear Magnetic Resonance (NMR) although fluorescence microscopy remains the dominant technique. In the future it is hoped that super-resolution microscopy such as Stimulated Emission Depletion (STED) or various forms of structured illumination microscopy may overcome the problems imposed by the diffraction limit.
# Controversy about lipid rafts
The role of rafts in cellular signaling, trafficking, and structure has yet to be determined despite many experiments involving several different methods.
Arguments against the existence of lipid rafts include the following:
- First, a line tension should exist between the Lα and Lo phases. This line has been seen in model membranes, but has not been readily observed in cell systems.
- Second, there is no consensus on lipid raft size, which has been reported anywhere between 1 and 1000 nanometres.
- Third, the time scale of lipid raft existence is unknown. If lipid rafts exist, they may only occur on a time scale that is irrelevant to biological processes.
- Fourth, the entire membrane may exist in the Lo phase.
A first rebuttal to this point suggests that the Lo phase of the rafts is more tightly packed due to the intermolecular hydrogen bonding exhibited between sphingolipids and cholesterol that is not seen elsewhere.
A second argument questions the effectiveness of the experimental design when disrupting lipid rafts. Pike and Miller discuss potential pitfalls of using cholesterol depletion to determine lipid raft function. They noted that most researchers were using acute methods of cholesterol depletion, which disrupt the rafts, but also disrupt another lipid known as PIP(4,5)P2. PIP(4,5)P2 plays a large role in regulating the cell’s cytoskeleton, and disrupting PIP(4,5)P2 causes many of the same results as this type of cholesterol depletion, including lateral diffusion of the proteins in the membrane. Because the methods disrupt both rafts and PIP(4,5)P2, Kwik et al concluded that loss of a particular cellular function after cholesterol depletion cannot necessarily be attributed solely to lipid raft disruption, as other processes independent of rafts may also be affected. Finally, while lipid rafts are believed to be connected in some way to proteins, Edidin argues that proteins attract the lipids in the raft by interactions of proteins with the acyl chains on the lipids, and not the other way around. | Lipid raft
# Overview
A lipid raft is a cholesterol-enriched microdomain in cell membranes. Since 1972, it has been believed that, in cell membranes, phospholipids and membrane proteins are ubiquitously distributed according to a fluid mosaic model.[1] However, in 1988, Kai Simons at the European Molecular Biology Laboratory (EMBL) in Germany and Gerrit van Meer from the University of Utrecht, Netherlands suggested the novel idea that there exist microdomains, which are enriched with many kinds of lipids such as cholesterol, glycolipids, and sphingolipids, present in cell membranes.[2] This was the first time these microdomains were called "lipid rafts". The original concept of rafts was used as an explanation for the transport of cholesterol from the trans Golgi network to the plasma membrane. The idea was more formally developed in 1997 by Simons and Ikonen.[3]
# Properties of lipid rafts
Rietveld & Simons related lipid rafts in model membranes to the immiscibility of ordered (Lo phase) and disordered Ld or Lα phase) liquid phases.[4] The cause of this immiscibility is uncertain, but the immiscibility is thought to minimize the free energy between the two phases.
By one early definition of lipid rafts, lipid rafts differ from the rest of the plasma membrane. In fact, researchers have hypothesized that the lipid rafts can be extracted from a plasma membrane. The extraction would take advantage of lipid raft resistance to non-ionic detergents, such as Triton X-100 or Brij-98 at low temperatures (e.g., 4°C). When such a detergent is added to cells, the fluid membrane will dissolve while the lipid rafts may remain intact and could be extracted.
Because of their composition and detergent resistance, lipid rafts are also called detergent-insoluble glycolipid-enriched complexes (GEMs) or DIGs[5] or Detergent Resistant Membranes (DRMs). However the validity of the detergent resistance methodology of membranes has recently been called into question due to ambiguities in the lipids and proteins recovered and the observation that they can also cause solid areas to form where there were none previously.[6]
# Examples
Certain proteins associated with cellular signaling processes have been shown to associate with lipid rafts.[7] Proteins that have shown association to the lipid rafts include glycosylphosphatidylinositol (GPI)-anchored proteins, doubly-acylated tyrosine kinases of the Src family, and transmembrane proteins. This association can at least be partially contributed to the acylated, saturated tails of both the tyrosine kinases and the GPI-anchored proteins, which matches the properties of sphingolipids more so than the rest of the membrane (Simons & Ikonen, 1997). While these proteins tend to continuously be present in lipid rafts, there are others that associate with lipid rafts only when the protein is activated. Some examples of these include, but are not limited to, B cell receptors (BCRs), T cell receptors (TCRs), PAG, and an enzyme called CD39.[8][9][10][11]
Other proteins are excluded from rafts, such as transferrin-receptor and a member of the Ras family. Typically the inclusion or exclusion of proteins is determined by whether or not they are found in membrane fragments extracted using Triton - the DRM definition of a raft.
Researchers have tested the presence and importance of lipid rafts in cellular signaling by first understanding the initial signaling processes, and then disrupting the lipid rafts at which point they observe any changes in cellular function. Lipid rafts are typically disrupted by removing the cholesterol from the membrane, using systems such as cyclodextrin.
In normal B cells, when the cell encounters an antigen, the BCR shifts into a lipid raft domain and then relays a signal that causes the cell to proliferate into plasma cells and produce antibodies. However, when the cholesterol was depleted from B lymphocytes, presumably destroying lipid rafts, the BCRs were no longer able to relay the signal that they had encountered an antigen, and no antibodies were produced.[11] In a similar fashion, when rafts were depleted in T lymphocytes, the TCRs lost their ability to relay signals due to antigen attachment as well.[9] Lipid raft depletion also affected the function of CD39 an enzyme that plays a role in platelet aggregation.
Rafts have been implicated in a number of other processes and systems both physiological and pathological. These include cell signalling, molecular trafficking, the function of the immune, vasular, digestive and reproductive systems. The pathogenesis of diseases such as HIV (viral), Salmonella (bacterial) and malaria (eukaryotic) has been linked to the role of rafts. Typically this involves the 'hi-jacking' of the host cell raft function by the pathogen for it's own purposes, e.g. to gain access to the interior of a host cell.
# Visualization of lipid rafts
Due to their size being below the classical diffraction limit of the light microscope, lipid rafts have proved difficult to visualize directly. Despite this, fluorescence microscopy is used extensively in the field. For example, fluorophores conjugated to cholera-toxin B-subunit, which binds to the raft constituent ganglioside GM1 is used extensively. Also used are lipophilic membrane dyes which either partition between rafts and the bulk membrane, or change their fluorescent properties in response to membrane phase. Laurdan is one of the prime examples of such a dye. Rafts may also be labeled by genetic expression of fluorescent fusion proteins such as Lck-GFP.
To combat the problems of small size and dynamic nature, single particle and molecule tracking using cooled, sensitive CCD cameras and total internal reflection (TIRF) microscopy is coming to prominence. This allows information of the diffusivity of particles in the membrane to be extracted as well as revealing membrane corrals, barriers and sites of confinement. The Kusumi lab are some of the leaders in this field of raft study.
Other optical techniques are also used: Fluorescence Correlation and Cross-Correlation Spectroscopy (FCS/FCCS) can be used to gain information of fluorophore mobility in the membrane, Fluorescence Resonance Energy Transfer (FRET) can detect when fluorophores are in close proximity and optical tweezer techniques can give information on membrane viscosity.
Also used are atomic force microscopy (AFM), Scanning Ion Conductance Microscopy (SICM), Nuclear Magnetic Resonance (NMR) although fluorescence microscopy remains the dominant technique. In the future it is hoped that super-resolution microscopy such as Stimulated Emission Depletion (STED) or various forms of structured illumination microscopy may overcome the problems imposed by the diffraction limit.
# Controversy about lipid rafts
The role of rafts in cellular signaling, trafficking, and structure has yet to be determined despite many experiments involving several different methods.
Arguments against the existence of lipid rafts include the following:
- First, a line tension should exist between the Lα and Lo phases. This line has been seen in model membranes, but has not been readily observed in cell systems.
- Second, there is no consensus on lipid raft size, which has been reported anywhere between 1 and 1000 nanometres.
- Third, the time scale of lipid raft existence is unknown. If lipid rafts exist, they may only occur on a time scale that is irrelevant to biological processes.
- Fourth, the entire membrane may exist in the Lo phase.
A first rebuttal to this point suggests that the Lo phase of the rafts is more tightly packed due to the intermolecular hydrogen bonding exhibited between sphingolipids and cholesterol that is not seen elsewhere.[12]
A second argument questions the effectiveness of the experimental design when disrupting lipid rafts. Pike and Miller discuss potential pitfalls of using cholesterol depletion to determine lipid raft function.[13] They noted that most researchers were using acute methods of cholesterol depletion, which disrupt the rafts, but also disrupt another lipid known as PIP(4,5)P2. PIP(4,5)P2 plays a large role in regulating the cell’s cytoskeleton,[14] and disrupting PIP(4,5)P2 causes many of the same results as this type of cholesterol depletion, including lateral diffusion of the proteins in the membrane.[15] Because the methods disrupt both rafts and PIP(4,5)P2, Kwik et al concluded that loss of a particular cellular function after cholesterol depletion cannot necessarily be attributed solely to lipid raft disruption, as other processes independent of rafts may also be affected. Finally, while lipid rafts are believed to be connected in some way to proteins, Edidin argues that proteins attract the lipids in the raft by interactions of proteins with the acyl chains on the lipids, and not the other way around.[16] | https://www.wikidoc.org/index.php/Lipid_raft | |
3ea289ca4ebedc6d735a79c80b873acc5a295542 | wikidoc | Lipotropin | Lipotropin
Lipotropin is a hormone produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-LPH).
# β-Lipotropin
β-Lipotropin is a 90-amino acid polypeptide that is the carboxy-terminal fragment of POMC. It was initially reported to stimulate melanocytes to produce melanin. It was also reported to perform lipid-mobilizing functions such as lipolysis and steroidogenesis. However, no subsequent studies have been published that support these early findings and no receptor has been identified for β-lipotropin.
β-Lipotropin can be cleaved into smaller peptides. In humans, γ-lipotropin, β-MSH, and β-endorphin, are all possible fragments of β-lipotropin. β-Lipotropin is the predominant opioid of the anterior human and rat pituitary gland. It is found in essentially equimolar concentrations to that of corticotropin. Evidence shows that β-Lipotropin is metabolized into endorphins that can greatly affect mood and behavior and is thus regarded as a prohormone.
# γ-Lipotropin
γ-lipotropin is the amino-terminal peptide fragment of β-lipotropin. In humans, it has 56 amino acids. Gamma lipotropin is identical to the first 56 amino acid sequences of β-lipotropin. It can be cleaved to β-melanocyte stimulating hormone.
# Use in sport
Lipotropin has also, under its alternate name AOD-9604 (Anti-Obesity Drug-9604), been connected with controversies in Australian Rules Football. Allegations have arisen around the use of the drug and its administration to players of the Essendon Football Club as a supplement, including weekly administration to players in the 2012 season. The matters are currently under investigation due to the relationship between Lipotropin and growth hormones, as noted by club medical staff. | Lipotropin
Lipotropin is a hormone produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-LPH).
# β-Lipotropin
β-Lipotropin is a 90-amino acid polypeptide that is the carboxy-terminal fragment of POMC. It was initially reported to stimulate melanocytes to produce melanin. It was also reported to perform lipid-mobilizing functions such as lipolysis[1] and steroidogenesis. However, no subsequent studies have been published that support these early findings and no receptor has been identified for β-lipotropin.
β-Lipotropin can be cleaved into smaller peptides. In humans, γ-lipotropin, β-MSH, and β-endorphin, are all possible fragments of β-lipotropin.[2] β-Lipotropin is the predominant opioid of the anterior human and rat pituitary gland. It is found in essentially equimolar concentrations to that of corticotropin. Evidence shows that β-Lipotropin is metabolized into endorphins that can greatly affect mood and behavior and is thus regarded as a prohormone.[3]
# γ-Lipotropin
γ-lipotropin is the amino-terminal peptide fragment of β-lipotropin. In humans, it has 56 amino acids. Gamma lipotropin is identical to the first 56 amino acid sequences of β-lipotropin. It can be cleaved to β-melanocyte stimulating hormone.
# Use in sport
Lipotropin has also, under its alternate name AOD-9604 (Anti-Obesity Drug-9604),[4] been connected with controversies in Australian Rules Football. Allegations have arisen around the use of the drug and its administration to players of the Essendon Football Club as a supplement, including weekly administration to players in the 2012 season. The matters are currently under investigation due to the relationship between Lipotropin and growth hormones, as noted by club medical staff.[5] | https://www.wikidoc.org/index.php/Lipotropin | |
f4dff23aa608656b60cfcd7ce45d5945468913dd | wikidoc | Liquid gas | Liquid gas
Due to the age of this content, you may be looking for:
- liquid oxygen
- liquid nitrogen
- paramagnetism (oxygen)
- superconducting metals
- ferromagnetism (magnets)
- liquified petroleum gas
# In 1911
Liquid gas: Low temperatures have very marked effects upon the magnetic properties of various substances. Oxygen, long known to be slightly magnetic in the gaseous state, is powerfully attracted in the liquid condition by a magnet, and the same is true, though to a less extent, of liquid air, owing to the proportion of liquid oxygen it contains. A magnet of ordinary carbon steel has its magnetic moment temporarily increased by cooling, that is, after it has been brought to a permanent magnetic condition ( aged ). The effect of the first immersion of such a magnet in liquid air is a large diminution in its magnetic moment, which decreases still further when it is allowed to warm up to ordinary temperatures. A second cooling, however, increases the magnetic moment, which is again decreased by warming, and after a few repetitions of this cycle of cooling and heating the steel is brought into a condition such that its magnetic moment at the temperature of liquid air is greater by a constant percentage than it is at the ordinary temperature of the air. The increase of magnetic moment seems then to have reached a limit, because on further cooling to the temperature of liquid hydrogen hardly any further increase is observed. The percentage differs with the composition of the steel and with its physical condition. It is greater, for example, with a specimen tempered very soft than it is with another specimen of the same steel tempered glass hard.
Aluminium steels show the same kind of phenomena as carbon ones, and the same may be said of chrome steels in the permanent condition, though the effect of the first cooling with them is a slight increase of magnetic moment. Nickel steels present some curious phenomena. When containing small percentages of nickel (e.g. 084 or 3-82), they behave under changes of temperature much like carbon steel. With a sample containing 7.65%, the phenomena after the permanent state had been reached were similar, but the first cooling produced a slight increase in magnetic moment. But steels containing 18-64 and 29% of nickel behaved very differently. The result of the first cooling was a reduction of the magnetic moment, to the extent of nearly 50% in the case of the former. Warming again brought about an increase, and the final condition was that at the barometric pressure of liquid air the magnetic moment was always less than at ordinary temperatures. This anomaly is all the more remarkable in that the behaviour of pure nickel is normal, as also appears to be generally the case with soft and hard iron. Silicon, tungsten and manganese steels are also substantially normal in their behaviour, although there are considerable differences in the magnitudes of the variations they display.
## Temperature
Low temperatures also affect the permeability of iron, i.e. the degree of magnetization it is capable of acquiring under the influence of a certain magnetic force. With fine Swedish iron, carefully annealed, the permeability is slightly. Hard iron, however, in the same circumstances suffers a large increase of permeability.
## Liquid air
At the Lister Institute of Preventive Medicine, liquid air has been brought into use as an agent in biological research. An inquiry into the intracellular constituents of the typhoid bacillus, initiated under the direction of Dr Allan Macfadyen, necessitated the separation of the cell-plasma of the organism. The method at first adopted for the disintegration of the bacteria was to mix them with silver-sand and churn the whole up in a closed vessel in which a series of horizontal vanes revolved at a high speed. But certain disadvantages attached to this procedure, and accordingly some means was sought to do away with the sand and triturate the bacilli per se. This was found in liquid air, which, as had long before been shown at the Royal Institution, has the power of reducing materials like grass or the leaves of plants to such a state of brittleness that they can easily be powdered in a mortar. By its aid a complete trituration of the typhoid bacilli has been accomplished at the Jenner Institute, and the same process, already applied with success also to yeast cells and animal cells, is being extended in other directions.
When air is liquefied the oxygen and nitrogen are condensed simultaneously. However, owing to its greater volatility the latter boils off the more quickly of the two, so that the remaining liquid becomes gradually richer and richer in oxygen.
# Liquefied natural gas
Liquefied natural gas is the different physical form of Natural gas. Since transportation of natural gas requires a large network of pipeline which is difficult across some terrains and oceans, and also need huge investment and long term planning. So the natural gas is liquefied, put under high pressure which transforms it into liquid. The liquefied gas is transported through Tankers with special air tight compartments. When the tank is opened and the liquid exposed to atmospheric pressure it spontaneously transforms into gas. | Liquid gas
Due to the age of this content, you may be looking for:
- liquid oxygen
- liquid nitrogen
- paramagnetism (oxygen)
- superconducting metals
- ferromagnetism (magnets)
- liquified petroleum gas
# In 1911
Template:1911
Liquid gas: Low temperatures have very marked effects upon the magnetic properties of various substances. Oxygen, long known to be slightly magnetic in the gaseous state, is powerfully attracted in the liquid condition by a magnet, and the same is true, though to a less extent, of liquid air, owing to the proportion of liquid oxygen it contains. A magnet of ordinary carbon steel has its magnetic moment temporarily increased by cooling, that is, after it has been brought to a permanent magnetic condition ( aged ). The effect of the first immersion of such a magnet in liquid air is a large diminution in its magnetic moment, which decreases still further when it is allowed to warm up to ordinary temperatures. A second cooling, however, increases the magnetic moment, which is again decreased by warming, and after a few repetitions of this cycle of cooling and heating the steel is brought into a condition such that its magnetic moment at the temperature of liquid air is greater by a constant percentage than it is at the ordinary temperature of the air. The increase of magnetic moment seems then to have reached a limit, because on further cooling to the temperature of liquid hydrogen hardly any further increase is observed. The percentage differs with the composition of the steel and with its physical condition. It is greater, for example, with a specimen tempered very soft than it is with another specimen of the same steel tempered glass hard.
Aluminium steels show the same kind of phenomena as carbon ones, and the same may be said of chrome steels in the permanent condition, though the effect of the first cooling with them is a slight increase of magnetic moment. Nickel steels present some curious phenomena. When containing small percentages of nickel (e.g. 084 or 3-82), they behave under changes of temperature much like carbon steel. With a sample containing 7.65%, the phenomena after the permanent state had been reached were similar, but the first cooling produced a slight increase in magnetic moment. But steels containing 18-64 and 29% of nickel behaved very differently. The result of the first cooling was a reduction of the magnetic moment, to the extent of nearly 50% in the case of the former. Warming again brought about an increase, and the final condition was that at the barometric pressure of liquid air the magnetic moment was always less than at ordinary temperatures. This anomaly is all the more remarkable in that the behaviour of pure nickel is normal, as also appears to be generally the case with soft and hard iron. Silicon, tungsten and manganese steels are also substantially normal in their behaviour, although there are considerable differences in the magnitudes of the variations they display.
## Temperature
Low temperatures also affect the permeability of iron, i.e. the degree of magnetization it is capable of acquiring under the influence of a certain magnetic force. With fine Swedish iron, carefully annealed, the permeability is slightly. Hard iron, however, in the same circumstances suffers a large increase of permeability.
## Liquid air
At the Lister Institute of Preventive Medicine, liquid air has been brought into use as an agent in biological research. An inquiry into the intracellular constituents of the typhoid bacillus, initiated under the direction of Dr Allan Macfadyen, necessitated the separation of the cell-plasma of the organism. The method at first adopted for the disintegration of the bacteria was to mix them with silver-sand and churn the whole up in a closed vessel in which a series of horizontal vanes revolved at a high speed. But certain disadvantages attached to this procedure, and accordingly some means was sought to do away with the sand and triturate the bacilli per se. This was found in liquid air, which, as had long before been shown at the Royal Institution, has the power of reducing materials like grass or the leaves of plants to such a state of brittleness that they can easily be powdered in a mortar. By its aid a complete trituration of the typhoid bacilli has been accomplished at the Jenner Institute, and the same process, already applied with success also to yeast cells and animal cells, is being extended in other directions.
When air is liquefied the oxygen and nitrogen are condensed simultaneously. However, owing to its greater volatility the latter boils off the more quickly of the two, so that the remaining liquid becomes gradually richer and richer in oxygen.
# Liquefied natural gas
Liquefied natural gas is the different physical form of Natural gas. Since transportation of natural gas requires a large network of pipeline which is difficult across some terrains and oceans, and also need huge investment and long term planning. So the natural gas is liquefied, put under high pressure which transforms it into liquid. The liquefied gas is transported through Tankers with special air tight compartments. When the tank is opened and the liquid exposed to atmospheric pressure it spontaneously transforms into gas. | https://www.wikidoc.org/index.php/Liquid_gas | |
430794c31a31814c1c8db455bec21efa0d509052 | wikidoc | Lisinopril | Lisinopril
- When pregnancy is detected, enalapril maleate should be discontinued as soon as possible.
- Dosing Information
- Initial dose (not receiving a diuretic): Lisinopril 10 mg PO qd should be used.
- Usual dosage range: 20-40 mg/day
- Initial dose (with receiving a diuretic): Lisinopril 5 mg PO qd should be used.
- The diuretic should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL to reduce the likelihood of hypotension.
- Maintenance dose: Lisinopril 20-40 mg PO qd on two divided doses, adjust dose based on response (MAX 80 mg/day)
- Dosing Information: Adjunct
- Initial dose : Lisinopril 5 mg PO qd
- When initiating treatment with lisinopril in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. (See WARNINGS and PRECAUTIONS, Drug Interactions.) The appearance of hypotension after the initial dose of PRINIVIL does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.
- Maintenance dose: Lisinopril 5-20 mg PO qd
- Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia:
- In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or moderate to severe renal impairment (creatinine clearance less than or equal to 30 mL/min or serum creatinine greater than 3 mg/dL), therapy with PRINIVIL should be initiated at a dose of 2.5 mg once a day under close medical supervision.
- Dosing Information
- For hemodynamical stable patients within 24 hours of the onset of symptoms of acute myocardial infarction:
- Initial dose : 5 mg PO
- Followed by: 5 mg PO after 24 hours 10 mg after 48 hours
- Maintenance dose: 10 mg PO qd
- Dosing should continue for 6 weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. Patients with a low systolic blood pressure (less than or equal to 120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of PRINIVIL (see WARNINGS). If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour) PRINIVIL should be withdrawn. For patients who develop symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
- Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosage adjustment in myocardial infarction patients with severe renal impairment has been performed.
## Use in Elderly
- Dosing information
- In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so that dosage adjustments should be made with particular caution.
- Dosing information
- Recommended dosage: 40 mg PO qd
- Dosing information
- Recommended dosage: 10 mg/day
- Dosing information
- 2.5 mg PO qd
- Dosing information
- Initial dosage: 10 mg/day
- Maximum dosage: 40 mg/day
- Dosing information
- Monotherapy: 10 mg/day
- Combination Therapy: Adding candesartan to ACE inhibitor therapy produced significant reductions in blood pressure and urinary protein excretion among normotensive patients with chronic renal disease and proteinuria, based on an open-label, controlled, crossover trial (n=60)
- Dosing information
- Recommended dosage: 10 mg PO qd for 12 weeks.
- 10--25 mg PO qd
- Dosing Information for children 6 years or older
- Initial dose : Lisinopril 0.07 mg/kg po qd (up to 5 mg total) should be used.
- Maintenance dose: Lisinopril adjust based on response; doses above 0.61 mg/kg/day or 40 mg/day have not been studied.
- Patients with hereditary or idiopathic angioedema.
Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. In such cases PRINIVIL should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).
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.
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g., AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
# Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high-dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7 percent) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.
In patients at risk of excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of PRINIVIL or concomitant diuretic may be necessary.
## Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
## Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis 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.
# PRECAUTIONS
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including PRINIVIL, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia(serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1 percent of hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with myocardial infarction. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. PRINIVIL should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium. (See Drug Interactions.)
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, PRINIVIL may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
## Hypertension
- In clinical trials in patients with hypertension treated with lisinopril, discontinuation of therapy due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
- For adverse experiences occurring in greater than 1% of patients with hypertension treated with lisinopril or lisinopril plus hydrochlorothiazide in controlled clinical trials, and more frequently with lisinopril and/or lisinopril plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below.
## Heart Failure
- In patients with heart failure treated with lisinopril for up to four years, discontinuation of therapy due to clinical adverse experiences occurred in 11.0% of patients. In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with lisinopril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.
- The following table lists those adverse experiences which occurred in greater than 1% of patients with heart failure treated with lisinopril or placebo for up to 12 weeks in controlled clinical trials, and more frequently on lisinopril than placebo.
- Also observed at >1% with lisinopril but more frequent or as frequent on placebo than lisinopril in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough, and pruritus.
- Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia, depression, chest sound abnormalities, and pulmonary edema were also seen in controlled clinical trials, but were more common on placebo than lisinopril.
## Acute Myocardial Infarction
- In the GISSI-3 trial, in patients treated with lisinopril for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.
- Patients treated with lisinopril had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking lisinopril.
- In the GISSI-3 trial, hypotension (9.7%), renal dysfunction (2.0%), cough (0.5%), post infarction angina (0.3%), skin rash and generalized edema (0.01%), and angioedema (0.01%) resulted in withdrawal of treatment. In elderly patients treated with lisinopril, discontinuation due to renal dysfunction was 4.2%.
- Other clinical adverse experiences occurring in 0.3% to 1.0% of patients with hypertension or heart failure treated with lisinopril in controlled clinical trials and rarer, serious, possibly drug-related events reported in uncontrolled studies or marketing experience are listed below, and within each category are in order of decreasing severity.
## Body as a Whole
- Anaphylactoid reactions , syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial edema, virus infection, fever, chills, malaise.
## Cardiovascular
- Cardiac arrest; myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients; pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.
## Digestive
- Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) , vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry mouth.
## Hematologic
- Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia.
## Endocrine
- Diabetes mellitus.
## Metabolic
- Weight loss, dehydration, fluid overload, gout, weight gain.
## Musculoskeletal
- Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain, shoulder pain, arm pain, lumbago.
## Nervous System/Psychiatric
- Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability and nervousness.
## Respiratory System
- Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, bronchitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
## Skin
- Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.
## Special Senses
- Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing.
## Urogenital
- Renal failure, oliguria, renal dysfunction (see ]|] and Warnings and Precautions]] and Dosage and Administration, flank pain, gynecomastia, impotence.
## Miscellaneous
- A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.
## Angioedema
- Angioedema has been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately (see ]|] and Warnings and Precautions]]).
## Hypotension
- In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see ]).
## Fetal/Neonatal Morbidity and Mortality
- See ], Fetal/Neonatal Morbidity and Mortality.
## Cough
## Pediatric Patients
- The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
## Clinical Laboratory Test Findings
## Serum Electrolytes
- Hyperkalemia (see Warnings and Precautions), hyponatremia.
## Creatinine, Blood Urea Nitrogen
- In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalaprilat alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see Warnings and Precautions). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalaprilat and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.
## Hematology
- Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalaprilat but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded.
## Liver Function Tests
- Elevations of liver enzymes and/or serum bilirubin have occurred (see ], Hepatic Failure).
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
- Patients on diuretics and especially those in whom diuretic therapywas recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close medical supervision after the initial dose until blood pressure has stabilized. When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic.
## Indomethacin
- In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.
## Other Agents
- Lisinopril have been used concomitantly with nitrates and/or digoxin without evidence of clinically significant adverse interactions. This included post myocardial infarction patients who were receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions occurred when lisinopril were used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.
## Agents Increasing Serum Potassium
- Lisinopril attenuate potassium loss caused by thiazide-type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure who are receiving lisinopril.
## Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored frequently if lisinopril are administered concomitantly with lithium.
- Lisinopril is not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/ min/1.73m2.
- The usual dose of lisinopril tablets (10 mg) is recommended for patients with creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≥10 mL/min ≤30 mL/min (serum creatinine ≥3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance <10 mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
## Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia
- In patients with heart failure who have hyponatremia (serum sodium 3 mg/dL), therapy with lisinopril tablets should be initiated at a dose of 2.5 mg once a day under close medical supervision.
## Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment
- In acute myocardial infarction, treatment with lisinopril tablets should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed.
- Lisinopril tablets are indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. The appearance of hypotension after the initial dose of lisinopril tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
## Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia
- In patients with heart failure who have hyponatremia (serum sodium 3 mg/dL), therapy with lisinopril tablets should be initiated at a dose of 2.5 mg once a day under close medical supervision.
## Acute Myocardial Infarction
- In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, the first dose of lisinopril tablets is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of lisinopril tablets once daily. Dosing should continue for six weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Patients with a low systolic blood pressure (≤120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of lisinopril tablets. If hypotension occurs (systolic blood pressure ≤100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure ≤90 mmHg for more than 1 hour) lisinopril tablets should be withdrawn. For patients who develop symptoms of heart failure.
## Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment
- In acute myocardial infarction, treatment with lisinopril tablets should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed.
Lisinopril can be removed by hemodialysis. (See Warnings and Precautions, Anaphylactoid reactions during membrane exposure.)
- The beneficial effects of isinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated. While the mechanism through which lisinopril lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril are antihypertensive even in patients with low-renin hypertension.
- Although lisinopril were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than nonblack patients.
- Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial differences in blood pressure response were no longer evident.
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the active ingredient lisinopril, each tablet contains the following inactive ingredients: calcium phosphate, mannitol, magnesium stearate, and starch. The 10 mg and 20 mg tablets also contain iron oxide.
- In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.
- In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy. The antihypertensive effects of lisinopril are maintained during long term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.
- Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of lisinopril was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20 or 80 mg of lisinopril. In controlled clinical studies, lisinopril 20-80 mg have been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-200 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic pressure in a population that was 3/4 caucasian. Lisinopril were approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.
- Lisinopril had similar effectiveness and adverse effects in younger and older (>65 years) patients. They were less effective in blacks than in caucasians.
- In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
- In patients with renovascular hypertension lisinopril have been shown to be well tolerated and effective in controlling blood pressure.
- The absolute bioavailability of lisinopril is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers. Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
- Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and the area under the plasma concentration time curve (AUC) than younger patients. Lisinopril can be removed by hemodialysis.
- Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
- There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times- the maximum recommended daily human dose,
based on body weight and body surface area, respectively).
- There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 84 times- the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice. *Calculations assume a human weight of 50 kg and human body surface area of 1.62 m2. Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed 1.25 mg (0.02 mg/kg). This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
# heart failure
During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg, PRINIVIL as adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the studies beneficial response was also noted for: orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The effect of lisinopril on mortality in patients with heart failure has not been evaluated.
The once daily dosing for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses.
# Acute Myocardial Infarction
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI - 3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2 x 2 factorial design, to six weeks of either
PRINIVIL alone (n=4841),
nitrates alone (n=4869),
PRINIVIL plus nitrates (n=4841), or
-pen control (n=4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe heart failure, cardiogenic shock and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria >500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol. (See DOSAGE AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at six months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction ≤35%, or an akinetic-dyskinetic score ≥45%. Patients receiving PRINIVIL (n=9646) alone or with nitrates, had an 11 percent lower risk of death (2p =0.04) compared to patients receiving no PRINIVIL (n=9672) (6.4 percent versus 7.2 percent, respectively) at six weeks. Although patients randomized to receive PRINIVIL for up to six weeks also fared numerically better on the combined end-point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus 3.7 percent, respectively) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). (See ADVERSE REACTIONS, ACUTE myocardial infarction.)
2.5 mg Tablets (NDC 0310-0135) white, round, biconvex, uncoated tablets identified as “ZESTRIL 2 1/2” on one side and “135” on the other
side are supplied in bottles of 100 tablets.
## 5 mg Tablets
5 mg Tablets (NDC 0310-0130) pink, capsule-shaped, biconvex, bisected, uncoated tablets, identified “ZESTRIL” on one side and “130” on
the other side are supplied in bottles of 100 tablets and unit dose packages of 100 tablets.
## 10 mg Tablets
10 mg Tablets (NDC 0310-0131) pink, round, biconvex, uncoated tablets identified “ZESTRIL 10” debossed on one side, and “131”
debossed on the other side are supplied in bottles of 100 tablets and unit dose packages of 100 tablets.
## 20 mg Tablets
20 mg Tablets (NDC 0310-0132) red, round, biconvex, uncoated tablets identified “ZESTRIL 20” debossed on one side, and “132” debossed
-n the other side are supplied in bottles of 100 tablets and unit dose packages of 100 tablets.
## 30 mg Tablets
30 mg Tablets (NDC 0310-0133) red, round, biconvex, uncoated tablets identified “ZESTRIL 30” debossed on one side, and “133” debossed
-n the other side are supplied in bottles of 100 tablets.
## 40 mg Tablets
40 mg Tablets (NDC 0310-0134) yellow, round, biconvex, uncoated tablets identified “ZESTRIL 40” debossed on one side, and “134”
debossed on the other side are supplied in bottles of 100 tablets.
Dispense in a tight container, if product package is subdivided.
- Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.
- Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.
- Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use. (See Drug Interactions.)
- Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.
- Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to PRINIVIL during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Zestril - Zegerid
Zestril - Zetia
Zestril - ZyPREXA
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lisinopril) may be subject to a variety of adverse reactions, some of them serious.
## Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril. This may occur at any time during treatment. In such cases Lisinopril should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.
## 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.
## Anaphylactoid reactions during desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
## Anaphylactoid reactions during membrane exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
## Hypotension
- Excessive hypotension is rare in uncomplicated hypertensive patients treated with Lisinopril alone. Patients with heart failure given Lisinopril commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with Lisinopril in patients at risk for excessive hypotension who are able to tolerate such adjustments. In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
- If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of Lisinopril, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of Lisinopril or concomitant diuretic may be necessary.
## Neutropenia/Agranulocytosis
- Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
## 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.
## Fetal/Neonatal Morbidity and Mortality
- ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
- In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated.
- The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
- These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Lisinopril as soon as possible.
- Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
- If oligohydramnios is observed, Lisinopril should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
- Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
- No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
# Aortic Stenosis/Hypertrophic Cardiomyopathy
As with all vasodilators, lisinopril should be given with caution to patients with
-bstruction in the outflow tract of the left ventricle.
# Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be
anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of
the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including Lisinopril, may be associated
with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur.
Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of
Lisinopril and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood
urea nitrogen and serum creatinine, usually minor and transient, especially when Lisinoprilhas been given concomitantly with a diuretic. This
is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril
may be required.
- Patients with acute myocardial infarction in the GISSI-3 trial treated with Lisinoprilhad a higher (2.4% versus 1.1%) incidence of renal
dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). In acute myocardial infarction, treatment with Lisinopril should be initiated with caution in patients with evidence of
renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with Lisinopril
(serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal
-f Lisinopril.
- Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function.
# Hyperkalemia
- In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2% of hypertensive
patients and 4.8% of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients, 0.6% of patients with heart failure
and 0.1% of patients with myocardial infarction. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes
mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes,
which should be used cautiously, if at all, with lisinopril.
# Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been
reported with all ACE inhibitors, almost always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be
considered in the differential diagnosis of cough.
# Surgery/Anesthesia
- In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block
angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it
can be corrected by volume expansion.
# Angioedema
- Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme
inhibitors, including lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting
angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they
have consulted with the prescribing physician.
# Symptomatic Hypotension
- Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual
syncope occurs, the patient should be told to discontinue the drug until they have consulted with the prescribing physician.
- All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of
reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients
should be advised to consult with their physician.
# Hyperkalemia
- Patients should be told not to use salt substitutes containing potassium without consulting their physician.
# Leukopenia/Neutropenia
- Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a
sign of leukopenia/neutropenia.
# Pregnancy
- Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE
inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE inhibitor exposure that
has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
- ↑ Schjoedt KJ, Astrup AS, Persson F, Frandsen E, Boomsma F, Rossing K et al. (2009) Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia 52 (1):46-9. DOI:10.1007/s00125-008-1184-8 PMID: 18974967
- ↑ Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A et al. (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 351 (9095):28-31. PMID: 9433426
- ↑ Midtvedt K, Stokke ES, Hartmann A (1996) Successful long-term treatment of post-transplant erythrocytosis with losartan. Nephrol Dial Transplant 11 (12):2495-7. PMID: 9017632
- ↑ Pisani F, Tisone G, Alciati E, Vennarecci G, Pieragostini E, Casciani CU (1994) Role of ACE inhibitors in the treatment of erythrocytosis in patients with renal allograft. Transplant Proc 26 (5):2602-3. PMID: 7940809
- ↑ Brozena SC, Johnson MR, Ventura H, Hobbs R, Miller L, Olivari MT et al. (1996) Effectiveness and safety of diltiazem or lisinopril in treatment of hypertension after heart transplantation. Results of a prospective, randomized multicenter trail. J Am Coll Cardiol 27 (7):1707-12. PMID: 8636558
- ↑ Shiigai T, Shichiri M (2001) Late escape from the antiproteinuric effect of ace inhibitors in nondiabetic renal disease. Am J Kidney Dis 37 (3):477-83. PMID: 11228170
- ↑ Kincaid-Smith P, Fairley K, Packham D (2002) Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria. Nephrol Dial Transplant 17 (4):597-601. PMID: 11917051
- ↑ Schrader H, Stovner LJ, Helde G, Sand T, Bovim G (2001) Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 322 (7277):19-22. PMID: 11141144
- ↑ Bender WI (1995) ACE inhibitors for prophylaxis of migraine headaches. Headache 35 (8):470-1. PMID: 7591740
- ↑ "Lisinopril". The American Society of Health-System Pharmacists. Retrieved 3 April 2011..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}
- ↑ "". External link in |title= (help) | Lisinopril
- When pregnancy is detected, enalapril maleate should be discontinued as soon as possible.
- Dosing Information
- Initial dose (not receiving a diuretic): Lisinopril 10 mg PO qd should be used.
- Usual dosage range: 20-40 mg/day
- Initial dose (with receiving a diuretic): Lisinopril 5 mg PO qd should be used.
- The diuretic should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL to reduce the likelihood of hypotension.
- Maintenance dose: Lisinopril 20-40 mg PO qd on two divided doses, adjust dose based on response (MAX 80 mg/day)
- Dosing Information: Adjunct
- Initial dose : Lisinopril 5 mg PO qd
- When initiating treatment with lisinopril in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. (See WARNINGS and PRECAUTIONS, Drug Interactions.) The appearance of hypotension after the initial dose of PRINIVIL does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.
- Maintenance dose: Lisinopril 5-20 mg PO qd
- Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia:
- In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or moderate to severe renal impairment (creatinine clearance less than or equal to 30 mL/min or serum creatinine greater than 3 mg/dL), therapy with PRINIVIL should be initiated at a dose of 2.5 mg once a day under close medical supervision.
- Dosing Information
- For hemodynamical stable patients within 24 hours of the onset of symptoms of acute myocardial infarction:
- Initial dose : 5 mg PO
- Followed by: 5 mg PO after 24 hours 10 mg after 48 hours
- Maintenance dose: 10 mg PO qd
- Dosing should continue for 6 weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. Patients with a low systolic blood pressure (less than or equal to 120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of PRINIVIL (see WARNINGS). If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour) PRINIVIL should be withdrawn. For patients who develop symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
- Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosage adjustment in myocardial infarction patients with severe renal impairment has been performed.
### Use in Elderly
- Dosing information
- In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so that dosage adjustments should be made with particular caution.
- Dosing information
- Recommended dosage: 40 mg PO qd[1]
- Dosing information
- Recommended dosage: 10 mg/day[2]
- Dosing information
- 2.5 mg PO qd[3][4]
- Dosing information
- Initial dosage: 10 mg/day
- Maximum dosage: 40 mg/day[5]
- Dosing information
- Monotherapy: 10 mg/day[6]
- Combination Therapy: Adding candesartan to ACE inhibitor therapy produced significant reductions in blood pressure and urinary protein excretion among normotensive patients with chronic renal disease and proteinuria, based on an open-label, controlled, crossover trial (n=60)[7]
- Dosing information
- Recommended dosage: 10 mg PO qd for 12 weeks.[8]
- 10--25 mg PO qd [9]
- Dosing Information for children 6 years or older
- Initial dose : Lisinopril 0.07 mg/kg po qd (up to 5 mg total) should be used.
- Maintenance dose: Lisinopril adjust based on response; doses above 0.61 mg/kg/day or 40 mg/day have not been studied.
- Patients with hereditary or idiopathic angioedema.
Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. In such cases PRINIVIL should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).
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.
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g., AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
## Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high-dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7 percent) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.
In patients at risk of excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of PRINIVIL or concomitant diuretic may be necessary.
### Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
### Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis 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.
## PRECAUTIONS
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including PRINIVIL, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia(serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1 percent of hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with myocardial infarction. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. PRINIVIL should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium. (See Drug Interactions.)
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, PRINIVIL may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
### Hypertension
- In clinical trials in patients with hypertension treated with lisinopril, discontinuation of therapy due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
- For adverse experiences occurring in greater than 1% of patients with hypertension treated with lisinopril or lisinopril plus hydrochlorothiazide in controlled clinical trials, and more frequently with lisinopril and/or lisinopril plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below.
### Heart Failure
- In patients with heart failure treated with lisinopril for up to four years, discontinuation of therapy due to clinical adverse experiences occurred in 11.0% of patients. In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with lisinopril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.
- The following table lists those adverse experiences which occurred in greater than 1% of patients with heart failure treated with lisinopril or placebo for up to 12 weeks in controlled clinical trials, and more frequently on lisinopril than placebo.
- Also observed at >1% with lisinopril but more frequent or as frequent on placebo than lisinopril in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough, and pruritus.
- Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia, depression, chest sound abnormalities, and pulmonary edema were also seen in controlled clinical trials, but were more common on placebo than lisinopril.
### Acute Myocardial Infarction
- In the GISSI-3 trial, in patients treated with lisinopril for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.
- Patients treated with lisinopril had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking lisinopril.
- In the GISSI-3 trial, hypotension (9.7%), renal dysfunction (2.0%), cough (0.5%), post infarction angina (0.3%), skin rash and generalized edema (0.01%), and angioedema (0.01%) resulted in withdrawal of treatment. In elderly patients treated with lisinopril, discontinuation due to renal dysfunction was 4.2%.
- Other clinical adverse experiences occurring in 0.3% to 1.0% of patients with hypertension or heart failure treated with lisinopril in controlled clinical trials and rarer, serious, possibly drug-related events reported in uncontrolled studies or marketing experience are listed below, and within each category are in order of decreasing severity.
### Body as a Whole
- Anaphylactoid reactions , syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial edema, virus infection, fever, chills, malaise.
### Cardiovascular
- Cardiac arrest; myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients; pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.
### Digestive
- Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) , vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry mouth.
### Hematologic
- Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia.
### Endocrine
- Diabetes mellitus.
### Metabolic
- Weight loss, dehydration, fluid overload, gout, weight gain.
### Musculoskeletal
- Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain, shoulder pain, arm pain, lumbago.
### Nervous System/Psychiatric
- Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability and nervousness.
### Respiratory System
- Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, bronchitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
### Skin
- Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.
### Special Senses
- Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing.
### Urogenital
- Renal failure, oliguria, renal dysfunction (see [[Lisinopril#[[Lisinopril#Warnings|Warnings and Warnings and Precautions]]|[[Lisinopril#Warnings|Warnings and Warnings and Precautions]] and Warnings and Precautions]] and Dosage and Administration, flank pain, gynecomastia, impotence.
### Miscellaneous
- A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.
### Angioedema
- Angioedema has been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately (see [[Lisinopril#[[Lisinopril#Warnings|Warnings and Warnings and Precautions]]|[[Lisinopril#Warnings|Warnings and Warnings and Precautions]] and Warnings and Precautions]]).
### Hypotension
- In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see [[Lisinopril#Warnings|Warnings and Warnings and Precautions]]).
### Fetal/Neonatal Morbidity and Mortality
- See [[Lisinopril#Warnings|Warnings and Warnings and Precautions]], Fetal/Neonatal Morbidity and Mortality.
### Cough
### Pediatric Patients
- The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
### Clinical Laboratory Test Findings
### Serum Electrolytes
- Hyperkalemia (see Warnings and Precautions), hyponatremia.
### Creatinine, Blood Urea Nitrogen
- In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalaprilat alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see Warnings and Precautions). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalaprilat and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.
### Hematology
- Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalaprilat but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded.
### Liver Function Tests
- Elevations of liver enzymes and/or serum bilirubin have occurred (see [[Lisinopril#Warnings|Warnings and Warnings and Precautions]], Hepatic Failure).
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
- Patients on diuretics and especially those in whom diuretic therapywas recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril. If it is necessary to continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close medical supervision after the initial dose until blood pressure has stabilized. When a diuretic is added to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic.
### Indomethacin
- In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.
### Other Agents
- Lisinopril have been used concomitantly with nitrates and/or digoxin without evidence of clinically significant adverse interactions. This included post myocardial infarction patients who were receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions occurred when lisinopril were used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of lisinopril.
### Agents Increasing Serum Potassium
- Lisinopril attenuate potassium loss caused by thiazide-type diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure who are receiving lisinopril.
### Lithium
- Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored frequently if lisinopril are administered concomitantly with lithium.
- Lisinopril is not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/ min/1.73m2.
- The usual dose of lisinopril tablets (10 mg) is recommended for patients with creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≥10 mL/min ≤30 mL/min (serum creatinine ≥3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance <10 mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
### Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia
- In patients with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to severe renal impairment (creatinine clearance ≤30 mL/min or serum creatinine >3 mg/dL), therapy with lisinopril tablets should be initiated at a dose of 2.5 mg once a day under close medical supervision.
### Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment
- In acute myocardial infarction, treatment with lisinopril tablets should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed.
- Lisinopril tablets are indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. The appearance of hypotension after the initial dose of lisinopril tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
### Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia
- In patients with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to severe renal impairment (creatinine clearance ≤30 mL/min or serum creatinine >3 mg/dL), therapy with lisinopril tablets should be initiated at a dose of 2.5 mg once a day under close medical supervision.
### Acute Myocardial Infarction
- In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, the first dose of lisinopril tablets is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of lisinopril tablets once daily. Dosing should continue for six weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Patients with a low systolic blood pressure (≤120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of lisinopril tablets. If hypotension occurs (systolic blood pressure ≤100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure ≤90 mmHg for more than 1 hour) lisinopril tablets should be withdrawn. For patients who develop symptoms of heart failure.
### Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment
- In acute myocardial infarction, treatment with lisinopril tablets should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed.
Lisinopril can be removed by hemodialysis. (See Warnings and Precautions, Anaphylactoid reactions during membrane exposure.)
- The beneficial effects of isinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated. While the mechanism through which lisinopril lower blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril are antihypertensive even in patients with low-renin hypertension.
- Although lisinopril were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than nonblack patients.
- Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial differences in blood pressure response were no longer evident.
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the active ingredient lisinopril, each tablet contains the following inactive ingredients: calcium phosphate, mannitol, magnesium stearate, and starch. The 10 mg and 20 mg tablets also contain iron oxide.
- In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.
- In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy. The antihypertensive effects of lisinopril are maintained during long term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.
- Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of lisinopril was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20 or 80 mg of lisinopril. In controlled clinical studies, lisinopril 20-80 mg have been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-200 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic pressure in a population that was 3/4 caucasian. Lisinopril were approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.
- Lisinopril had similar effectiveness and adverse effects in younger and older (>65 years) patients. They were less effective in blacks than in caucasians.
- In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
- In patients with renovascular hypertension lisinopril have been shown to be well tolerated and effective in controlling blood pressure.
- The absolute bioavailability of lisinopril is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers. Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
- Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and the area under the plasma concentration time curve (AUC) than younger patients. Lisinopril can be removed by hemodialysis.
- Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
- There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum recommended daily human dose,
based on body weight and body surface area, respectively).
- There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice. *Calculations assume a human weight of 50 kg and human body surface area of 1.62 m2. Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with consistent antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
## heart failure
During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg, PRINIVIL as adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the studies beneficial response was also noted for: orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The effect of lisinopril on mortality in patients with heart failure has not been evaluated.
The once daily dosing for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses.
## Acute Myocardial Infarction
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI - 3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2 x 2 factorial design, to six weeks of either
PRINIVIL alone (n=4841),
nitrates alone (n=4869),
PRINIVIL plus nitrates (n=4841), or
open control (n=4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe heart failure, cardiogenic shock and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria >500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol. (See DOSAGE AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at six months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction ≤35%, or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving PRINIVIL (n=9646) alone or with nitrates, had an 11 percent lower risk of death (2p [two-tailed]=0.04) compared to patients receiving no PRINIVIL (n=9672) (6.4 percent versus 7.2 percent, respectively) at six weeks. Although patients randomized to receive PRINIVIL for up to six weeks also fared numerically better on the combined end-point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus 3.7 percent, respectively) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). (See ADVERSE REACTIONS, ACUTE myocardial infarction.)
2.5 mg Tablets (NDC 0310-0135) white, round, biconvex, uncoated tablets identified as “ZESTRIL 2 1/2” on one side and “135” on the other
side are supplied in bottles of 100 tablets.
### 5 mg Tablets
5 mg Tablets (NDC 0310-0130) pink, capsule-shaped, biconvex, bisected, uncoated tablets, identified “ZESTRIL” on one side and “130” on
the other side are supplied in bottles of 100 tablets and unit dose packages of 100 tablets.
### 10 mg Tablets
10 mg Tablets (NDC 0310-0131) pink, round, biconvex, uncoated tablets identified “ZESTRIL 10” debossed on one side, and “131”
debossed on the other side are supplied in bottles of 100 tablets and unit dose packages of 100 tablets.
### 20 mg Tablets
20 mg Tablets (NDC 0310-0132) red, round, biconvex, uncoated tablets identified “ZESTRIL 20” debossed on one side, and “132” debossed
on the other side are supplied in bottles of 100 tablets and unit dose packages of 100 tablets.
### 30 mg Tablets
30 mg Tablets (NDC 0310-0133) red, round, biconvex, uncoated tablets identified “ZESTRIL 30” debossed on one side, and “133” debossed
on the other side are supplied in bottles of 100 tablets.
### 40 mg Tablets
40 mg Tablets (NDC 0310-0134) yellow, round, biconvex, uncoated tablets identified “ZESTRIL 40” debossed on one side, and “134”
debossed on the other side are supplied in bottles of 100 tablets.
Dispense in a tight container, if product package is subdivided.
- Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.
- Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.
- Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use. (See Drug Interactions.)
- Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.
- Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to PRINIVIL during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Zestril - Zegerid
Zestril - Zetia
Zestril - ZyPREXA[11]
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lisinopril) may be subject to a variety of adverse reactions, some of them serious.
### Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril. This may occur at any time during treatment. In such cases Lisinopril should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.
### 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.
### Anaphylactoid reactions during desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
### Anaphylactoid reactions during membrane exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
### Hypotension
- Excessive hypotension is rare in uncomplicated hypertensive patients treated with Lisinopril alone. Patients with heart failure given Lisinopril commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with Lisinopril in patients at risk for excessive hypotension who are able to tolerate such adjustments. In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
- If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of Lisinopril, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of Lisinopril or concomitant diuretic may be necessary.
### Neutropenia/Agranulocytosis
- Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
### 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.
### Fetal/Neonatal Morbidity and Mortality
- ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
- In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been repeated.
- The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
- These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Lisinopril as soon as possible.
- Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
- If oligohydramnios is observed, Lisinopril should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
- Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
- No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
## Aortic Stenosis/Hypertrophic Cardiomyopathy
As with all vasodilators, lisinopril should be given with caution to patients with
obstruction in the outflow tract of the left ventricle.
## Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be
anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of
the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including Lisinopril, may be associated
with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
- In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur.
Experience with another angiotensin-converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of
Lisinopril and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood
urea nitrogen and serum creatinine, usually minor and transient, especially when Lisinoprilhas been given concomitantly with a diuretic. This
is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril
may be required.
- Patients with acute myocardial infarction in the GISSI-3 trial treated with Lisinoprilhad a higher (2.4% versus 1.1%) incidence of renal
dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). In acute myocardial infarction, treatment with Lisinopril should be initiated with caution in patients with evidence of
renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with Lisinopril
(serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal
of Lisinopril.
- Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function.
## Hyperkalemia
- In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2% of hypertensive
patients and 4.8% of patients with heart failure. In most cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients, 0.6% of patients with heart failure
and 0.1% of patients with myocardial infarction. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes
mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes,
which should be used cautiously, if at all, with lisinopril.
## Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been
reported with all ACE inhibitors, almost always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be
considered in the differential diagnosis of cough.
## Surgery/Anesthesia
- In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block
angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it
can be corrected by volume expansion.
## Angioedema
- Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin-converting enzyme
inhibitors, including lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting
angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they
have consulted with the prescribing physician.
## Symptomatic Hypotension
- Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual
syncope occurs, the patient should be told to discontinue the drug until they have consulted with the prescribing physician.
- All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of
reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients
should be advised to consult with their physician.
## Hyperkalemia
- Patients should be told not to use salt substitutes containing potassium without consulting their physician.
## Leukopenia/Neutropenia
- Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a
sign of leukopenia/neutropenia.
## Pregnancy
- Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE
inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE inhibitor exposure that
has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
- ↑ Schjoedt KJ, Astrup AS, Persson F, Frandsen E, Boomsma F, Rossing K et al. (2009) Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia 52 (1):46-9. DOI:10.1007/s00125-008-1184-8 PMID: 18974967
- ↑ Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A et al. (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 351 (9095):28-31. PMID: 9433426
- ↑ Midtvedt K, Stokke ES, Hartmann A (1996) Successful long-term treatment of post-transplant erythrocytosis with losartan. Nephrol Dial Transplant 11 (12):2495-7. PMID: 9017632
- ↑ Pisani F, Tisone G, Alciati E, Vennarecci G, Pieragostini E, Casciani CU (1994) Role of ACE inhibitors in the treatment of erythrocytosis in patients with renal allograft. Transplant Proc 26 (5):2602-3. PMID: 7940809
- ↑ Brozena SC, Johnson MR, Ventura H, Hobbs R, Miller L, Olivari MT et al. (1996) Effectiveness and safety of diltiazem or lisinopril in treatment of hypertension after heart transplantation. Results of a prospective, randomized multicenter trail. J Am Coll Cardiol 27 (7):1707-12. PMID: 8636558
- ↑ Shiigai T, Shichiri M (2001) Late escape from the antiproteinuric effect of ace inhibitors in nondiabetic renal disease. Am J Kidney Dis 37 (3):477-83. PMID: 11228170
- ↑ Kincaid-Smith P, Fairley K, Packham D (2002) Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria. Nephrol Dial Transplant 17 (4):597-601. PMID: 11917051
- ↑ Schrader H, Stovner LJ, Helde G, Sand T, Bovim G (2001) Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 322 (7277):19-22. PMID: 11141144
- ↑ Bender WI (1995) ACE inhibitors for prophylaxis of migraine headaches. Headache 35 (8):470-1. PMID: 7591740
- ↑ "Lisinopril". The American Society of Health-System Pharmacists. Retrieved 3 April 2011..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}
- ↑ "https://www.ismp.org". External link in |title= (help) | https://www.wikidoc.org/index.php/Lisinopril | |
0d46153951e1739ec8ce50de2530808a13fe38f9 | wikidoc | Live birth | Live birth
For organisms where the embryo develops inside the mother as opposed to an egg, see vivipary.
# Overview
A live birth occurs when a fetus, whatever its gestational age, exits the maternal body and subsequently shows any sign of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord, for however brief a time and regardless of whether the umbilical cord or placenta are intact.
# Historical Perspective
This definition of the term "live birth" was created by the World Health Organization in 1950 and is chiefly used for public health and statistical purposes. Whether the birth is vaginal or by Caesarean section, and whether the neonate is ultimately viable, is not relevant to this statistical definition. However, the term "live birth" was in common use long before 1950.
In the United States, the term "born alive" is defined by federal statute. | Live birth
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
For organisms where the embryo develops inside the mother as opposed to an egg, see vivipary.
# Overview
A live birth occurs when a fetus, whatever its gestational age, exits the maternal body and subsequently shows any sign of life, such as voluntary movement, heartbeat, or pulsation of the umbilical cord, for however brief a time and regardless of whether the umbilical cord or placenta are intact.[1]
# Historical Perspective
This definition of the term "live birth" was created by the World Health Organization in 1950 and is chiefly used for public health and statistical purposes. Whether the birth is vaginal or by Caesarean section, and whether the neonate is ultimately viable, is not relevant to this statistical definition. However, the term "live birth" was in common use long before 1950.
In the United States, the term "born alive" is defined by federal statute. | https://www.wikidoc.org/index.php/Live_birth | |
b2d69530dc8eff80e4a8a390fc4df13df5fef01a | wikidoc | Lofentanil | Lofentanil
Lofentanil is an opioid analgesic that is an analogue of fentanyl and was developed in the early 1980s.
Lofentanil is most similar to the highly potent opioid carfentanil (4-carbomethoxyfentanyl). Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. However it is interesting to note that while 3-methylfentanyl is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil. This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance which prevents μ-opioid affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl, the stereoisomerism of lofentanil is very important, with some stereoisomers being much more potent than others.
Lofentanil is very similar to carfentanil in effects, but has a longer duration of action. This makes it unsuitable for most practical applications, with carfentanil being the preferred agent for tranquilizing large animals, and short-acting derivatives such as sufentanil or remifentanil being preferred for medical use in human surgical procedures. The long duration and high lipophilicity of lofentanil has been suggested as an advantage for certain types of analgesia, but the main application for lofentanil at the present time is research into opiate receptors.
Side effects from lofentanil would be predicted to be similar to other potent fentanyl analogues, and would include sedation, euphoria, nausea, and pronounced itching and respiratory depression. Side effects from lofentanil might be particularly problematic given its reportedly long duration of action. Another side effect which is characteristic of fentanyl and its derivatives is their tendency to rapidly induce tolerance, due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors. This might be expected to be a particular problem with lofentanil as it is not only one of the most potent drugs in the series, but also is longer acting than most other fentanyl analogues, meaning that development of tolerance triggered by receptor over-activation is likely to be especially rapid. | Lofentanil
Lofentanil is an opioid analgesic that is an analogue of fentanyl and was developed in the early 1980s.
Lofentanil is most similar to the highly potent opioid carfentanil (4-carbomethoxyfentanyl). Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. However it is interesting to note that while 3-methylfentanyl is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil.[1][2] This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance which prevents μ-opioid affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl, the stereoisomerism of lofentanil is very important, with some stereoisomers being much more potent than others.
Lofentanil is very similar to carfentanil in effects, but has a longer duration of action.[3] This makes it unsuitable for most practical applications, with carfentanil being the preferred agent for tranquilizing large animals, and short-acting derivatives such as sufentanil or remifentanil being preferred for medical use in human surgical procedures. The long duration and high lipophilicity of lofentanil has been suggested as an advantage for certain types of analgesia,[4] but the main application for lofentanil at the present time is research into opiate receptors.[5][6]
Side effects from lofentanil would be predicted to be similar to other potent fentanyl analogues, and would include sedation, euphoria, nausea, and pronounced itching and respiratory depression. Side effects from lofentanil might be particularly problematic given its reportedly long duration of action. Another side effect which is characteristic of fentanyl and its derivatives is their tendency to rapidly induce tolerance, due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors.[7] This might be expected to be a particular problem with lofentanil as it is not only one of the most potent drugs in the series, but also is longer acting than most other fentanyl analogues, meaning that development of tolerance triggered by receptor over-activation is likely to be especially rapid. | https://www.wikidoc.org/index.php/Lofentanil | |
cc1c7c50a6b1e6cebddd10d18d61538b519260b2 | wikidoc | Lofexidine | Lofexidine
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# Overview
Lofexidine is a central alpha-2 adrenergic agonist that is FDA approved for the mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. Common adverse reactions include orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Lofexidine is indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.
- The usual lofexidine starting dosage is three 0.18 mg tablets taken orally 4 times daily during the period of peak withdrawal symptoms (generally the first 5 to 7 days following last use of opioid) with dosing guided by symptoms and side effects. There should be 5 to 6 hours between each dose. The total daily dosage of lofexidine should not exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets).
- Lofexidine treatment may be continued for up to 14 days with dosing guided by symptoms.
- Discontinue lofexidine with a gradual dose reduction over a 2- to 4-day period to mitigate lofexidine withdrawal symptoms (e.g., reducing by 1 tablet per dose every 1 to 2 days). The lofexidine dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to lofexidine side effects. Lower doses may be appropriate as opioid withdrawal symptoms wane.
- Lofexidine can be administered in the presence or absence of food.
- Recommended dosage adjustments based on the degree of hepatic impairment are shown in Table 1.
- Recommended dosage adjustments based on the degree of renal impairment are shown in Table 2. Lofexidine may be administered without regard to the timing of dialysis
- Lofexidine is available as round, peach-colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side. Each tablet contains 0.18 mg lofexidine (equivalent to 0.2 mg of lofexidine hydrochloride).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding lofexidine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding lofexidine 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 Lofexidine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding lofexidine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding lofexidine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Lofexidine can cause a decrease in blood pressure, a decrease in pulse, and syncope. Monitor vital signs before dosing. Monitor symptoms related to bradycardia and orthostasis.
- Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.
- Inform patients that lofexidine may cause hypotension and that patients moving from a supine to an upright position may be at increased risk for hypotension and orthostatic effects. Instruct patients to stay hydrated, on how to recognize symptoms of low blood pressure, and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Instruct outpatients to withhold lofexidine doses when experiencing symptoms of hypotension or bradycardia and to contact their healthcare provider for guidance on how to adjust dosing.
- Avoid using lofexidine in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, and in patients with marked bradycardia.
- Avoid using lofexidine in combination with medications that decrease pulse or blood pressure to avoid the risk of excessive bradycardia and hypotension.
- Lofexidine prolongs the QT interval.
- Avoid using lofexidine in patients with congenital long QT syndrome.
- Monitor ECG in patients with congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking other medicinal products that lead to QT prolongation (e.g., methadone). In patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), correct these abnormalities first, and monitor ECG upon initiation of lofexidine.
- Lofexidine potentiates the CNS depressive effects of benzodiazepines and can also be expected to potentiate the CNS depressive effects of alcohol, barbiturates, and other sedating drugs. Advise patients to inform their healthcare provider of other medications they are taking, including alcohol.
- Advise patients using lofexidine in an outpatient setting that, until they learn how they respond to lofexidine, they should be careful or avoid doing activities such as driving or operating heavy machinery.
- Lofexidine is not a treatment for opioid use disorder. Patients who complete opioid discontinuation are likely to have a reduced tolerance to opioids and are at increased risk of fatal overdose should they resume opioid use. Use lofexidine in patients with opioid use disorder only in conjunction with a comprehensive management program for the treatment of opioid use disorder and inform patients and caregivers of this increased risk of overdose.
- Stopping lofexidine abruptly can cause a marked rise in blood pressure. Symptoms including diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain have also been observed with lofexidine discontinuation. Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy with lofexidine tablets, gradually reduce the dose.
- Symptoms related to discontinuation can be managed by administration of the previous lofexidine dose and subsequent taper.
# 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 adverse reaction rates observed for another drug and may not reflect the rates observed in practice.
- The safety of lofexidine was supported by three randomized, double-blind, placebo-controlled clinical trials, an open-label study, and clinical pharmacology studies with concomitant administration of either methadone, buprenorphine, or naltrexone.
- The three randomized, double-blind, placebo-controlled clinical trials enrolled 935 subjects dependent on short-acting opioids undergoing abrupt opioid withdrawal. Patients were monitored before each dose in an inpatient setting.
- Table 3 presents the incidence, rounded to the nearest percent, of adverse events that occurred in at least 10% of subjects treated with lofexidine and for which the incidence in patients treated with lofexidine was greater than the incidence in subjects treated with placebo in a study that tested two doses of lofexidine, 2.16 mg per day and 2.88 mg per day, and placebo. The overall safety profile in the combined dataset was similar.
- Orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth were notably more common in subjects treated with lofexidine than subjects treated with placebo.
- Other notable adverse reactions associated with the use of lofexidine but reported in <10% of patients in the lofexidine group included:
- Syncope: 0.9%, 1.4% and 0% for lofexidine 2.16 mg/day and 2.88 mg/day and placebo, respectively
- Tinnitus: 0.9%, 3.2% and 0% for lofexidine 2.16 mg/day and 2.88 mg/day and placebo, respectively
- Elevations in blood pressure above normal values (≥ 140 mmHg systolic) and above a subject's pre-treatment baseline are associated with discontinuing lofexidine, and peaked on the second day after discontinuation, as shown in Table 4. Blood pressure values were evaluated for 3 days following the last dose of a 5-day course of lofexidine 2.88 mg/day.
- Blood pressure elevations of a similar magnitude and incidence were observed in a small number of patients (N=10) that had a one-day, 50% dose reduction prior to discontinuation.
- After stopping treatment, subjects that were taking lofexidine also had a higher incidence of diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain compared to subjects who were taking placebo.
- Four out of 101 females (4%) had serious cardiovascular adverse events compared to 3 out of 289 (1%) of males assigned to receive lofexidine 2.88 mg per day.
- Discontinuations and dose holds due to bradycardia and orthostatic hypotension, which are the most common adverse reactions associated with lofexidine, occurred with a greater incidence in females assigned to receive the highest studied dose of lofexidine, 2.88 mg per day as shown in Table 5.
## Postmarketing Experience
- Lofexidine is marketed in other countries for relief of opioid withdrawal symptoms. The following events have been identified during postmarketing use of lofexidine. 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.
- Since lofexidine's initial market introduction in 1992, the most frequently reported postmarketing adverse event with lofexidine has been hypotension. There has been one report of QT prolongation, bradycardia, torsades de pointes, and cardiac arrest with successful resuscitation in a patient that received lofexidine and three reports of clinically significant QT prolongation in subjects concurrently receiving methadone with lofexidine.
# Drug Interactions
- Methadone
- Oral Naltrexone
- CNS Depressant Drugs
- CYP2D6 Inhibitor - Paroxetine
- Lofexidine and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and lofexidine.
- Coadministration of lofexidine and oral naltrexone resulted in statistically significant differences in the steady-state pharmacokinetics of naltrexone. It is possible that oral naltrexone efficacy may be reduced if used concomitantly within 2 hours of lofexidine. This interaction is not expected if naltrexone is administered by non-oral routes.
- Lofexidine potentiates the CNS depressant effects of benzodiazepines and may potentiate the CNS depressant effects of alcohol, barbiturates, and other sedating drugs. Advise patients to inform their healthcare provider of other medications they are taking, including alcohol.
- Coadministration of lofexidine and paroxetine resulted in 28% increase in the extent of absorption of lofexidine. Monitor for orthostatic hypotension and bradycardia when an inhibitor of CYP2D6 is used concomitantly with lofexidine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The safety of lofexidine in pregnant women has not been established. In animal reproduction studies, oral administration of lofexidine during organogenesis to pregnant rats and rabbits caused a reduction in fetal weights, increases in fetal resorptions, and litter loss at exposures below that in humans. When oral lofexidine was administered from the beginning of organogenesis through lactation, increased stillbirths and litter loss were noted along with decreased viability and lactation indices. The offspring exhibited delays in sexual maturation, auditory startle, and surface righting. These effects occurred at exposures below that in humans.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects in the U.S. general population is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
- Increased incidence of resorptions, decreased number of implantations, and a concomitant reduction in the number of fetuses were observed when pregnant rabbits were orally administered lofexidine hydrochloride during organogenesis (from gestation day 7 to 19) at a daily dose of 5.0 mg/kg/day (approximately 0.08 times the maximum recommended human dose of 2.88 mg lofexidine base on an AUC basis). Maternal toxicity evidenced by increased mortality was noted at the highest tested dose of 15 mg/kg/day (approximately 0.4 times the MRHD on an AUC basis).
- Decreased implantations per dam and decreased mean fetal weights were noted in a study in which pregnant rats were treated with oral lofexidine hydrochloride during organogenesis (from GD 7 to 16) at a daily dose of 3.0 mg/kg/day (approximately 0.9 times the MRHD on an AUC basis). This dose was associated with maternal toxicity (decreased body weight gain and mortality). No malformations or evidence of developmental toxicity were evident at 1.0 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis).
- A dose-dependent increase in pup mortality was noted in all doses of lofexidine hydrochloride administered orally to pregnant rats from GD 6 through lactation at an exposure less than the human exposure based on AUC comparisons. Doses higher than 1.0 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis) resulted in incidences of total litter loss and maternal toxicity (piloerection and decreased body weight gain). The highest dose tested of 2.0 mg/kg/day (approximately 0.6 times the MRHD on an AUC basis), increased stillbirths as well as decreased viability and lactation indices were reported. Surviving offspring exhibited lower body weights, developmental delays, and increased delays in auditory startle at doses of 1.0 mg/kg/day or higher. Sexual maturation was delayed in male offspring (preputial separation) at 2.0 mg/kg/day and in female offspring (vaginal opening) at 1.0 mg/kg/day or higher.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lofexidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lofexidine during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of lofexidine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Caution should be exercised when lofexidine is administered to a nursing woman.
- The developmental and health benefits should be considered along with the mother's clinical need for lofexidine and any other potential adverse effects on breastfed children from lofexidine or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of lofexidine have not been established in pediatric patients.
### Geriatic Use
- No studies have been performed to characterize the pharmacokinetics of lofexidine or establish its safety and effectiveness in geriatric patients. Caution should be exercised when it is administered to patients over 65 years of age. Dosing adjustments similar to those recommended in patients with renal impairment should be considered.
### Gender
There is no FDA guidance on the use of Lofexidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lofexidine with respect to specific racial populations.
### Renal Impairment
- Renal impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of renal impairment.
- Only a negligible fraction of the lofexidine dose is removed during a typical dialysis session, so no additional dose needs to be administered after a dialysis session; lofexidine may be administered without regard to the timing of dialysis.
- Clinically relevant QT prolongation may occur in subjects with renal impairment.
### Hepatic Impairment
- Hepatic impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of hepatic impairment.
- Clinically relevant QT prolongation may occur in subjects with hepatic impairment.
### Females of Reproductive Potential and Males
- In animal studies that included some fertility endpoints, lofexidine decreased breeding rate and increased resorptions at exposures below human exposures. The impact of lofexidine on male fertility has not been adequately characterized in animal studies.
### Immunocompromised Patients
There is no FDA guidance one the use of Lofexidine in patients who are immunocompromised.
### CYP2D6 Poor Metabolizers
- Although the pharmacokinetics of lofexidine have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to lofexidine would be increased similarly to taking strong CYP2D6 inhibitors (approximately 28%). Monitor adverse events such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).
# Administration and Monitoring
### Administration
- Oral.
### Monitoring
- Reduction in signs and symptoms of opioid withdrawal and compliance with therapy is indicative of efficacy.
- Vital signs: Prior to dosing.
- Symptoms related to bradycardia and orthostasis: During therapy.
- ECG: In patients with congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking other medicinal products that lead to QT prolongation (eg, methadone). Correct electrolyte abnormalities prior to ECG monitoring and initiation of therapy.
# IV Compatibility
There is limited information regarding the compatibility of Lofexidine and IV administrations.
# Overdosage
- Overdose with lofexidine may manifest as hypotension, bradycardia, and sedation. In the event of acute overdose, perform gastric lavage where appropriate. Dialysis will not remove a substantial portion of the drug. Initiate general symptomatic and supportive measures in cases of overdosage.
# Pharmacology
## Mechanism of Action
- Lofexidine is a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.
## Structure
## Pharmacodynamics
- Single lofexidine doses of 1.44 to 1.8 mg produced maximum mean change from baseline in QTcF (ΔQTcF) of 14.4 msec (upper two-sided 90% CI: 22.3 msec) and 13.6 msec (17.4 msec) for 1.44 and 1.8 mg respectively in healthy normal volunteers.
- In a Phase 3 placebo-controlled, dose response study in opioid dependent subjects, lofexidine was associated with a maximum mean prolongation of the QTcF interval 7.3 (8.8) and 9.3 (10.9) msec at doses of 2.16 and 2.88 mg/day, respectively.
Patients With Hepatic Impairment
- Administration of lofexidine to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairment.
Patients With Renal Impairment
- Administration of lofexidine to subjects with renal impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe renal impairment.
Lofexidine Coadministered With Methadone
- Lofexidine (2.88 mg/day) coadministered with methadone in 18 methadone-maintained patients (80-120 mg/day) resulted in a maximum mean increase from methadone-alone baseline in QTcF of 9.1 (14.2) msec.
Lofexidine Coadministered With Buprenorphine
- Lofexidine (2.88 mg/day) coadministered with buprenorphine in 21 buprenorphine-maintained patients (16-24 mg/day) resulted in a maximum mean QTcF increase in QTcF of 15 (5.6) msec compared to a buprenorphine-alone baseline.
- Lofexidine exhibits in vitro binding affinity and functional agonist activity with alpha-2A and alpha-2C adrenoreceptors at concentrations within clinical exposure plasma levels (Ki values of approximately 7.2 nM and 12 nM, and EC50 values of 4.9 nM and 0.9 nM, respectively).
## Pharmacokinetics
- Lofexidine is well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose.
- Lofexidine shows approximately dose-proportional pharmacokinetics. Administration of lofexidine with food does not alter its pharmacokinetics.
- The absolute bioavailability of a single oral lofexidine dose ( 0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean lofexidine Cmax after the oral dose and intravenous infusion was 0.82 ng/mL (at median Tmax of 3 hours) and 0.64 ng/mL (at median Tmax of 4 hours), respectively. Mean estimates of overall systemic exposure (AUCinf) were 14.9 ng∙h/mL and 12.0 ng∙h/mL, respectively.
- Mean lofexidine apparent volume of distribution and volume of distribution values following the administration of an oral dose and an intravenous dose were 480.0 L and 297.9 L, respectively, which are appreciably greater than total body volume, suggesting extensive lofexidine distribution into body tissue.
- Lofexidine protein binding is approximately 55%.
- Lofexidine is not preferentially taken up by blood cells. In a study comparing lofexidine concentrations in plasma and whole blood at the time of peak lofexidine concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the lofexidine concentration of the plasma.
Metabolism
- From absolute bioavailability results, approximately 30% of the administered lofexidine dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut.
- Lofexidine and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by lofexidine, with an IC50 of 4551 nM (approximately 225 times the steady-state Cmax for lofexidine with 0.72 mg 4 times daily dosing). Any lofexidine interaction with CYP2D6 substrates is not expected to be clinically significant.
- Lofexidine is metabolized when incubated in vitro with human liver microsomes, the major contributor to the hepatic metabolism of lofexidine is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing lofexidine.
Excretion
- The elimination half-life is approximately 12 hours and mean clearance is 17.6 L/h following an IV infusion.
- Lofexidine has a terminal half-life of approximately 11 to 13 hours following the first dose. At steady-state, the terminal half-life is approximately 17 to 22 hours. Accumulation occurs up to 4 days with repeat dosing, following the recommended dosing regimen.
- A mass balance study of lofexidine showed nearly complete recovery of radiolabel in urine (93.5%) over 144 hours postdose, with an additional 0.92% recovered in the feces over 216 hours postdose. Thus, it appears that all, or nearly all, of the dose was absorbed, and that the primary route of elimination of the parent drug and its metabolites is via the kidney. Renal elimination of unchanged drug accounts for approximately 15% to 20% of the administered dose.
Hepatic Impairment
- Hepatic impairment slows the elimination of lofexidine, but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in mild, moderate, and severe hepatically impaired subjects to subjects with normal hepatic function (6 subjects in each hepatic function group), mean Cmax values were similar for subjects with normal, mild, and moderate hepatic impairment as shown in Table 6.
Renal Impairment
- Renal impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 8 end-stage renal disease subjects on 3 times weekly hemodialysis to 8 subjects with normal renal function matched for sex, age, and body mass index, mean Cmax values were similar for end-stage renal disease and normal renal function subjects, indicating no change in maximum lofexidine exposure with renal impairment as shown in Table 7.
- The impact of dialysis on the overall pharmacokinetics of lofexidine during a typical 4-hour dialysis was minimal; the drop in lofexidine plasma concentrations produced during the dialysis session was transient, with a rebound to nearly predialysis concentrations after re-equilibration within a few hours following completion of the dialysis cycle.
- In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 6 subjects each with normal renal function, mild renal impairment, and moderate renal impairment as well as 5 subjects with severe renal impairment but not requiring dialysis, there were similar increases in mean Cmax values in subjects with mild and moderate renal impairment in comparison to subjects with normal renal function with additional increase in mean Cmax values in subjects with severe renal impairment. Mean AUClast, AUC∞, and t1/2 increased with severity of renal impairment as shown in Table 7.
Lofexidine coadministered with methadone
- In a double-blind placebo-controlled study of 23 patients maintained on a methadone dose of 80-120 mg/day and concomitantly administered lofexidine up to 2.88 mg/day, lofexidine did not alter the pharmacokinetics of methadone. Lofexidine concentrations may be slightly increased when coadministered with methadone; however, the increase at concentrations expected with recommended dosing is not clinically meaningful.
Lofexidine coadministered with buprenorphine
- In a double-blind placebo-controlled study of 30 subjects maintained on buprenorphine (16-24 mg/day) concomitantly administered lofexidine up to 2.88 mg/day, no pharmacokinetic or pharmacodynamic interactions between lofexidine and buprenorphine were seen.
Lofexidine coadministered with oral naltrexone
- In an open-label, single-arm study of 24 healthy subjects, oral naltrexone (50 mg/day) did not significantly alter the single-dose pharmacokinetics of lofexidine (0.36 mg). The alteration in steady-state pharmacokinetics of oral naltrexone was statistically significant in the presence of lofexidine. The tmax was delayed for both naltrexone and 6ß-naltrexol (2-3 hours), and overall exposure was slightly reduced when naltrexone was administered with lofexidine.
Lofexidine coadministered with paroxetine
- In an open-label, single-sequence study of 24 healthy subjects, the strong CYP2D6 inhibitor paroxetine (40 mg/day) increased lofexidine (0.36 mg) Cmax and AUC∞ by approximately 11% and 28%, respectively.
## Nonclinical Toxicology
- No adequate long-term animal studies have been completed to evaluate the carcinogenic potential of lofexidine.
- Lofexidine tested positive in the in vitro mouse lymphoma assay. Lofexidine tested negative in the in vitro bacterial reverse mutation assay (Ames assay) and in the in vivo rat micronucleus assay.
- In a female fertility study in rabbits, fertility was not adversely impacted by administration of lofexidine hydrochloride up to 6.4 mg/kg/day (approximately 0.1 times the MRHD of 2.88 mg on an AUC basis) when administered orally to female rabbits starting 2 weeks prior to mating and through gestation and lactation. However, decreased breeding rate and higher post-implantation loss was observed at this dose, which correlated with higher resorptions and reduced litter size. Maternal toxicity, which included increased mortality rate, reduced body weight gain, and moderate sedation was observed at 6.4 mg/kg/day. The NOAEL for female fertility was 6.4 mg/kg/day and the NOAEL for female-mediated developmental parameters was 0.4 mg/kg/day (approximately 0.005 times the MRHD on an AUC basis).
- In a fertility study in rats, fertility was unaffected by administration of lofexidine up to 0.88 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis) via diet to male and female rats prior to mating and to the dams through gestation and lactation. No evidence of maternal toxicity was observed. However, no assessment of sperm or reproductive organs were performed in this study.
- Reduced testes, epididymis, and seminiferous tubule weights, as well as delayed sexual maturation of males and females and decreases in the number of corpora lutea and implantations after mating, were noted in offspring of pregnant rats administered lofexidine hydrochloride orally from GD 6 through lactation at exposures less than the human exposure based on AUC comparisons.
# Clinical Studies
- Two randomized, double-blind, placebo-controlled trials supported the efficacy of lofexidine.
- Study 1 was a 2-part efficacy, safety, and dose-response study conducted in the United States in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). The first part of the study was an inpatient, randomized, double-blind, placebo-controlled design consisting of 7 days of inpatient treatment (Days 1 – 7) with lofexidine 2.16 mg total daily dose (0.54 mg 4 times daily) (n=229), lofexidine 2.88 mg total daily dose (0.72 mg 4 times daily) (n=222), or matching placebo (n=151). Patients also had access to a variety of support medications for withdrawal symptoms (guaifenesin, antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, and zolpidem). The second part of the study (Days 8 – 14) was an open-label design where all patients who successfully completed Days 1 – 7 were eligible to receive open-label treatment with variable dose lofexidine treatment (as determined by the investigator, but not to exceed 2.88 mg total daily dose) for up to an additional 7 days (Days 8 – 14) in either an inpatient or outpatient setting as determined by the investigator and the patient. No patient received lofexidine for more than 14 days.
- The two endpoints to support efficacy were the mean Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) total score on Days 1 – 7 of treatment and the proportion of patients that completed 7 days of treatment. The SOWS-Gossop, a patient-reported outcome (PRO) instrument, evaluates the following opioid withdrawal symptoms: feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes and insomnia/problems sleeping. For each opioid withdrawal symptom, patients are asked to rate their symptom severity using four response options (none, mild, moderate, and severe). The SOWS-Gossop total score ranges from 0 to 30 where a higher score indicates a greater withdrawal symptom severity. The SOWS-Gossop was administered at baseline and once daily 3.5 hours after the first morning dose on Days 1 – 7.
- Of the randomized and treated patients, 28% of placebo patients, 41% of lofexidine 2.16 mg and 40% of lofexidine 2.88 mg patients completed 7 days of treatment. The difference in proportion in both lofexidine groups was significant compared to placebo. See FIGURE 1. Patients in the placebo group were more likely to drop out of the study prematurely due to lack of efficacy than patients treated with lofexidine.
- The mean SOWS-Gossop scores for Days 1 – 7 were 8.8, 6.5, and 6.1 for placebo, lofexidine 2.16 mg and lofexidine 2.88 mg, respectively. Results are shown in Figure 2. The mean difference between lofexidine 2.16 mg and placebo was -2.3 with a 95% CI of (-3.4, -1.2). The mean difference between lofexidine 2.88 mg and placebo was -2.7 with a 95% CI of (-3.9, -1.6). They were both significant. Symptoms assessed on the SOWS-Gossop were recorded as absent or mild for almost all patients remaining to the end of the assessment period.
- Study 2 was an inpatient, randomized, multicenter, double-blind, placebo-controlled study carried out in the United States in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). Patients were treated with lofexidine tablets (2.88 mg/day ) or matching placebo for 5 days (Days 1 – 5). Patients also had access to a variety of support medications for withdrawal symptoms (guaifenesin, antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, and zolpidem). All patients then received placebo on Days 6 and 7 and were discharged on Day 8.
- The two endpoints to support efficacy were the mean SOWS-Gossop total score on Days 1 – 5 of treatment and the proportion of patients that completed 5 days of treatment. The SOWS-Gossop was administered at baseline and once daily 3.5 hours after the first morning dose on Days 1 – 5.
- A total of 264 patients were randomized into the study. Of these, 134 patients were randomized to lofexidine 2.88 mg/day and 130 patients to placebo.
- Of the randomized and treated patients, 33% of placebo patients and 49% of lofexidine patients completed 5 days of treatment. The difference in proportion between the two groups was significant. See FIGURE 3. Patients in the placebo group were more likely to drop out of the study prematurely due to lack of efficacy than patients treated with lofexidine.
- The mean SOWS-Gossop scores for Days 1 – 5 were 8.9 and 7.0 for placebo and lofexidine 2.88 mg, respectively. Results are shown in Figure 4. The mean difference was -1.9 with a 95% CI of (-3.2, -0.6) and was statistically significant.
# How Supplied
- Available as 0.18 mg round, convex-shaped, peach colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side; approximately 7 mm in diameter.
- Bottles of 36 tablets NDC 27505-050-36
- Bottles of 96 tablets NDC 27505-050-96
## Storage
- Store in original container at controlled room temperature, 25°C (77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F). Keep lofexidine away from excess heat and moisture both in the pharmacy and after dispensing. Do not remove desiccant packs from bottles until all tablets are used. Keep lofexidine and all medicines out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling.
- Lofexidine may mitigate, but not completely prevent, the symptoms associated with opioid withdrawal syndrome, which may include feeling sick, stomach cramps, muscle spasms or twitching, feeling of cold, heart pounding, muscular tension, aches and pains, yawning, runny eyes and sleep problems (insomnia). Patients should be advised that withdrawal will not be easy. Additional supportive measures should be clearly advised, as needed.
- Inform patients to be alert for any symptoms of low blood pressure or pulse (e.g., dizziness, lightheadedness, or feelings of faintness at rest or on abruptly standing). Advise patients on how to reduce the risk of serious consequences should hypotension occur (sit or lie down, carefully rise from a sitting or lying position).
- Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis and bradycardia and advised to withhold lofexidine doses and contact their healthcare provider for instructions if they experience these signs or related symptoms.
- Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope.
- Review with patients all concomitant medications being taken and request that they immediately inform their healthcare provider of any changes in concomitant medications, including any other medications that may be used to treat individual symptoms of withdrawal.
- Inform patients of the increased risk of CNS depression with concomitant use of benzodiazepines, alcohol, barbiturates, or other sedating drugs.
- Advise patients using lofexidine in an outpatient setting that, until they learn how they respond to lofexidine, they should be careful or avoid doing activities such as driving or operating heavy machinery.
- Sudden Discontinuation of lofexidine.
- Advise patients that after a period of not using opioid drugs, they may be more sensitive to the effects of opioids and at greater risk of overdosing.
# Precautions with Alcohol
Alcohol-Lofexidine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Lucemyra
# Look-Alike Drug Names
There is limited information regarding Lofexidine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Lofexidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
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# Overview
Lofexidine is a central alpha-2 adrenergic agonist that is FDA approved for the mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. Common adverse reactions include orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Lofexidine is indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.
- The usual lofexidine starting dosage is three 0.18 mg tablets taken orally 4 times daily during the period of peak withdrawal symptoms (generally the first 5 to 7 days following last use of opioid) with dosing guided by symptoms and side effects. There should be 5 to 6 hours between each dose. The total daily dosage of lofexidine should not exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets).
- Lofexidine treatment may be continued for up to 14 days with dosing guided by symptoms.
- Discontinue lofexidine with a gradual dose reduction over a 2- to 4-day period to mitigate lofexidine withdrawal symptoms (e.g., reducing by 1 tablet per dose every 1 to 2 days). The lofexidine dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to lofexidine side effects. Lower doses may be appropriate as opioid withdrawal symptoms wane.
- Lofexidine can be administered in the presence or absence of food.
- Recommended dosage adjustments based on the degree of hepatic impairment are shown in Table 1.
- Recommended dosage adjustments based on the degree of renal impairment are shown in Table 2. Lofexidine may be administered without regard to the timing of dialysis
- Lofexidine is available as round, peach-colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side. Each tablet contains 0.18 mg lofexidine (equivalent to 0.2 mg of lofexidine hydrochloride).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding lofexidine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding lofexidine 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 Lofexidine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding lofexidine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding lofexidine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Lofexidine can cause a decrease in blood pressure, a decrease in pulse, and syncope. Monitor vital signs before dosing. Monitor symptoms related to bradycardia and orthostasis.
- Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.
- Inform patients that lofexidine may cause hypotension and that patients moving from a supine to an upright position may be at increased risk for hypotension and orthostatic effects. Instruct patients to stay hydrated, on how to recognize symptoms of low blood pressure, and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Instruct outpatients to withhold lofexidine doses when experiencing symptoms of hypotension or bradycardia and to contact their healthcare provider for guidance on how to adjust dosing.
- Avoid using lofexidine in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, and in patients with marked bradycardia.
- Avoid using lofexidine in combination with medications that decrease pulse or blood pressure to avoid the risk of excessive bradycardia and hypotension.
- Lofexidine prolongs the QT interval.
- Avoid using lofexidine in patients with congenital long QT syndrome.
- Monitor ECG in patients with congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking other medicinal products that lead to QT prolongation (e.g., methadone). In patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), correct these abnormalities first, and monitor ECG upon initiation of lofexidine.
- Lofexidine potentiates the CNS depressive effects of benzodiazepines and can also be expected to potentiate the CNS depressive effects of alcohol, barbiturates, and other sedating drugs. Advise patients to inform their healthcare provider of other medications they are taking, including alcohol.
- Advise patients using lofexidine in an outpatient setting that, until they learn how they respond to lofexidine, they should be careful or avoid doing activities such as driving or operating heavy machinery.
- Lofexidine is not a treatment for opioid use disorder. Patients who complete opioid discontinuation are likely to have a reduced tolerance to opioids and are at increased risk of fatal overdose should they resume opioid use. Use lofexidine in patients with opioid use disorder only in conjunction with a comprehensive management program for the treatment of opioid use disorder and inform patients and caregivers of this increased risk of overdose.
- Stopping lofexidine abruptly can cause a marked rise in blood pressure. Symptoms including diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain have also been observed with lofexidine discontinuation. Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy with lofexidine tablets, gradually reduce the dose.
- Symptoms related to discontinuation can be managed by administration of the previous lofexidine dose and subsequent taper.
# 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 adverse reaction rates observed for another drug and may not reflect the rates observed in practice.
- The safety of lofexidine was supported by three randomized, double-blind, placebo-controlled clinical trials, an open-label study, and clinical pharmacology studies with concomitant administration of either methadone, buprenorphine, or naltrexone.
- The three randomized, double-blind, placebo-controlled clinical trials enrolled 935 subjects dependent on short-acting opioids undergoing abrupt opioid withdrawal. Patients were monitored before each dose in an inpatient setting.
- Table 3 presents the incidence, rounded to the nearest percent, of adverse events that occurred in at least 10% of subjects treated with lofexidine and for which the incidence in patients treated with lofexidine was greater than the incidence in subjects treated with placebo in a study that tested two doses of lofexidine, 2.16 mg per day and 2.88 mg per day, and placebo. The overall safety profile in the combined dataset was similar.
- Orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth were notably more common in subjects treated with lofexidine than subjects treated with placebo.
- Other notable adverse reactions associated with the use of lofexidine but reported in <10% of patients in the lofexidine group included:
- Syncope: 0.9%, 1.4% and 0% for lofexidine 2.16 mg/day and 2.88 mg/day and placebo, respectively
- Tinnitus: 0.9%, 3.2% and 0% for lofexidine 2.16 mg/day and 2.88 mg/day and placebo, respectively
- Elevations in blood pressure above normal values (≥ 140 mmHg systolic) and above a subject's pre-treatment baseline are associated with discontinuing lofexidine, and peaked on the second day after discontinuation, as shown in Table 4. Blood pressure values were evaluated for 3 days following the last dose of a 5-day course of lofexidine 2.88 mg/day.
- Blood pressure elevations of a similar magnitude and incidence were observed in a small number of patients (N=10) that had a one-day, 50% dose reduction prior to discontinuation.
- After stopping treatment, subjects that were taking lofexidine also had a higher incidence of diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain compared to subjects who were taking placebo.
- Four out of 101 females (4%) had serious cardiovascular adverse events compared to 3 out of 289 (1%) of males assigned to receive lofexidine 2.88 mg per day.
- Discontinuations and dose holds due to bradycardia and orthostatic hypotension, which are the most common adverse reactions associated with lofexidine, occurred with a greater incidence in females assigned to receive the highest studied dose of lofexidine, 2.88 mg per day as shown in Table 5.
## Postmarketing Experience
- Lofexidine is marketed in other countries for relief of opioid withdrawal symptoms. The following events have been identified during postmarketing use of lofexidine. 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.
- Since lofexidine's initial market introduction in 1992, the most frequently reported postmarketing adverse event with lofexidine has been hypotension. There has been one report of QT prolongation, bradycardia, torsades de pointes, and cardiac arrest with successful resuscitation in a patient that received lofexidine and three reports of clinically significant QT prolongation in subjects concurrently receiving methadone with lofexidine.
# Drug Interactions
- Methadone
- Oral Naltrexone
- CNS Depressant Drugs
- CYP2D6 Inhibitor - Paroxetine
- Lofexidine and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and lofexidine.
- Coadministration of lofexidine and oral naltrexone resulted in statistically significant differences in the steady-state pharmacokinetics of naltrexone. It is possible that oral naltrexone efficacy may be reduced if used concomitantly within 2 hours of lofexidine. This interaction is not expected if naltrexone is administered by non-oral routes.
- Lofexidine potentiates the CNS depressant effects of benzodiazepines and may potentiate the CNS depressant effects of alcohol, barbiturates, and other sedating drugs. Advise patients to inform their healthcare provider of other medications they are taking, including alcohol.
- Coadministration of lofexidine and paroxetine resulted in 28% increase in the extent of absorption of lofexidine. Monitor for orthostatic hypotension and bradycardia when an inhibitor of CYP2D6 is used concomitantly with lofexidine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The safety of lofexidine in pregnant women has not been established. In animal reproduction studies, oral administration of lofexidine during organogenesis to pregnant rats and rabbits caused a reduction in fetal weights, increases in fetal resorptions, and litter loss at exposures below that in humans. When oral lofexidine was administered from the beginning of organogenesis through lactation, increased stillbirths and litter loss were noted along with decreased viability and lactation indices. The offspring exhibited delays in sexual maturation, auditory startle, and surface righting. These effects occurred at exposures below that in humans.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects in the U.S. general population is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
- Increased incidence of resorptions, decreased number of implantations, and a concomitant reduction in the number of fetuses were observed when pregnant rabbits were orally administered lofexidine hydrochloride during organogenesis (from gestation day [GD] 7 to 19) at a daily dose of 5.0 mg/kg/day (approximately 0.08 times the maximum recommended human dose [MRHD] of 2.88 mg lofexidine base on an AUC basis). Maternal toxicity evidenced by increased mortality was noted at the highest tested dose of 15 mg/kg/day (approximately 0.4 times the MRHD on an AUC basis).
- Decreased implantations per dam and decreased mean fetal weights were noted in a study in which pregnant rats were treated with oral lofexidine hydrochloride during organogenesis (from GD 7 to 16) at a daily dose of 3.0 mg/kg/day (approximately 0.9 times the MRHD on an AUC basis). This dose was associated with maternal toxicity (decreased body weight gain and mortality). No malformations or evidence of developmental toxicity were evident at 1.0 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis).
- A dose-dependent increase in pup mortality was noted in all doses of lofexidine hydrochloride administered orally to pregnant rats from GD 6 through lactation at an exposure less than the human exposure based on AUC comparisons. Doses higher than 1.0 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis) resulted in incidences of total litter loss and maternal toxicity (piloerection and decreased body weight gain). The highest dose tested of 2.0 mg/kg/day (approximately 0.6 times the MRHD on an AUC basis), increased stillbirths as well as decreased viability and lactation indices were reported. Surviving offspring exhibited lower body weights, developmental delays, and increased delays in auditory startle at doses of 1.0 mg/kg/day or higher. Sexual maturation was delayed in male offspring (preputial separation) at 2.0 mg/kg/day and in female offspring (vaginal opening) at 1.0 mg/kg/day or higher.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lofexidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lofexidine during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of lofexidine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Caution should be exercised when lofexidine is administered to a nursing woman.
- The developmental and health benefits should be considered along with the mother's clinical need for lofexidine and any other potential adverse effects on breastfed children from lofexidine or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of lofexidine have not been established in pediatric patients.
### Geriatic Use
- No studies have been performed to characterize the pharmacokinetics of lofexidine or establish its safety and effectiveness in geriatric patients. Caution should be exercised when it is administered to patients over 65 years of age. Dosing adjustments similar to those recommended in patients with renal impairment should be considered.
### Gender
There is no FDA guidance on the use of Lofexidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lofexidine with respect to specific racial populations.
### Renal Impairment
- Renal impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of renal impairment.
- Only a negligible fraction of the lofexidine dose is removed during a typical dialysis session, so no additional dose needs to be administered after a dialysis session; lofexidine may be administered without regard to the timing of dialysis.
- Clinically relevant QT prolongation may occur in subjects with renal impairment.
### Hepatic Impairment
- Hepatic impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of hepatic impairment.
- Clinically relevant QT prolongation may occur in subjects with hepatic impairment.
### Females of Reproductive Potential and Males
- In animal studies that included some fertility endpoints, lofexidine decreased breeding rate and increased resorptions at exposures below human exposures. The impact of lofexidine on male fertility has not been adequately characterized in animal studies.
### Immunocompromised Patients
There is no FDA guidance one the use of Lofexidine in patients who are immunocompromised.
### CYP2D6 Poor Metabolizers
- Although the pharmacokinetics of lofexidine have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to lofexidine would be increased similarly to taking strong CYP2D6 inhibitors (approximately 28%). Monitor adverse events such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).
# Administration and Monitoring
### Administration
- Oral.
### Monitoring
- Reduction in signs and symptoms of opioid withdrawal and compliance with therapy is indicative of efficacy.
- Vital signs: Prior to dosing.
- Symptoms related to bradycardia and orthostasis: During therapy.
- ECG: In patients with congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking other medicinal products that lead to QT prolongation (eg, methadone). Correct electrolyte abnormalities prior to ECG monitoring and initiation of therapy.
# IV Compatibility
There is limited information regarding the compatibility of Lofexidine and IV administrations.
# Overdosage
- Overdose with lofexidine may manifest as hypotension, bradycardia, and sedation. In the event of acute overdose, perform gastric lavage where appropriate. Dialysis will not remove a substantial portion of the drug. Initiate general symptomatic and supportive measures in cases of overdosage.
# Pharmacology
## Mechanism of Action
- Lofexidine is a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.
## Structure
## Pharmacodynamics
- Single lofexidine doses of 1.44 to 1.8 mg produced maximum mean change from baseline in QTcF (ΔQTcF) of 14.4 msec (upper two-sided 90% CI: 22.3 msec) and 13.6 msec (17.4 msec) for 1.44 and 1.8 mg respectively in healthy normal volunteers.
- In a Phase 3 placebo-controlled, dose response study in opioid dependent subjects, lofexidine was associated with a maximum mean prolongation of the QTcF interval 7.3 (8.8) and 9.3 (10.9) msec at doses of 2.16 and 2.88 mg/day, respectively.
Patients With Hepatic Impairment
- Administration of lofexidine to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairment.
Patients With Renal Impairment
- Administration of lofexidine to subjects with renal impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe renal impairment.
Lofexidine Coadministered With Methadone
- Lofexidine (2.88 mg/day) coadministered with methadone in 18 methadone-maintained patients (80-120 mg/day) resulted in a maximum mean increase from methadone-alone baseline in QTcF of 9.1 (14.2) msec.
Lofexidine Coadministered With Buprenorphine
- Lofexidine (2.88 mg/day) coadministered with buprenorphine in 21 buprenorphine-maintained patients (16-24 mg/day) resulted in a maximum mean QTcF increase in QTcF of 15 (5.6) msec compared to a buprenorphine-alone baseline.
- Lofexidine exhibits in vitro binding affinity and functional agonist activity with alpha-2A and alpha-2C adrenoreceptors at concentrations within clinical exposure plasma levels (Ki values of approximately 7.2 nM and 12 nM, and EC50 values of 4.9 nM and 0.9 nM, respectively).
## Pharmacokinetics
- Lofexidine is well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose.
- Lofexidine shows approximately dose-proportional pharmacokinetics. Administration of lofexidine with food does not alter its pharmacokinetics.
- The absolute bioavailability of a single oral lofexidine dose ( 0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean lofexidine Cmax after the oral dose and intravenous infusion was 0.82 ng/mL (at median Tmax of 3 hours) and 0.64 ng/mL (at median Tmax of 4 hours), respectively. Mean estimates of overall systemic exposure (AUCinf) were 14.9 ng∙h/mL and 12.0 ng∙h/mL, respectively.
- Mean lofexidine apparent volume of distribution and volume of distribution values following the administration of an oral dose and an intravenous dose were 480.0 L and 297.9 L, respectively, which are appreciably greater than total body volume, suggesting extensive lofexidine distribution into body tissue.
- Lofexidine protein binding is approximately 55%.
- Lofexidine is not preferentially taken up by blood cells. In a study comparing lofexidine concentrations in plasma and whole blood at the time of peak lofexidine concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the lofexidine concentration of the plasma.
Metabolism
- From absolute bioavailability results, approximately 30% of the administered lofexidine dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut.
- Lofexidine and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by lofexidine, with an IC50 of 4551 nM (approximately 225 times the steady-state Cmax for lofexidine with 0.72 mg 4 times daily dosing). Any lofexidine interaction with CYP2D6 substrates is not expected to be clinically significant.
- Lofexidine is metabolized when incubated in vitro with human liver microsomes, the major contributor to the hepatic metabolism of lofexidine is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing lofexidine.
Excretion
- The elimination half-life is approximately 12 hours and mean clearance is 17.6 L/h following an IV infusion.
- Lofexidine has a terminal half-life of approximately 11 to 13 hours following the first dose. At steady-state, the terminal half-life is approximately 17 to 22 hours. Accumulation occurs up to 4 days with repeat dosing, following the recommended dosing regimen.
- A mass balance study of lofexidine showed nearly complete recovery of radiolabel in urine (93.5%) over 144 hours postdose, with an additional 0.92% recovered in the feces over 216 hours postdose. Thus, it appears that all, or nearly all, of the dose was absorbed, and that the primary route of elimination of the parent drug and its metabolites is via the kidney. Renal elimination of unchanged drug accounts for approximately 15% to 20% of the administered dose.
Hepatic Impairment
- Hepatic impairment slows the elimination of lofexidine, but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in mild, moderate, and severe hepatically impaired subjects to subjects with normal hepatic function (6 subjects in each hepatic function group), mean Cmax values were similar for subjects with normal, mild, and moderate hepatic impairment as shown in Table 6.
Renal Impairment
- Renal impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 8 end-stage renal disease subjects on 3 times weekly hemodialysis to 8 subjects with normal renal function matched for sex, age, and body mass index, mean Cmax values were similar for end-stage renal disease and normal renal function subjects, indicating no change in maximum lofexidine exposure with renal impairment as shown in Table 7.
- The impact of dialysis on the overall pharmacokinetics of lofexidine during a typical 4-hour dialysis was minimal; the drop in lofexidine plasma concentrations produced during the dialysis session was transient, with a rebound to nearly predialysis concentrations after re-equilibration within a few hours following completion of the dialysis cycle.
- In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 6 subjects each with normal renal function, mild renal impairment, and moderate renal impairment as well as 5 subjects with severe renal impairment but not requiring dialysis, there were similar increases in mean Cmax values in subjects with mild and moderate renal impairment in comparison to subjects with normal renal function with additional increase in mean Cmax values in subjects with severe renal impairment. Mean AUClast, AUC∞, and t1/2 increased with severity of renal impairment as shown in Table 7.
Lofexidine coadministered with methadone
- In a double-blind placebo-controlled study of 23 patients maintained on a methadone dose of 80-120 mg/day and concomitantly administered lofexidine up to 2.88 mg/day, lofexidine did not alter the pharmacokinetics of methadone. Lofexidine concentrations may be slightly increased when coadministered with methadone; however, the increase at concentrations expected with recommended dosing is not clinically meaningful.
Lofexidine coadministered with buprenorphine
- In a double-blind placebo-controlled study of 30 subjects maintained on buprenorphine (16-24 mg/day) concomitantly administered lofexidine up to 2.88 mg/day, no pharmacokinetic or pharmacodynamic interactions between lofexidine and buprenorphine were seen.
Lofexidine coadministered with oral naltrexone
- In an open-label, single-arm study of 24 healthy subjects, oral naltrexone (50 mg/day) did not significantly alter the single-dose pharmacokinetics of lofexidine (0.36 mg). The alteration in steady-state pharmacokinetics of oral naltrexone was statistically significant in the presence of lofexidine. The tmax was delayed for both naltrexone and 6ß-naltrexol (2-3 hours), and overall exposure was slightly reduced when naltrexone was administered with lofexidine.
Lofexidine coadministered with paroxetine
- In an open-label, single-sequence study of 24 healthy subjects, the strong CYP2D6 inhibitor paroxetine (40 mg/day) increased lofexidine (0.36 mg) Cmax and AUC∞ by approximately 11% and 28%, respectively.
## Nonclinical Toxicology
- No adequate long-term animal studies have been completed to evaluate the carcinogenic potential of lofexidine.
- Lofexidine tested positive in the in vitro mouse lymphoma assay. Lofexidine tested negative in the in vitro bacterial reverse mutation assay (Ames assay) and in the in vivo rat micronucleus assay.
- In a female fertility study in rabbits, fertility was not adversely impacted by administration of lofexidine hydrochloride up to 6.4 mg/kg/day (approximately 0.1 times the MRHD of 2.88 mg on an AUC basis) when administered orally to female rabbits starting 2 weeks prior to mating and through gestation and lactation. However, decreased breeding rate and higher post-implantation loss was observed at this dose, which correlated with higher resorptions and reduced litter size. Maternal toxicity, which included increased mortality rate, reduced body weight gain, and moderate sedation was observed at 6.4 mg/kg/day. The NOAEL for female fertility was 6.4 mg/kg/day and the NOAEL for female-mediated developmental parameters was 0.4 mg/kg/day (approximately 0.005 times the MRHD on an AUC basis).
- In a fertility study in rats, fertility was unaffected by administration of lofexidine up to 0.88 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis) via diet to male and female rats prior to mating and to the dams through gestation and lactation. No evidence of maternal toxicity was observed. However, no assessment of sperm or reproductive organs were performed in this study.
- Reduced testes, epididymis, and seminiferous tubule weights, as well as delayed sexual maturation of males and females and decreases in the number of corpora lutea and implantations after mating, were noted in offspring of pregnant rats administered lofexidine hydrochloride orally from GD 6 through lactation at exposures less than the human exposure based on AUC comparisons.
# Clinical Studies
- Two randomized, double-blind, placebo-controlled trials supported the efficacy of lofexidine.
- Study 1 was a 2-part efficacy, safety, and dose-response study conducted in the United States in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). The first part of the study was an inpatient, randomized, double-blind, placebo-controlled design consisting of 7 days of inpatient treatment (Days 1 – 7) with lofexidine 2.16 mg total daily dose (0.54 mg 4 times daily) (n=229), lofexidine 2.88 mg total daily dose (0.72 mg 4 times daily) (n=222), or matching placebo (n=151). Patients also had access to a variety of support medications for withdrawal symptoms (guaifenesin, antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, and zolpidem). The second part of the study (Days 8 – 14) was an open-label design where all patients who successfully completed Days 1 – 7 were eligible to receive open-label treatment with variable dose lofexidine treatment (as determined by the investigator, but not to exceed 2.88 mg total daily dose) for up to an additional 7 days (Days 8 – 14) in either an inpatient or outpatient setting as determined by the investigator and the patient. No patient received lofexidine for more than 14 days.
- The two endpoints to support efficacy were the mean Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) total score on Days 1 – 7 of treatment and the proportion of patients that completed 7 days of treatment. The SOWS-Gossop, a patient-reported outcome (PRO) instrument, evaluates the following opioid withdrawal symptoms: feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes and insomnia/problems sleeping. For each opioid withdrawal symptom, patients are asked to rate their symptom severity using four response options (none, mild, moderate, and severe). The SOWS-Gossop total score ranges from 0 to 30 where a higher score indicates a greater withdrawal symptom severity. The SOWS-Gossop was administered at baseline and once daily 3.5 hours after the first morning dose on Days 1 – 7.
- Of the randomized and treated patients, 28% of placebo patients, 41% of lofexidine 2.16 mg and 40% of lofexidine 2.88 mg patients completed 7 days of treatment. The difference in proportion in both lofexidine groups was significant compared to placebo. See FIGURE 1. Patients in the placebo group were more likely to drop out of the study prematurely due to lack of efficacy than patients treated with lofexidine.
- The mean SOWS-Gossop scores for Days 1 – 7 were 8.8, 6.5, and 6.1 for placebo, lofexidine 2.16 mg and lofexidine 2.88 mg, respectively. Results are shown in Figure 2. The mean difference between lofexidine 2.16 mg and placebo was -2.3 with a 95% CI of (-3.4, -1.2). The mean difference between lofexidine 2.88 mg and placebo was -2.7 with a 95% CI of (-3.9, -1.6). They were both significant. Symptoms assessed on the SOWS-Gossop were recorded as absent or mild for almost all patients remaining to the end of the assessment period.
- Study 2 was an inpatient, randomized, multicenter, double-blind, placebo-controlled study carried out in the United States in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). Patients were treated with lofexidine tablets (2.88 mg/day [0.72 mg four times daily]) or matching placebo for 5 days (Days 1 – 5). Patients also had access to a variety of support medications for withdrawal symptoms (guaifenesin, antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, and zolpidem). All patients then received placebo on Days 6 and 7 and were discharged on Day 8.
- The two endpoints to support efficacy were the mean SOWS-Gossop total score on Days 1 – 5 of treatment and the proportion of patients that completed 5 days of treatment. The SOWS-Gossop was administered at baseline and once daily 3.5 hours after the first morning dose on Days 1 – 5.
- A total of 264 patients were randomized into the study. Of these, 134 patients were randomized to lofexidine 2.88 mg/day and 130 patients to placebo.
- Of the randomized and treated patients, 33% of placebo patients and 49% of lofexidine patients completed 5 days of treatment. The difference in proportion between the two groups was significant. See FIGURE 3. Patients in the placebo group were more likely to drop out of the study prematurely due to lack of efficacy than patients treated with lofexidine.
- The mean SOWS-Gossop scores for Days 1 – 5 were 8.9 and 7.0 for placebo and lofexidine 2.88 mg, respectively. Results are shown in Figure 4. The mean difference was -1.9 with a 95% CI of (-3.2, -0.6) and was statistically significant.
# How Supplied
- Available as 0.18 mg round, convex-shaped, peach colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side; approximately 7 mm in diameter.
- Bottles of 36 tablets NDC 27505-050-36
- Bottles of 96 tablets NDC 27505-050-96
## Storage
- Store in original container at controlled room temperature, 25°C (77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F). Keep lofexidine away from excess heat and moisture both in the pharmacy and after dispensing. Do not remove desiccant packs from bottles until all tablets are used. Keep lofexidine and all medicines out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling.
- Lofexidine may mitigate, but not completely prevent, the symptoms associated with opioid withdrawal syndrome, which may include feeling sick, stomach cramps, muscle spasms or twitching, feeling of cold, heart pounding, muscular tension, aches and pains, yawning, runny eyes and sleep problems (insomnia). Patients should be advised that withdrawal will not be easy. Additional supportive measures should be clearly advised, as needed.
- Inform patients to be alert for any symptoms of low blood pressure or pulse (e.g., dizziness, lightheadedness, or feelings of faintness at rest or on abruptly standing). Advise patients on how to reduce the risk of serious consequences should hypotension occur (sit or lie down, carefully rise from a sitting or lying position).
- Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis and bradycardia and advised to withhold lofexidine doses and contact their healthcare provider for instructions if they experience these signs or related symptoms.
- Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope.
- Review with patients all concomitant medications being taken and request that they immediately inform their healthcare provider of any changes in concomitant medications, including any other medications that may be used to treat individual symptoms of withdrawal.
- Inform patients of the increased risk of CNS depression with concomitant use of benzodiazepines, alcohol, barbiturates, or other sedating drugs.
- Advise patients using lofexidine in an outpatient setting that, until they learn how they respond to lofexidine, they should be careful or avoid doing activities such as driving or operating heavy machinery.
- Sudden Discontinuation of lofexidine.
- Advise patients that after a period of not using opioid drugs, they may be more sensitive to the effects of opioids and at greater risk of overdosing.
# Precautions with Alcohol
Alcohol-Lofexidine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Lucemyra
# Look-Alike Drug Names
There is limited information regarding Lofexidine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Lofexidine | |
dfa3b81fb357bc906cd26aff903af47727f5e030 | wikidoc | Logorrhoea | Logorrhoea
# Overview
Logorrhoea or logorrhea (Greek λογορροια, logorrhoia, “word-flux”) is defined as an “excessive flow of words” and, when used medically, refers to incoherent talkativeness that occurs in certain kinds of mental illness, such as mania. The spoken form of logorrhoea (in the non-medical sense) is a kind of verbosity that uses superfluous or fancy words to disguise a useless or simple message as useful or intellectual, and is commonly known as “verbal diarrhea” or “diarrhea of the mouth.”
# Logorrhoea as a description of rhetoric
The word logorrhoea is often used pejoratively to describe prose that is highly abstract and consequently contains little concrete language. Since abstract writing is hard to visualize, it often seems as though it makes no sense and all the words are excessive. Writers in academic fields that concern themselves mostly with the abstract, such as philosophy and especially postmodernism, often fail to include extensive concrete examples of their ideas, and so an examination (superficial or otherwise, according to various points of view) of their work might lead one to believe that it is all nonsense, hence the pejorative epithet “pomobabble” (a neologism inspired from postmodern babble) and "archibabble" (another neologism, this one meaning "architect babble.")
The widespread expectation that scholarly works in these fields will look at first glance like nonsense is the source of humor that pokes fun at these fields by comparing actual nonsense with real academic writing. Several computer programs have been made that can generate texts resembling the styles of these fields but which are actually nonsensical. A physics professor, Alan Sokal even had such an essay published in a respected journal (Social Text) as a practical joke, which the journal kept defending as a genuine article even after its author rebuked it publicly in a subsequent article in another academic journal. (See Sokal Affair.)
Logorrhoea can also be used as a form of euphemism, to disguise unpleasant facts and ideas.
The term is also sometimes less precisely applied to unnecessarily (and often redundantly) wordy speech in general; this is more usually referred to as prolixity.
Use of additional words that are not strictly necessary, however, is often idiomatic, a matter of artistic preference, or helpful in explaining complex ideas or messages that might otherwise be unclear. Such uses are not logorrhoeic.
# Examples of logorrhoea
In his essay “Politics and the English Language” (1946), the English writer George Orwell wrote about logorrhoea in politics. He took the following verse (9:11) from the book of Ecclesiastes in the Bible:
“I returned and saw under the sun, that the race is not to the swift, nor the battle to the strong, neither yet bread to the wise, nor yet riches to men of understanding, nor yet favour to men of skill; but time and chance happeneth to them all.”
He rewrote it like this:
“Objective considerations of contemporary phenomena compel the conclusion that success or failure in competitive activities exhibits no tendency to be commensurate with innate capacity, but that a considerable element of the unpredictable must invariably be taken into account.”
Note Orwell’s deliberate usage of unnecessary words that only serve to further complicate the statement. For instance, the words “objective” and “invariably” could be cut with virtually no loss of meaning. (Ironically, however, because the King James translation contains archaic grammar, some contemporary academics may find Orwell’s version actually easier to understand.) What both the Bible and Orwell were trying to say could be paraphrased (albeit obtusely) in three simple words: “Success is stochastic.”
In his anecdote collection Surely You’re Joking, Mr. Feynman!, the physicist and raconteur Richard Feynman describes a time when he participated in a multi-disciplinary conference discussing the nebulous topic “the ethics of equality.” Feynman was at first apprehensive, having read none of the books the conference organizers had recommended. A sociologist brought a paper he had written beforehand to the committee where Feynman served, asking everyone to read it. Feynman found it completely incomprehensible and feared that he was out of his depth — until he decided to pick one sentence at random and parse it until he understood. The sentence he chose (to the best of his recollection) was:
Feynman “translated” the sentence and discovered it meant “People read.” The rest of the paper soon made sense in the same fashion.
Further examples are easy to create:
A classic riddle example:
Nigel Hawthorne’s delivery of the character Sir Humphrey Appleby’s pieces of logorrhoea was a mainstay of the British comedy TV series Yes Minister. An example:
Another, taken from the sequel, Yes, Prime Minister:
# The benefits of being concise
While some authors may feel that using long and obscure words gives them the appearance of greater intelligence, a recent study from the Psychology department of Princeton University found that this was not the case. Dr. Daniel Oppenheimer conducted a series of five experiments which found that when shown samples of writing with varying word length, undergraduate students rated those with short, concise text, as being written by the most intelligent authors. By contrast, those who needlessly used excessively long words or complex font types were perceived to be less intelligent. For example, the author of “The principal educational aspiration I have established for myself is to utilize my capabilities to the fullest” was rated as less intelligent than the author of the more concise “The primary academic goal I have set for myself is to use my potential to the fullest.”
In the United Kingdom there is a pressure group called the Plain English Campaign who offer editing and training to authors in order to help achieve “Plain English”: “language that the intended audience can understand and act upon from a single reading.”
# Logorrhoea as a form of mental illness
Logorrhoea is a language disorder present in a variety of psychiatric and neurological disorders including aphasia, localised cortical lesions in the thalamus, or most typically in catatonic schizophrenia.
Examples of logorrhoea might include talking or mumbling monotonously either to others or more likely oneself. This may include the repetition of particular words of phrases, often incoherently. The causes for logorrhoea remain poorly understood, but appear to be localized to frontal lobe structures known to be associated with language. As is the case, for example, in emotional lability in a wide variety of neurological conditions, other symptoms take priority in clinical management and research efforts.
Logorrhoea should not be confused with pressure of speech, which is characterised by the “flighty” alternation from topic to topic by tenuous links such as rhyming or punning. Logorrhoea is a symptom of an underlying illness and should be treated by a medical professional. Several of the possible causes of logorrhoea respond well to medication. | Logorrhoea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Logorrhoea or logorrhea (Greek λογορροια, logorrhoia, “word-flux”) is defined as an “excessive flow of words” and, when used medically, refers to incoherent talkativeness that occurs in certain kinds of mental illness, such as mania. The spoken form of logorrhoea (in the non-medical sense) is a kind of verbosity that uses superfluous or fancy words to disguise a useless or simple message as useful or intellectual, and is commonly known as “verbal diarrhea” or “diarrhea of the mouth.”
# Logorrhoea as a description of rhetoric
The word logorrhoea is often used pejoratively to describe prose that is highly abstract and consequently contains little concrete language. Since abstract writing is hard to visualize, it often seems as though it makes no sense and all the words are excessive. Writers in academic fields that concern themselves mostly with the abstract, such as philosophy and especially postmodernism, often fail to include extensive concrete examples of their ideas, and so an examination (superficial or otherwise, according to various points of view) of their work might lead one to believe that it is all nonsense, hence the pejorative epithet “pomobabble” (a neologism inspired from postmodern babble) and "archibabble" (another neologism, this one meaning "architect babble.")
The widespread expectation that scholarly works in these fields will look at first glance like nonsense is the source of humor that pokes fun at these fields by comparing actual nonsense with real academic writing. Several computer programs have been made that can generate texts resembling the styles of these fields but which are actually nonsensical. A physics professor, Alan Sokal even had such an essay published in a respected journal (Social Text) as a practical joke, which the journal kept defending as a genuine article even after its author rebuked it publicly in a subsequent article in another academic journal. (See Sokal Affair.)
Logorrhoea can also be used as a form of euphemism, to disguise unpleasant facts and ideas.
The term is also sometimes less precisely applied to unnecessarily (and often redundantly) wordy speech in general; this is more usually referred to as prolixity.
Use of additional words that are not strictly necessary, however, is often idiomatic, a matter of artistic preference, or helpful in explaining complex ideas or messages that might otherwise be unclear. Such uses are not logorrhoeic.
# Examples of logorrhoea
In his essay “Politics and the English Language” (1946), the English writer George Orwell wrote about logorrhoea in politics. He took the following verse (9:11) from the book of Ecclesiastes in the Bible:
“I returned and saw under the sun, that the race is not to the swift, nor the battle to the strong, neither yet bread to the wise, nor yet riches to men of understanding, nor yet favour to men of skill; but time and chance happeneth to them all.”
He rewrote it like this:
“Objective considerations of contemporary phenomena compel the conclusion that success or failure in competitive activities exhibits no tendency to be commensurate with innate capacity, but that a considerable element of the unpredictable must invariably be taken into account.”
Note Orwell’s deliberate usage of unnecessary words that only serve to further complicate the statement. For instance, the words “objective” and “invariably” could be cut with virtually no loss of meaning. (Ironically, however, because the King James translation contains archaic grammar, some contemporary academics may find Orwell’s version actually easier to understand.) What both the Bible and Orwell were trying to say could be paraphrased (albeit obtusely) in three simple words: “Success is stochastic.”
In his anecdote collection Surely You’re Joking, Mr. Feynman!, the physicist and raconteur Richard Feynman describes a time when he participated in a multi-disciplinary conference discussing the nebulous topic “the ethics of equality.” Feynman was at first apprehensive, having read none of the books the conference organizers had recommended. A sociologist brought a paper he had written beforehand to the committee where Feynman served, asking everyone to read it. Feynman found it completely incomprehensible and feared that he was out of his depth — until he decided to pick one sentence at random and parse it until he understood. The sentence he chose (to the best of his recollection) was:
Feynman “translated” the sentence and discovered it meant “People read.” The rest of the paper soon made sense in the same fashion.
Further examples are easy to create:
A classic riddle example:
Nigel Hawthorne’s delivery of the character Sir Humphrey Appleby’s pieces of logorrhoea was a mainstay of the British comedy TV series Yes Minister. An example:
Another, taken from the sequel, Yes, Prime Minister:
# The benefits of being concise
While some authors may feel that using long and obscure words gives them the appearance of greater intelligence, a recent study from the Psychology department of Princeton University found that this was not the case. Dr. Daniel Oppenheimer conducted a series of five experiments which found that when shown samples of writing with varying word length, undergraduate students rated those with short, concise text, as being written by the most intelligent authors. By contrast, those who needlessly used excessively long words or complex font types were perceived to be less intelligent. For example, the author of “The principal educational aspiration I have established for myself is to utilize my capabilities to the fullest” was rated as less intelligent than the author of the more concise “The primary academic goal I have set for myself is to use my potential to the fullest.”
In the United Kingdom there is a pressure group called the Plain English Campaign who offer editing and training to authors in order to help achieve “Plain English”: “language that the intended audience can understand and act upon from a single reading.”
# Logorrhoea as a form of mental illness
Logorrhoea is a language disorder present in a variety of psychiatric and neurological disorders including aphasia[2], localised cortical lesions in the thalamus[3][4], or most typically in catatonic schizophrenia.
Examples of logorrhoea might include talking or mumbling monotonously either to others or more likely oneself. This may include the repetition of particular words of phrases, often incoherently. The causes for logorrhoea remain poorly understood, but appear to be localized to frontal lobe structures known to be associated with language. As is the case, for example, in emotional lability in a wide variety of neurological conditions, other symptoms take priority in clinical management and research efforts.
Logorrhoea should not be confused with pressure of speech, which is characterised by the “flighty” alternation from topic to topic by tenuous links such as rhyming or punning[5]. Logorrhoea is a symptom of an underlying illness and should be treated by a medical professional. Several of the possible causes of logorrhoea respond well to medication. | https://www.wikidoc.org/index.php/Logorrhoea | |
3373bec5e3541780c7831ad81b309c6ed38eafe3 | wikidoc | Lomitapide | Lomitapide
# Disclaimer
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# Black Box Warning
# Overview
Lomitapide is an antihyperlipedemic that is FDA approved for the treatment of homozygous familial hypercholesterolemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include chest pain,weight decreased, abdominal discomfort, abdominal distension, abdominal pain,constipation,diarrhea, flatulence, indigestion, nausea, vomiting, nasopharyngitis, fatigue and influenza.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Homozygous Familial Hypercholesterolemia
### Indication
- Juxtapid is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
Limitations of Use
- The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH.
- The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined.
Dosing information
- Before beginning treatment with Juxtapid:
- Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin ;
- Obtain a negative pregnancy test in females of reproductive potential ; and,
- Initiate a low-fat diet supplying <20% of energy from fat .
Recommended starting dosage: 5 mg PO qd , and the dose should be escalated gradually based on acceptable safety and tolerability.
- Transaminases should be measured prior to any increase in dose.
- The maintenance dosage of Juxtapid should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment, to a maximum of 60 mg daily as described in Table 1. Modify dosing for patients taking concomitant CYP3A4 inhibitors, renal impairment, or baseline hepatic impairment . Dose adjustments are also required for patients who develop transaminase values ≥3x the upper limit of normal (ULN) during treatment with Juxtapid .
- To reduce the risk of developing a fat-soluble nutrient deficiency due to Juxtapid’s mechanism of action in the small intestine, patients treated with Juxtapid should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) .
### Dosing with Cytochrome P450 3A4 Inhibitors
Dosing information
- Juxtapid is contraindicated with concomitant use of moderate and strong cytochrome P450 3A4 (CYP3A4) inhibitors .
- Recommended maximum dosage: 30 mg PO qd with concomitant use of weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, oral contraceptives, pazopanib, ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, zileuton) .
- Juxtapid should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal because administration with food may increase the risk of gastrointestinal adverse reactions . Patients should swallow Juxtapid capsules whole. Capsules should not be opened, crushed, dissolved, or chewed.
### Dose Modification Based on Elevated Transaminases
Dosing information
- Table 2 summarizes recommendations for dose adjustment and monitoring for patients who develop elevated transaminases during therapy with Juxtapid .
- If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with Juxtapid and investigate to identify the probable cause .
### Dosing in Patients with Renal Impairment
Dosing information
- Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily. There are no data available to guide dosing in other patients with renal impairment .
### Dosing in Patients with Baseline Hepatic Impairment
Dosing information
- Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Lomitapide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomitapide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lomitapide 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 Lomitapide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomitapide in pediatric patients.
# Contraindications
- Juxtapid is contraindicated in the following conditions:
- Pregnancy .
- Concomitant administration of Juxtapid with moderate or strong CYP3A4 inhibitors, as this can increase Juxtapid exposure .
- Patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases.
# Warnings
## Risk of Hepatotoxicity
- Juxtapid can cause elevations in transaminases and hepatic steatosis, as described below . To what extent Juxtapid-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction (elevated transaminases with increase in bilirubin or INR) or hepatic failure have not been reported, there is concern that Juxtapid could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of Juxtapid in HoFH would have been unlikely to detect this adverse outcome given their size and duration .
### Elevation of Transaminases
- Elevations in transaminases (alanine aminotransferase and/or aspartate aminotransferase ) are associated with Juxtapid. In the clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3x ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5x ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase.
- During the 78-week HoFH clinical trial, no patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the HoFH extension study, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between Juxtapid and the strong CYP3A4 inhibitor clarithromycin.
- Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiation of treatment with Juxtapid . Juxtapid is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases. If the baseline liver-related tests are abnormal, one may consider initiating Juxtapid after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 months and before any increase in dose. Modify the dose of Juxtapid if elevations of transaminases are observed and discontinue Juxtapid for persistent or clinically significant elevations.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with Juxtapid and identify the probable cause.
### Hepatic Steatosis
- Juxtapid increases hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with Juxtapid treatment are unknown. During the HoFH clinical trial, the median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS) . Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with Juxtapid, but whether histological sequelae remain is unknown, especially after long-term use; protocol liver biopsies were not performed in the HoFH clinical trial.
- Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Juxtapid should not consume more than one alcoholic drink per day.
- Caution should be exercised when Juxtapid is used with other medications known to have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of Juxtapid with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
- Juxtapid has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
### Juxtapid REMS Program
- Because of the risk of hepatotoxicity associated with Juxtapid therapy, Juxtapid is available through a restricted program under the REMS. Under the Juxtapid REMS, only certified healthcare providers and pharmacies may prescribe and distribute Juxtapid. Further information is available at www.JuxtapidREMSProgram.com or by telephone at 1-85-Juxtapid (1-855-898-2743).
## Embryo-Fetal Toxicity
- Juxtapid may cause fetal harm when administered to a pregnant woman based on findings of teratogenicity in rats and ferrets . Females of reproductive potential should have a negative pregnancy test before starting Juxtapid and should use effective contraception during therapy with Juxtapid If oral contraceptives are used, the maximum recommended dosage of Juxtapid is 30 mg daily .
## Reduced Absorption of Fat-Soluble Vitamins and Serum Fatty Acids
- Given its mechanism of action in the small intestine, Juxtapid may reduce the absorption of fat-soluble nutrients. In the HoFH clinical trial, patients were provided daily dietary supplements of vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In this trial, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid decreased from baseline to Week 26 but remained above the lower limit of the reference range. Adverse clinical consequences of these reductions were not observed with Juxtapid treatment of up to 78 weeks. Patients treated with Juxtapid should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA . Patients with chronic bowel or pancreatic diseases that predispose to malabsorption may be at increased risk for deficiencies in these nutrients with use of Juxtapid.
## Gastrointestinal Adverse Reactions
- Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the HoFH clinical trial. Diarrhea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation, and flatulence.
- Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the HoFH clinical trial, with the most common being diarrhea (4 patients, 14%); vomiting (3 patients, 10%); and abdominal pain, distension, and/or discomfort (2 patients, 7%). Gastrointestinal reactions contributed to the reasons for early discontinuation from the trial for 4 (14%) patients.
- Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.
- To reduce the risk of gastrointestinal adverse events, patients should adhere to a low-fat diet supplying <20% of energy from fat and the dosage of Juxtapid should be increased gradually .
## Concomitant Use of CYP3A4 Inhibitors
- CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with Juxtapid is contraindicated . In the Juxtapid clinical trials, one patient with HoFH developed markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) within days of initiating the strong CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors is unavoidable, Juxtapid should be stopped during the course of treatment.
- Grapefruit juice must be omitted from the diet while being treated with Juxtapid.
- Weak CYP3A4 inhibitors increase the exposure of lomitapide approximately 2-fold; therefore, Juxtapid dosage should not exceed 30 mg daily when it is used concomitantly with these inhibitors, including atorvastatin and oral contraceptives
## Risk of Myopathy with Concomitant Use of Simvastatin or Lovastatin
- The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose related. Lomitapide approximately doubles the exposure to simvastatin; therefore, it is recommended to reduce the dose of simvastatin by 50% when initiating Juxtapid . While taking Juxtapid, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for additional dosing recommendations.
- Interaction between lovastatin and lomitapide has not been studied. However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that Juxtapid may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating Juxtapid.
## Risk of Supratherapeutic or Subtherapeutic Anticoagulation with Warfarin
- Juxtapid increases the plasma concentrations of warfarin. Increases in the dose of Juxtapid may lead to supra therapeutic anticoagulation, and decreases in the dose of Juxtapid may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the HoFH clinical trial for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in Juxtapid dosage. The dose of warfarin should be adjusted as clinically indicated .
## Risk of Malabsorption with Rare Hereditary Disorders of Galactose Intolerance
- Patients with rare, hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should avoid Juxtapid as this may result in diarrhea and malabsorption.
# Adverse Reactions
## Clinical Trials Experience
- The following important adverse reactions have been observed and are discussed in detail in other sections of the label:
- Risk of hepatotoxicity
- Reduced absorption of fat-soluble vitamins, and serum fatty acids
- Gastrointestinal adverse 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.
- One single-arm, open-label, 78-week trial has been conducted in 29 patients with HoFH, 23 of whom completed at least one year of treatment. The initial dosage of Juxtapid was 5 mg daily, with titration up to 60 mg daily during an 18-week period based on safety and tolerability. In this trial, the mean age was 30.7 years (range, 18 to 55 years), 16 (55%) patients were men, 25 (86%) patients were Caucasian, 2 (7%) were Asian, 1 (3%) was African American, and 1 (3%) was multi-racial.
- Five (17%) of the 29 patients with HoFH that participated in the clinical trial discontinued treatment due to an adverse reaction. The adverse reactions that contributed to treatment discontinuations included diarrhea (2 patients; 7%) and abdominal pain, nausea, gastroenteritis, weight loss, headache, and difficulty controlling INR on warfarin (1 patient each; 3%).
- The most common adverse reactions were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions reported by ≥8 (28%) patients in the HoFH clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue.
- The adverse reactions reported in at least 10% of patients during the HoFH clinical trial are presented in Table 3.
- Adverse reactions of severe intensity were reported by 8 (28%) of 29 patients, with the most common being diarrhea (4 patients, 14%), vomiting (3 patients, 10%), increased ALT or hepatotoxicity (3 patients, 10%), and abdominal pain, distension, and/or discomfort (2 patients, 7%).
Transaminase Elevations
- During the HoFH clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥3x ULN . No clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed. Transaminases typically fell within one to four weeks of reducing the dose or withholding Juxtapid.
- Among the 19 patients who enrolled in an extension study following the HoFH clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between Juxtapid and the strong CYP3A4 inhibitor clarithromycin .
Hepatic Steatosis
- Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the HoFH clinical trial. After 26 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 8% (range, 0% to 30%). After 78 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 7% (range, 0% to 18%). Among the 23 patients with evaluable data, on at least one occasion during the trial, 18 (78%) exhibited an increase in hepatic fat >5% and 3 (13%) exhibited an increase >20%. Data from individuals who had repeat measurements after stopping Juxtapid show that hepatic fat accumulation is reversible, but whether histological sequelae remain is unknown.
## Postmarketing Experience
- FDA Package Insert for Lomitapide contains no information regarding postmarketing experience.
# Drug Interactions
## Moderate and Strong CYP3A4 Inhibitors
- A strong CYP3A4 inhibitor has been shown to increase lomitapide exposure approximately 27-fold . Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) with lomitapide is contraindicated. Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.
- Patients must avoid grapefruit juice while taking Juxtapid .
## Weak CYP3A4 Inhibitors
- Weak CYP3A4 inhibitors increase lomitapide exposure approximately 2-fold . Lomitapide dosage should not exceed 30 mg daily when it is used concomitantly with weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, oral contraceptives, pazopanib, ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, zileuton).
## Warfarin
- Lomitapide increases plasma concentrations of both R(+)- warfarin and S(-)-warfarin by approximately 30% and increased the INR 22%. Patients taking warfarin should undergo regular monitoring of INR, particularly after any changes in lomitapide dosage. The dose of warfarin should be adjusted as clinically indicated .
## Simvastatin and Lovastatin
- The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose related. Lomitapide approximately doubles the exposure of simvastatin; therefore, the recommended dose of simvastatin should be reduced by 50% when initiating Juxtapid . While taking Juxtapid, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for simvastatin dosing recommendations.
- Interaction between lovastatin and lomitapide has not been studied. However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that Juxtapid may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating Juxtapid.
## P-glycoprotein Substrates
- Lomitapide is an inhibitor of P-glycoprotein (P-gp). Coadministration of lomitapide with P-gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P-gp substrates. Dose reduction of the P-gp substrate should be considered when used concomitantly with lomitapide.
## Bile Acid Sequestrants
- Juxtapid has not been tested for interaction with bile acid sequestrants. Administration of Juxtapid and bile acid sequestrants should be separated by at least 4 hours since bile acid sequestrants can interfere with the absorption of oral medications.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
### Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Juxtapid during pregnancy. For additional information visit www.Juxtapid.com or call the Global Lomitapide Pregnancy Exposure Registry (PER) at 1-877-902-4099. Healthcare professionals are encouraged to call the PER at 1-877-902-4099 to enroll patients who become pregnant during Juxtapid treatment.
### Risk Summary
- Juxtapid is contraindicated during pregnancy because Juxtapid may cause fetal harm when administered to a pregnant woman. Lomitapide was teratogenic in rats and ferrets at exposures estimated to be less than human therapeutic exposure at 60 mg (AUC = 67 ng*h/mL) when administered during organogenesis. There was no evidence of teratogenicity in rabbits at 3 times the maximum recommended human dose (MRHD) of 60 mg based on body surface area. Embryo-fetal lethality was observed in rabbits at 6-times the MRHD. 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.
### Animal Data
- Oral gavage doses of 0.04, 0.4, or 4 mg/kg/day lomitapide given to pregnant rats from gestation day 6 through organogenesis were associated with fetal malformations at ≥2-times human exposure at the MRHD (60 mg) based on plasma AUC comparisons. Fetal malformations included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones.
- Oral gavage doses of 1.6, 4, 10, or 25 mg/kg/day lomitapide given to pregnant ferrets from gestation day 12 through organogenesis were associated with both maternal toxicity and fetal malformations at exposures that ranged from less than the human exposure at the MRHD to 5-times the human exposure at the MRHD. Fetal malformations included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail.
- Oral gavage doses of 0.1, 1, or 10 mg/kg/day lomitapide given to pregnant rabbits from gestation day 6 through organogenesis were not associated with adverse effects at systemic exposures up to 3-times the MRHD of 60 mg based on body surface area comparison. Treatment at doses of ≥20 mg/kg/day, ≥6-times the MRHD, resulted in embryo-fetal lethality.
- Pregnant female rats given oral gavage doses of 0.1, 0.3, or 1 mg/kg/day lomitapide from gestation day 7 through termination of nursing on lactation day 20 were associated with malformations at systemic exposures equivalent to human exposure at the MRHD of 60 mg based on AUC. Increased pup mortality occurred at 4-times the MRHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lomitapide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lomitapide during labor and delivery.
### Nursing Mothers
- It is not known whether lomitapide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for lomitapide in a 2-year mouse study, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
- Clinical studies of Juxtapid did not include sufficient numbers of patients aged 65 years and over 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, dosing for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Lomitapide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lomitapide with respect to specific racial populations.
### Renal Impairment
- Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily since lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. Effects of mild, moderate, and severe renal impairment, including those with end-stage renal disease not yet receiving dialysis, on lomitapide exposure have not been studied. However, it is possible that patients with renal impairment who are not yet receiving dialysis may experience increases in lomitapide exposure exceeding 50% .
### Hepatic Impairment
- Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily since the lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. Juxtapid is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment since the lomitapide exposure in patients with moderate hepatic impairment increased 164% compared with healthy volunteers .
### Females of Reproductive Potential and Males
- Juxtapid may cause fetal harm . Females who become pregnant during Juxtapid therapy should stop Juxtapid immediately and notify their healthcare provider.
### Pregnancy testing
- Females of reproductive potential should have a negative pregnancy test before starting Juxtapid.
### Contraception
- Females of reproductive potential should use effective contraception during Juxtapid therapy. The recommended maximum dosage of Juxtapid is 30 mg daily with concomitant use of oral contraceptives, since oral contraceptives are weak CYP3A4 inhibitors . Hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking Juxtapid, warranting the use of additional contraceptive methods .
### Immunocompromised Patients
There is no FDA guidance one the use of Lomitapide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Lomitapide contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- There is no specific treatment in the event of overdose of Juxtapid. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver-related tests should be monitored. Hemodialysis is unlikely to be beneficial given that lomitapide is highly protein bound.
# Pharmacology
## Mechanism of Action
- Juxtapid directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C.
## Structure
- Juxtapid capsules contain lomitapide mesylate, a synthetic lipid-lowering agent for oral administration.
- The chemical name of lomitapide mesylate is N-(2,2,2-trifluoroethyl)-9--2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate salt. Its structural formula is:
- The empirical formula for lomitapide mesylate is C39H37F6N3O2 - CH4O3S and its molecular weight is 789.8.
- Lomitapide mesylate is a white to off-white powder that is slightly soluble in aqueous solutions of pH 2 to 5. Lomitapide mesylate is freely soluble in acetone, ethanol, and methanol; soluble in 2-butanol, methylene chloride, and acetonitrile; sparingly soluble in 1-octanol and 2-propanol; slightly soluble in ethyl acetate; and insoluble in heptane.
## Pharmacodynamics
### Effects on QT Interval
- At a concentration 23 times the Cmax of the maximum recommended dose, lomitapide does not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
### Absorption
- Upon oral administration of a single 60-mg dose of Juxtapid, the lomitapide tmax is around 6 hours in healthy volunteers. The absolute bioavailability of lomitapide is approximately 7%. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses from 10-100 mg.
### Distribution
- The mean lomitapide volume of distribution at steady state is 985-1292 liters. Lomitapide is 99.8% plasma-protein bound.
### Metabolism
- Lomitapide is metabolized extensively by the liver. The metabolic pathways include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitapide to its major metabolites, M1 and M3, as detected in plasma. The oxidative N-dealkylation pathway breaks the lomitapide molecule into M1 and M3. M1 is the moiety that retains the piperidine ring, whereas M3 retains the rest of the lomitapide molecule in vitro. CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize lomitapide to a small extent to M1. M1 and M3 do not inhibit activity of microsomal triglyceride transfer protein in vitro.
### Excretion
- In a mass-balance study, a mean of 59.5% and 33.4% of the dose was excreted in the urine and feces, respectively. In another mass-balance study, a mean of 52.9% and 35.1% of the dose was excreted in the urine and feces, respectively. Lomitapide was not detectable in urine samples. M1 is the major urinary metabolite. Lomitapide is the major component in the feces. The mean lomitapide terminal half-life is 39.7 hours.
## Specific Populations
### Hepatic Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and Cmax were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and Cmax were 47% and 4% higher, respectively, compared with healthy volunteers. Lomitapide has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15) .
### Renal Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in patients with end-stage renal disease receiving hemodialysis compared with healthy volunteers with normal renal function. Healthy volunteers had estimated creatinine clearance >80 mL/min by the Cockcroft-Gault equation. Compared with healthy volunteers, lomitapide AUC0-inf and Cmax were 40% and 50% higher, respectively, in patients with end-stage renal disease receiving hemodialysis. Effects of mild, moderate, and severe renal impairment as well as end-stage renal disease not yet on dialysis on lomitapide exposure have not been studied .
### In vitro Assessment of Drug Interactions
Lomitapide does not induce CYPs 1A2, 3A4, or 2B6. Lomitapide inhibits CYP3A4. Lomitapide does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. M1 and M3 do not induce CYPs 1A2, 3A4, or 2B6. M1 and M3 do not inhibit CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. Lomitapide is not a P-gp substrate. Lomitapide inhibits P-gp but does not inhibit breast cancer resistance protein (BCRP).
### Effects of other Drugs on Lomitapide
CYP3A4 Inhibitors
Lomitapide exposure increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Thus, concomitant use of strong CYP3A4 inhibitors and lomitapide is contraindicated. The effect of moderate CYP3A4 inhibitors on lomitapide exposure has not been studied. However, moderate CYP3A4 inhibitors will likely increase lomitapide exposure significantly based on the results of concomitant use of strong and weak CYP3A4 inhibitors . Thus, concomitant use of moderate CYP3A4 inhibitors and lomitapide is contraindicated.
Interaction between weak CYP3A4 inhibitors and lomitapide has not been studied. Based on cross-studies comparisons, the lomitapide exposure approximately doubles in the presence of oral contraceptives, which are weak CYP3A4 inhibitors. Do not exceed 30 mg daily of Juxtapid when used concomitantly with weak CYP3A4 inhibitors.
### Effect of Lomitapide on other Drugs
Table 6 summarizes the effects of lomitapide on the AUC and Cmax of coadministered drugs.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year dietary carcinogenicity study in mice, lomitapide was administered at doses of 0.3, 1.5, 7.5, 15, or 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenomas and carcinomas in males at doses ≥1.5 mg/kg/day (≥2-times the MRHD at 60 mg based on AUC) and in females at ≥7.5 mg/kg/day (≥10-times the human exposure at 60 mg based on AUC). Incidences of small intestinal carcinomas in males and combined adenomas and carcinomas in females were significantly increased at doses ≥15 mg/kg/day (≥23-times the human exposure at 60 mg based on AUC).
- In a 2-year carcinogenicity study in rats, lomitapide was administered by oral gavage for up to 99 weeks at doses of 0.25, 1.7, or 7.5 mg/kg/day in males and 0.03, 0.35, or 2.0 mg/kg/day in females. While the design of the study was suboptimal, there were no statistically significant drug-related increases in tumor incidences at exposures up to 6-times (males) and 8-times (females) higher than human exposure at the MRHD based on AUC.
- Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using primary human lymphocytes, and an oral micronucleus study in rats.
- Lomitapide had no effect on fertility in rats at doses up to 5 mg/kg/day at systemic exposures estimated to be 4-times (females) and 5-times (males) higher than in humans at 60 mg based on AUC.
# Clinical Studies
- The safety and effectiveness of Juxtapid as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, were evaluated in a multinational, single-arm, open-label, 78-week trial involving 29 adults with HoFH. A diagnosis of HoFH was defined by the presence of at least one of the following clinical criteria: (1) documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality, or (2) skin fibroblast LDL receptor activity 500 mg/dL and TG 250 mg/dL.
- Among the 29 patients enrolled, the mean age was 30.7 years (range, 18 to 55 years), 16 (55%) were men, and the majority (86%) were Caucasian. The mean body mass index (BMI) was 25.8 kg/m2, with four patients meeting BMI criteria for obesity; one patient had type 2 diabetes. Concomitant lipid-lowering treatments at baseline included one or more of the following: statins (93%), ezetimibe (76%), nicotinic acid (10%), bile acid sequestrant (3%), and fibrate (3%); 18 (62%) were receiving apheresis.
- After a six-week run-in period to stabilize lipid-lowering treatments, including the establishment of an LDL apheresis schedule if applicable, Juxtapid was initiated at 5 mg daily and titrated to daily doses of 10 mg, 20 mg, 40 mg, and 60 mg at weeks 2, 6, 10, and 14, respectively, based on tolerability and acceptable levels of transaminases. Patients were instructed to maintain a low-fat diet (<20% calories from fat) and to take dietary supplements that provided approximately 400 international units vitamin E, 210 mg alpha-linolenic acid (ALA), 200 mg linoleic acid, 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) per day. After efficacy was assessed at Week 26, patients remained on Juxtapid for an additional 52 weeks to assess long-term safety. During this safety phase, the dose of Juxtapid was not increased above each patient’s maximum tolerated dose established during the efficacy phase, but changes to concomitant lipid-lowering treatments were allowed.
- Twenty-three (79%) patients completed the efficacy endpoint at Week 26, all of whom went on to complete 78 weeks of treatment. Adverse events contributed to premature discontinuation for five patients . The maximum tolerated doses during the efficacy period were 5 mg (10%), 10 mg (7%), 20 mg (21%), 40 mg (24%), and 60 mg (34%).
The primary efficacy endpoint was percent change in LDL-C from baseline to Week 26. At Week 26, the mean and median percent changes in LDL-C from baseline were -40% (paired t-test p<0.001) and -50%, respectively, based on the intent-to-treat population with last observation carried forward (LOCF) for patients who discontinued prematurely. The mean percent change in LDL-C from baseline through Week 26 is shown in Figure 1 for the 23 patients who completed the efficacy period.
- Error bars represent 95% confidence intervals of the mean.
- Changes in lipids and lipoproteins through the efficacy endpoint at Week 26 are presented in Table 7.
- After week 26, during the safety phase of the study, adjustments to concomitant lipid-lowering treatments were allowed. For the study population overall, average reductions in LDL-C, TC, apo B, and non-HDL-C were sustained during chronic therapy.
# How Supplied
- 5 mg capsules:
- Orange/orange hard gelatin capsule printed with black ink “A733” and “5 mg”
- Bottles of 28 NDC 76431-* :*105-01
- 10 mg capsules:
- Orange/white hard gelatin capsule printed with black ink “A733” and “10 mg”
- Bottles of 28 NDC 76431-:*110-01
- 20 mg capsules:
- White/white hard gelatin capsule printed with black ink “A733” and “20 mg”
- Bottles of 28 NDC 76431-120-01
## Storage
- Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F). Brief exposure to temperatures up to 40°C (104°F) may be tolerated provided the mean kinetic temperature does not exceed 25°C (77°F); however, such exposure should be minimized. Keep container tightly closed and protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-approved labeling (Medication Guide)
- Patients should be informed that a registry for patients taking Juxtapid has been established in order to monitor and evaluate the long-term effects of Juxtapid. Patients are encouraged to participate in the registry and should be informed that their participation is voluntary. For information regarding the registry program visit www.Juxtapid.com or call 1-877-902-4099.
Advise patients of the following:
Risk of Hepatotoxicity
- Juxtapid can cause both elevations in transaminases and hepatic steatosis. Discuss with the patient the importance of monitoring of liver-related tests before taking Juxtapid, prior to each dose escalation, and periodically thereafter.
- Patients should be advised of the potential for increased risk of liver injury if alcohol is consumed while taking Juxtapid. It is recommended that patients taking Juxtapid limit consumption to not more than one alcoholic drink per day.
- Juxtapid is commonly associated with nausea, vomiting, and abdominal pain. Advise patients to promptly report these symptoms if they increase in severity, persist, or change in the character, as they might reflect liver injury. Patients should also report any other symptoms of possible liver injury, including fever, jaundice, lethargy, or flu-like symptoms.
Juxtapid REMS PROGRAM
- Juxtapid is only available through a restricted program called Juxtapid REMS PROGRAM and therefore, Juxtapid is only available from certified pharmacies that are enrolled in the program.
Females of Reproductive Potential
- Juxtapid is contraindicated in pregnancy.
- Advise females of reproductive potential that they should have a negative pregnancy test before starting Juxtapid and that they should use effective contraception while taking Juxtapid. If oral contraceptives are initiated while taking Juxtapid, the dose of Juxtapid may require adjustment. Hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking Juxtapid, warranting the use of additional contraceptive methods.
- Nursing Mothers: A decision should be made whether to discontinue nursing or discontinue Juxtapid.
Dietary Supplements
- Discuss with the patient the importance of taking daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA)
Gastrointestinal Adverse Reactions
- Inform the patient that gastrointestinal adverse reactions are common with Juxtapid. These include, but are not limited to, diarrhea, nausea/vomiting, abdominal pain/discomfort, flatulence, and constipation. Strict adherence to a low-fat diet (<20% of total calories from fat) may reduce these reactions.
- Tell the patient that taking Juxtapid with food may adversely impact gastrointestinal tolerability; therefore, they should take Juxtapid at least 2 hours after the evening meal, swallowing each capsule whole.
- Absorption of oral medications may be affected in patients who develop diarrhea or vomiting. For example, hormone absorption from oral contraceptives may be incomplete, warranting the use of additional contraceptive methods. Patients who develop these symptoms should seek advice from their healthcare provider.
Drug Interactions
- Tell the patient to omit grapefruit juice from his/her diet while on Juxtapid.
- Because multiple drug-drug interactions have been described with Juxtapid, advise the patient to tell their healthcare provider(s) about all medications, nutritional supplements, and vitamins that they are taking or may be taking while taking Juxtapid.
Missed Doses
- If a dose of Juxtapid is missed, the normal dose should be taken at the usual time the next day. If dosing is interrupted for more than a week, tell the patient to contact their healthcare provider before restarting treatment.
# Precautions with Alcohol
- Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Juxtapid should not consume more than one alcoholic drink per day.
- Patients should be advised of the potential for increased risk of liver injury if alcohol is consumed while taking Juxtapid. It is recommended that patients taking Juxtapid limit consumption to not more than one alcoholic drink per day.
# Brand Names
- Juxtapid
# Look-Alike Drug Names
- There is limited information about the look-alike drugs.
# Drug Shortage Status
# Price | Lomitapide
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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# Black Box Warning
# Overview
Lomitapide is an antihyperlipedemic that is FDA approved for the treatment of homozygous familial hypercholesterolemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include chest pain,weight decreased, abdominal discomfort, abdominal distension, abdominal pain,constipation,diarrhea, flatulence, indigestion, nausea, vomiting, nasopharyngitis, fatigue and influenza.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Homozygous Familial Hypercholesterolemia
### Indication
- Juxtapid is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
Limitations of Use
- The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH.
- The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined.
Dosing information
- Before beginning treatment with Juxtapid:
- Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin ;
- Obtain a negative pregnancy test in females of reproductive potential ; and,
- Initiate a low-fat diet supplying <20% of energy from fat .
Recommended starting dosage: 5 mg PO qd , and the dose should be escalated gradually based on acceptable safety and tolerability.
- Transaminases should be measured prior to any increase in dose.
- The maintenance dosage of Juxtapid should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment, to a maximum of 60 mg daily as described in Table 1. Modify dosing for patients taking concomitant CYP3A4 inhibitors, renal impairment, or baseline hepatic impairment . Dose adjustments are also required for patients who develop transaminase values ≥3x the upper limit of normal (ULN) during treatment with Juxtapid .
- To reduce the risk of developing a fat-soluble nutrient deficiency due to Juxtapid’s mechanism of action in the small intestine, patients treated with Juxtapid should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) .
### Dosing with Cytochrome P450 3A4 Inhibitors
Dosing information
- Juxtapid is contraindicated with concomitant use of moderate and strong cytochrome P450 3A4 (CYP3A4) inhibitors .
- Recommended maximum dosage: 30 mg PO qd with concomitant use of weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, oral contraceptives, pazopanib, ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, zileuton) .
- Juxtapid should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal because administration with food may increase the risk of gastrointestinal adverse reactions . Patients should swallow Juxtapid capsules whole. Capsules should not be opened, crushed, dissolved, or chewed.
### Dose Modification Based on Elevated Transaminases
Dosing information
- Table 2 summarizes recommendations for dose adjustment and monitoring for patients who develop elevated transaminases during therapy with Juxtapid .
- If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with Juxtapid and investigate to identify the probable cause .
### Dosing in Patients with Renal Impairment
Dosing information
- Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily. There are no data available to guide dosing in other patients with renal impairment .
### Dosing in Patients with Baseline Hepatic Impairment
Dosing information
- Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Lomitapide in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomitapide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lomitapide 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 Lomitapide in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomitapide in pediatric patients.
# Contraindications
- Juxtapid is contraindicated in the following conditions:
- Pregnancy .
- Concomitant administration of Juxtapid with moderate or strong CYP3A4 inhibitors, as this can increase Juxtapid exposure .
- Patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases.
# Warnings
## Risk of Hepatotoxicity
- Juxtapid can cause elevations in transaminases and hepatic steatosis, as described below . To what extent Juxtapid-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction (elevated transaminases with increase in bilirubin or INR) or hepatic failure have not been reported, there is concern that Juxtapid could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of Juxtapid in HoFH would have been unlikely to detect this adverse outcome given their size and duration .
### Elevation of Transaminases
- Elevations in transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) are associated with Juxtapid. In the clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3x ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5x ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase.
- During the 78-week HoFH clinical trial, no patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the HoFH extension study, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between Juxtapid and the strong CYP3A4 inhibitor clarithromycin.
- Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiation of treatment with Juxtapid . Juxtapid is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases. If the baseline liver-related tests are abnormal, one may consider initiating Juxtapid after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 months and before any increase in dose. Modify the dose of Juxtapid if elevations of transaminases are observed and discontinue Juxtapid for persistent or clinically significant elevations.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with Juxtapid and identify the probable cause.
### Hepatic Steatosis
- Juxtapid increases hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with Juxtapid treatment are unknown. During the HoFH clinical trial, the median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS) . Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with Juxtapid, but whether histological sequelae remain is unknown, especially after long-term use; protocol liver biopsies were not performed in the HoFH clinical trial.
- Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Juxtapid should not consume more than one alcoholic drink per day.
- Caution should be exercised when Juxtapid is used with other medications known to have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of Juxtapid with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
- Juxtapid has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
### Juxtapid REMS Program
- Because of the risk of hepatotoxicity associated with Juxtapid therapy, Juxtapid is available through a restricted program under the REMS. Under the Juxtapid REMS, only certified healthcare providers and pharmacies may prescribe and distribute Juxtapid. Further information is available at www.JuxtapidREMSProgram.com or by telephone at 1-85-Juxtapid (1-855-898-2743).
## Embryo-Fetal Toxicity
- Juxtapid may cause fetal harm when administered to a pregnant woman based on findings of teratogenicity in rats and ferrets . Females of reproductive potential should have a negative pregnancy test before starting Juxtapid and should use effective contraception during therapy with Juxtapid If oral contraceptives are used, the maximum recommended dosage of Juxtapid is 30 mg daily .
## Reduced Absorption of Fat-Soluble Vitamins and Serum Fatty Acids
- Given its mechanism of action in the small intestine, Juxtapid may reduce the absorption of fat-soluble nutrients. In the HoFH clinical trial, patients were provided daily dietary supplements of vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In this trial, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid decreased from baseline to Week 26 but remained above the lower limit of the reference range. Adverse clinical consequences of these reductions were not observed with Juxtapid treatment of up to 78 weeks. Patients treated with Juxtapid should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA . Patients with chronic bowel or pancreatic diseases that predispose to malabsorption may be at increased risk for deficiencies in these nutrients with use of Juxtapid.
## Gastrointestinal Adverse Reactions
- Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the HoFH clinical trial. Diarrhea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation, and flatulence.
- Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the HoFH clinical trial, with the most common being diarrhea (4 patients, 14%); vomiting (3 patients, 10%); and abdominal pain, distension, and/or discomfort (2 patients, 7%). Gastrointestinal reactions contributed to the reasons for early discontinuation from the trial for 4 (14%) patients.
- Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.
- To reduce the risk of gastrointestinal adverse events, patients should adhere to a low-fat diet supplying <20% of energy from fat and the dosage of Juxtapid should be increased gradually .
## Concomitant Use of CYP3A4 Inhibitors
- CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with Juxtapid is contraindicated . In the Juxtapid clinical trials, one patient with HoFH developed markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) within days of initiating the strong CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors is unavoidable, Juxtapid should be stopped during the course of treatment.
- Grapefruit juice must be omitted from the diet while being treated with Juxtapid.
- Weak CYP3A4 inhibitors increase the exposure of lomitapide approximately 2-fold; therefore, Juxtapid dosage should not exceed 30 mg daily when it is used concomitantly with these inhibitors, including atorvastatin and oral contraceptives
## Risk of Myopathy with Concomitant Use of Simvastatin or Lovastatin
- The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose related. Lomitapide approximately doubles the exposure to simvastatin; therefore, it is recommended to reduce the dose of simvastatin by 50% when initiating Juxtapid . While taking Juxtapid, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for additional dosing recommendations.
- Interaction between lovastatin and lomitapide has not been studied. However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that Juxtapid may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating Juxtapid.
## Risk of Supratherapeutic or Subtherapeutic Anticoagulation with Warfarin
- Juxtapid increases the plasma concentrations of warfarin. Increases in the dose of Juxtapid may lead to supra therapeutic anticoagulation, and decreases in the dose of Juxtapid may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the HoFH clinical trial for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in Juxtapid dosage. The dose of warfarin should be adjusted as clinically indicated .
## Risk of Malabsorption with Rare Hereditary Disorders of Galactose Intolerance
- Patients with rare, hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should avoid Juxtapid as this may result in diarrhea and malabsorption.
# Adverse Reactions
## Clinical Trials Experience
- The following important adverse reactions have been observed and are discussed in detail in other sections of the label:
- Risk of hepatotoxicity
- Reduced absorption of fat-soluble vitamins, and serum fatty acids
- Gastrointestinal adverse 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.
- One single-arm, open-label, 78-week trial has been conducted in 29 patients with HoFH, 23 of whom completed at least one year of treatment. The initial dosage of Juxtapid was 5 mg daily, with titration up to 60 mg daily during an 18-week period based on safety and tolerability. In this trial, the mean age was 30.7 years (range, 18 to 55 years), 16 (55%) patients were men, 25 (86%) patients were Caucasian, 2 (7%) were Asian, 1 (3%) was African American, and 1 (3%) was multi-racial.
- Five (17%) of the 29 patients with HoFH that participated in the clinical trial discontinued treatment due to an adverse reaction. The adverse reactions that contributed to treatment discontinuations included diarrhea (2 patients; 7%) and abdominal pain, nausea, gastroenteritis, weight loss, headache, and difficulty controlling INR on warfarin (1 patient each; 3%).
- The most common adverse reactions were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions reported by ≥8 (28%) patients in the HoFH clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue.
- The adverse reactions reported in at least 10% of patients during the HoFH clinical trial are presented in Table 3.
- Adverse reactions of severe intensity were reported by 8 (28%) of 29 patients, with the most common being diarrhea (4 patients, 14%), vomiting (3 patients, 10%), increased ALT or hepatotoxicity (3 patients, 10%), and abdominal pain, distension, and/or discomfort (2 patients, 7%).
Transaminase Elevations
- During the HoFH clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥3x ULN . No clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed. Transaminases typically fell within one to four weeks of reducing the dose or withholding Juxtapid.
- Among the 19 patients who enrolled in an extension study following the HoFH clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between Juxtapid and the strong CYP3A4 inhibitor clarithromycin .
Hepatic Steatosis
- Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the HoFH clinical trial. After 26 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 8% (range, 0% to 30%). After 78 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 7% (range, 0% to 18%). Among the 23 patients with evaluable data, on at least one occasion during the trial, 18 (78%) exhibited an increase in hepatic fat >5% and 3 (13%) exhibited an increase >20%. Data from individuals who had repeat measurements after stopping Juxtapid show that hepatic fat accumulation is reversible, but whether histological sequelae remain is unknown.
## Postmarketing Experience
- FDA Package Insert for Lomitapide contains no information regarding postmarketing experience.
# Drug Interactions
## Moderate and Strong CYP3A4 Inhibitors
- A strong CYP3A4 inhibitor has been shown to increase lomitapide exposure approximately 27-fold . Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) with lomitapide is contraindicated. Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.
- Patients must avoid grapefruit juice while taking Juxtapid .
## Weak CYP3A4 Inhibitors
- Weak CYP3A4 inhibitors increase lomitapide exposure approximately 2-fold . Lomitapide dosage should not exceed 30 mg daily when it is used concomitantly with weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, oral contraceptives, pazopanib, ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor, zileuton).
## Warfarin
- Lomitapide increases plasma concentrations of both R(+)- warfarin and S(-)-warfarin by approximately 30% and increased the INR 22%. Patients taking warfarin should undergo regular monitoring of INR, particularly after any changes in lomitapide dosage. The dose of warfarin should be adjusted as clinically indicated .
## Simvastatin and Lovastatin
- The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose related. Lomitapide approximately doubles the exposure of simvastatin; therefore, the recommended dose of simvastatin should be reduced by 50% when initiating Juxtapid . While taking Juxtapid, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for simvastatin dosing recommendations.
- Interaction between lovastatin and lomitapide has not been studied. However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that Juxtapid may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating Juxtapid.
## P-glycoprotein Substrates
- Lomitapide is an inhibitor of P-glycoprotein (P-gp). Coadministration of lomitapide with P-gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P-gp substrates. Dose reduction of the P-gp substrate should be considered when used concomitantly with lomitapide.
## Bile Acid Sequestrants
- Juxtapid has not been tested for interaction with bile acid sequestrants. Administration of Juxtapid and bile acid sequestrants should be separated by at least 4 hours since bile acid sequestrants can interfere with the absorption of oral medications.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
### Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Juxtapid during pregnancy. For additional information visit www.Juxtapid.com or call the Global Lomitapide Pregnancy Exposure Registry (PER) at 1-877-902-4099. Healthcare professionals are encouraged to call the PER at 1-877-902-4099 to enroll patients who become pregnant during Juxtapid treatment.
### Risk Summary
- Juxtapid is contraindicated during pregnancy because Juxtapid may cause fetal harm when administered to a pregnant woman. Lomitapide was teratogenic in rats and ferrets at exposures estimated to be less than human therapeutic exposure at 60 mg (AUC = 67 ng*h/mL) when administered during organogenesis. There was no evidence of teratogenicity in rabbits at 3 times the maximum recommended human dose (MRHD) of 60 mg based on body surface area. Embryo-fetal lethality was observed in rabbits at 6-times the MRHD. 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.
### Animal Data
- Oral gavage doses of 0.04, 0.4, or 4 mg/kg/day lomitapide given to pregnant rats from gestation day 6 through organogenesis were associated with fetal malformations at ≥2-times human exposure at the MRHD (60 mg) based on plasma AUC comparisons. Fetal malformations included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones.
- Oral gavage doses of 1.6, 4, 10, or 25 mg/kg/day lomitapide given to pregnant ferrets from gestation day 12 through organogenesis were associated with both maternal toxicity and fetal malformations at exposures that ranged from less than the human exposure at the MRHD to 5-times the human exposure at the MRHD. Fetal malformations included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail.
- Oral gavage doses of 0.1, 1, or 10 mg/kg/day lomitapide given to pregnant rabbits from gestation day 6 through organogenesis were not associated with adverse effects at systemic exposures up to 3-times the MRHD of 60 mg based on body surface area comparison. Treatment at doses of ≥20 mg/kg/day, ≥6-times the MRHD, resulted in embryo-fetal lethality.
- Pregnant female rats given oral gavage doses of 0.1, 0.3, or 1 mg/kg/day lomitapide from gestation day 7 through termination of nursing on lactation day 20 were associated with malformations at systemic exposures equivalent to human exposure at the MRHD of 60 mg based on AUC. Increased pup mortality occurred at 4-times the MRHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lomitapide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lomitapide during labor and delivery.
### Nursing Mothers
- It is not known whether lomitapide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for lomitapide in a 2-year mouse study, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
- Clinical studies of Juxtapid did not include sufficient numbers of patients aged 65 years and over 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, dosing for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Lomitapide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lomitapide with respect to specific racial populations.
### Renal Impairment
- Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily since lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. Effects of mild, moderate, and severe renal impairment, including those with end-stage renal disease not yet receiving dialysis, on lomitapide exposure have not been studied. However, it is possible that patients with renal impairment who are not yet receiving dialysis may experience increases in lomitapide exposure exceeding 50% .
### Hepatic Impairment
- Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily since the lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. Juxtapid is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment since the lomitapide exposure in patients with moderate hepatic impairment increased 164% compared with healthy volunteers .
### Females of Reproductive Potential and Males
- Juxtapid may cause fetal harm . Females who become pregnant during Juxtapid therapy should stop Juxtapid immediately and notify their healthcare provider.
### Pregnancy testing
- Females of reproductive potential should have a negative pregnancy test before starting Juxtapid.
### Contraception
- Females of reproductive potential should use effective contraception during Juxtapid therapy. The recommended maximum dosage of Juxtapid is 30 mg daily with concomitant use of oral contraceptives, since oral contraceptives are weak CYP3A4 inhibitors . Hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking Juxtapid, warranting the use of additional contraceptive methods .
### Immunocompromised Patients
There is no FDA guidance one the use of Lomitapide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Lomitapide contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- There is no specific treatment in the event of overdose of Juxtapid. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver-related tests should be monitored. Hemodialysis is unlikely to be beneficial given that lomitapide is highly protein bound.
# Pharmacology
## Mechanism of Action
- Juxtapid directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C.
## Structure
- Juxtapid capsules contain lomitapide mesylate, a synthetic lipid-lowering agent for oral administration.
- The chemical name of lomitapide mesylate is N-(2,2,2-trifluoroethyl)-9-[4-[4-[ [ [4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate salt. Its structural formula is:
- The empirical formula for lomitapide mesylate is C39H37F6N3O2 • CH4O3S and its molecular weight is 789.8.
- Lomitapide mesylate is a white to off-white powder that is slightly soluble in aqueous solutions of pH 2 to 5. Lomitapide mesylate is freely soluble in acetone, ethanol, and methanol; soluble in 2-butanol, methylene chloride, and acetonitrile; sparingly soluble in 1-octanol and 2-propanol; slightly soluble in ethyl acetate; and insoluble in heptane.
## Pharmacodynamics
### Effects on QT Interval
- At a concentration 23 times the Cmax of the maximum recommended dose, lomitapide does not prolong QTc to any clinically relevant extent.
## Pharmacokinetics
### Absorption
- Upon oral administration of a single 60-mg dose of Juxtapid, the lomitapide tmax is around 6 hours in healthy volunteers. The absolute bioavailability of lomitapide is approximately 7%. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses from 10-100 mg.
### Distribution
- The mean lomitapide volume of distribution at steady state is 985-1292 liters. Lomitapide is 99.8% plasma-protein bound.
### Metabolism
- Lomitapide is metabolized extensively by the liver. The metabolic pathways include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitapide to its major metabolites, M1 and M3, as detected in plasma. The oxidative N-dealkylation pathway breaks the lomitapide molecule into M1 and M3. M1 is the moiety that retains the piperidine ring, whereas M3 retains the rest of the lomitapide molecule in vitro. CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize lomitapide to a small extent to M1. M1 and M3 do not inhibit activity of microsomal triglyceride transfer protein in vitro.
### Excretion
- In a mass-balance study, a mean of 59.5% and 33.4% of the dose was excreted in the urine and feces, respectively. In another mass-balance study, a mean of 52.9% and 35.1% of the dose was excreted in the urine and feces, respectively. Lomitapide was not detectable in urine samples. M1 is the major urinary metabolite. Lomitapide is the major component in the feces. The mean lomitapide terminal half-life is 39.7 hours.
## Specific Populations
### Hepatic Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and Cmax were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and Cmax were 47% and 4% higher, respectively, compared with healthy volunteers. Lomitapide has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15) .
### Renal Impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in patients with end-stage renal disease receiving hemodialysis compared with healthy volunteers with normal renal function. Healthy volunteers had estimated creatinine clearance >80 mL/min by the Cockcroft-Gault equation. Compared with healthy volunteers, lomitapide AUC0-inf and Cmax were 40% and 50% higher, respectively, in patients with end-stage renal disease receiving hemodialysis. Effects of mild, moderate, and severe renal impairment as well as end-stage renal disease not yet on dialysis on lomitapide exposure have not been studied .
### In vitro Assessment of Drug Interactions
Lomitapide does not induce CYPs 1A2, 3A4, or 2B6. Lomitapide inhibits CYP3A4. Lomitapide does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. M1 and M3 do not induce CYPs 1A2, 3A4, or 2B6. M1 and M3 do not inhibit CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. Lomitapide is not a P-gp substrate. Lomitapide inhibits P-gp but does not inhibit breast cancer resistance protein (BCRP).
### Effects of other Drugs on Lomitapide
CYP3A4 Inhibitors
Lomitapide exposure increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Thus, concomitant use of strong CYP3A4 inhibitors and lomitapide is contraindicated. The effect of moderate CYP3A4 inhibitors on lomitapide exposure has not been studied. However, moderate CYP3A4 inhibitors will likely increase lomitapide exposure significantly based on the results of concomitant use of strong and weak CYP3A4 inhibitors . Thus, concomitant use of moderate CYP3A4 inhibitors and lomitapide is contraindicated.
Interaction between weak CYP3A4 inhibitors and lomitapide has not been studied. Based on cross-studies comparisons, the lomitapide exposure approximately doubles in the presence of oral contraceptives, which are weak CYP3A4 inhibitors. Do not exceed 30 mg daily of Juxtapid when used concomitantly with weak CYP3A4 inhibitors.
### Effect of Lomitapide on other Drugs
Table 6 summarizes the effects of lomitapide on the AUC and Cmax of coadministered drugs.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year dietary carcinogenicity study in mice, lomitapide was administered at doses of 0.3, 1.5, 7.5, 15, or 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenomas and carcinomas in males at doses ≥1.5 mg/kg/day (≥2-times the MRHD at 60 mg based on AUC) and in females at ≥7.5 mg/kg/day (≥10-times the human exposure at 60 mg based on AUC). Incidences of small intestinal carcinomas in males and combined adenomas and carcinomas in females were significantly increased at doses ≥15 mg/kg/day (≥23-times the human exposure at 60 mg based on AUC).
- In a 2-year carcinogenicity study in rats, lomitapide was administered by oral gavage for up to 99 weeks at doses of 0.25, 1.7, or 7.5 mg/kg/day in males and 0.03, 0.35, or 2.0 mg/kg/day in females. While the design of the study was suboptimal, there were no statistically significant drug-related increases in tumor incidences at exposures up to 6-times (males) and 8-times (females) higher than human exposure at the MRHD based on AUC.
- Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using primary human lymphocytes, and an oral micronucleus study in rats.
- Lomitapide had no effect on fertility in rats at doses up to 5 mg/kg/day at systemic exposures estimated to be 4-times (females) and 5-times (males) higher than in humans at 60 mg based on AUC.
# Clinical Studies
- The safety and effectiveness of Juxtapid as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, were evaluated in a multinational, single-arm, open-label, 78-week trial involving 29 adults with HoFH. A diagnosis of HoFH was defined by the presence of at least one of the following clinical criteria: (1) documented functional mutation(s) in both LDL receptor alleles or alleles known to affect LDL receptor functionality, or (2) skin fibroblast LDL receptor activity <20% normal, or (3) untreated TC >500 mg/dL and TG <300 mg/dL and both parents with documented untreated TC >250 mg/dL.
- Among the 29 patients enrolled, the mean age was 30.7 years (range, 18 to 55 years), 16 (55%) were men, and the majority (86%) were Caucasian. The mean body mass index (BMI) was 25.8 kg/m2, with four patients meeting BMI criteria for obesity; one patient had type 2 diabetes. Concomitant lipid-lowering treatments at baseline included one or more of the following: statins (93%), ezetimibe (76%), nicotinic acid (10%), bile acid sequestrant (3%), and fibrate (3%); 18 (62%) were receiving apheresis.
- After a six-week run-in period to stabilize lipid-lowering treatments, including the establishment of an LDL apheresis schedule if applicable, Juxtapid was initiated at 5 mg daily and titrated to daily doses of 10 mg, 20 mg, 40 mg, and 60 mg at weeks 2, 6, 10, and 14, respectively, based on tolerability and acceptable levels of transaminases. Patients were instructed to maintain a low-fat diet (<20% calories from fat) and to take dietary supplements that provided approximately 400 international units vitamin E, 210 mg alpha-linolenic acid (ALA), 200 mg linoleic acid, 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) per day. After efficacy was assessed at Week 26, patients remained on Juxtapid for an additional 52 weeks to assess long-term safety. During this safety phase, the dose of Juxtapid was not increased above each patient’s maximum tolerated dose established during the efficacy phase, but changes to concomitant lipid-lowering treatments were allowed.
- Twenty-three (79%) patients completed the efficacy endpoint at Week 26, all of whom went on to complete 78 weeks of treatment. Adverse events contributed to premature discontinuation for five patients . The maximum tolerated doses during the efficacy period were 5 mg (10%), 10 mg (7%), 20 mg (21%), 40 mg (24%), and 60 mg (34%).
The primary efficacy endpoint was percent change in LDL-C from baseline to Week 26. At Week 26, the mean and median percent changes in LDL-C from baseline were -40% (paired t-test p<0.001) and -50%, respectively, based on the intent-to-treat population with last observation carried forward (LOCF) for patients who discontinued prematurely. The mean percent change in LDL-C from baseline through Week 26 is shown in Figure 1 for the 23 patients who completed the efficacy period.
- Error bars represent 95% confidence intervals of the mean.
- Changes in lipids and lipoproteins through the efficacy endpoint at Week 26 are presented in Table 7.
- After week 26, during the safety phase of the study, adjustments to concomitant lipid-lowering treatments were allowed. For the study population overall, average reductions in LDL-C, TC, apo B, and non-HDL-C were sustained during chronic therapy.
# How Supplied
- 5 mg capsules:
- Orange/orange hard gelatin capsule printed with black ink “A733” and “5 mg”
- Bottles of 28 NDC 76431-* :*105-01
- 10 mg capsules:
- Orange/white hard gelatin capsule printed with black ink “A733” and “10 mg”
- Bottles of 28 NDC 76431-:*110-01
- 20 mg capsules:
- White/white hard gelatin capsule printed with black ink “A733” and “20 mg”
- Bottles of 28 NDC 76431-120-01
## Storage
- Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F). Brief exposure to temperatures up to 40°C (104°F) may be tolerated provided the mean kinetic temperature does not exceed 25°C (77°F); however, such exposure should be minimized. Keep container tightly closed and protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-approved labeling (Medication Guide)
- Patients should be informed that a registry for patients taking Juxtapid has been established in order to monitor and evaluate the long-term effects of Juxtapid. Patients are encouraged to participate in the registry and should be informed that their participation is voluntary. For information regarding the registry program visit www.Juxtapid.com or call 1-877-902-4099.
Advise patients of the following:
Risk of Hepatotoxicity
- Juxtapid can cause both elevations in transaminases and hepatic steatosis. Discuss with the patient the importance of monitoring of liver-related tests before taking Juxtapid, prior to each dose escalation, and periodically thereafter.
- Patients should be advised of the potential for increased risk of liver injury if alcohol is consumed while taking Juxtapid. It is recommended that patients taking Juxtapid limit consumption to not more than one alcoholic drink per day.
- Juxtapid is commonly associated with nausea, vomiting, and abdominal pain. Advise patients to promptly report these symptoms if they increase in severity, persist, or change in the character, as they might reflect liver injury. Patients should also report any other symptoms of possible liver injury, including fever, jaundice, lethargy, or flu-like symptoms.
Juxtapid REMS PROGRAM
- Juxtapid is only available through a restricted program called Juxtapid REMS PROGRAM and therefore, Juxtapid is only available from certified pharmacies that are enrolled in the program.
Females of Reproductive Potential
- Juxtapid is contraindicated in pregnancy.
- Advise females of reproductive potential that they should have a negative pregnancy test before starting Juxtapid and that they should use effective contraception while taking Juxtapid. If oral contraceptives are initiated while taking Juxtapid, the dose of Juxtapid may require adjustment. Hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking Juxtapid, warranting the use of additional contraceptive methods.
- Nursing Mothers: A decision should be made whether to discontinue nursing or discontinue Juxtapid.
Dietary Supplements
- Discuss with the patient the importance of taking daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA)
Gastrointestinal Adverse Reactions
- Inform the patient that gastrointestinal adverse reactions are common with Juxtapid. These include, but are not limited to, diarrhea, nausea/vomiting, abdominal pain/discomfort, flatulence, and constipation. Strict adherence to a low-fat diet (<20% of total calories from fat) may reduce these reactions.
- Tell the patient that taking Juxtapid with food may adversely impact gastrointestinal tolerability; therefore, they should take Juxtapid at least 2 hours after the evening meal, swallowing each capsule whole.
- Absorption of oral medications may be affected in patients who develop diarrhea or vomiting. For example, hormone absorption from oral contraceptives may be incomplete, warranting the use of additional contraceptive methods. Patients who develop these symptoms should seek advice from their healthcare provider.
Drug Interactions
- Tell the patient to omit grapefruit juice from his/her diet while on Juxtapid.
- Because multiple drug-drug interactions have been described with Juxtapid, advise the patient to tell their healthcare provider(s) about all medications, nutritional supplements, and vitamins that they are taking or may be taking while taking Juxtapid.
Missed Doses
- If a dose of Juxtapid is missed, the normal dose should be taken at the usual time the next day. If dosing is interrupted for more than a week, tell the patient to contact their healthcare provider before restarting treatment.
# Precautions with Alcohol
- Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking Juxtapid should not consume more than one alcoholic drink per day.
- Patients should be advised of the potential for increased risk of liver injury if alcohol is consumed while taking Juxtapid. It is recommended that patients taking Juxtapid limit consumption to not more than one alcoholic drink per day.
# Brand Names
- Juxtapid
# Look-Alike Drug Names
- There is limited information about the look-alike drugs.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lomitapide | |
533ca03c7fdb4e9f6372a21bf3e64f11aa223078 | wikidoc | Loneliness | Loneliness
Loneliness is a feeling where people experience a powerful surge of emptiness and solitude. Loneliness is more than the feeling of wanting company or wanting to do something with another person. Someone who is lonely may find it hard to form human contact.
One of the first recorded uses of the word "lonely" was in William Shakespeare's Coriolanus, Act IV Scene 1.
# Distinction from solitude
Loneliness is not the same as being alone. Many people have times when they are alone through circumstances or choice. Being alone can be experienced as positive, pleasurable, and emotionally refreshing if it is under the individual's control. Solitude is the state of being alone and secluded from other people, and often implies having made a conscious choice to be alone. Loneliness does not require aloneness and is often experienced even in crowded places. It can be described as the absence of identifaction, understanding or compassion.
In their growth as individuals, humans start a separation process at birth, which continues with growing independence towards adulthood. As such, feeling alone can be a healthy emotion and, indeed, choosing to be alone for a period of solitude can be enriching. To experience loneliness, however, can be to feel overwhelmed by an unbearable feeling of separateness at a profound level. This can manifest in feelings of abandonment, rejection, depression, insecurity, anxiety, hopelessness, unworthiness, meaninglessness, and resentment. If these feelings are prolonged they may become debilitating and prevent the affected individual from developing healthy relationships and lifestyles. If the individual is convinced he or she is unlovable, this will increase the experience of suffering and the likelihood of avoiding social contact. Low self-esteem will often trigger the social disconnection which can lead to loneliness.
In some people, temporary or prolonged loneliness can lead to notable artistic and creative expression, for example, as was the case with Emily Dickinson. This is not to imply that loneliness itself ensures this creativity; rather, it may have an influence on the subject matter of the artist.
# Common causes
People can experience loneliness for many reasons, and many life events are associated with it. The lack of friendship relations during childhood and adolescence, or the physical absence of meaningful people around a person are causes for loneliness, depression, and involuntary celibacy. At the same time loneliness may be a symptom of another social or psychological problem (for example chronic depression) which should be analyzed.
Many people experience loneliness for the first time when they are left alone as an infant. It is also a very common though normally temporary consequence of divorce or the breakup or loss of any important long-term relationship. In these cases, it may stem both from the loss of a specific person and from the withdrawal from social circles caused by the event or the associated sadness.
Loss of a significant person in one's life will typically initiate a grief response; here, one might feel lonely, even in the company of others. Loneliness may also occur after the birth of a child, after marriage or any socially disruptive event, such as moving from one's home town to a university campus. Loneliness can occur within marriages or similar close relationships where there is anger, resentment, or where love cannot be given or received. It may represent a dysfunction of communication. Learning to cope with changes in life patterns is essential in overcoming loneliness.
# Typology
## Common types
Loneliness can be summarized as falling into these categories:
- Situational / circumstantial - loss of a relationship, move to a new city
- Developmental - a need for intimacy balanced by a need for individualism
- Internal - often including feelings of low self-esteem and vulnerability
## Common symptoms
Loneliness can evoke feelings that 'everyone else' has friends, or that one is socially inadequate and socially unskilled. A lonely person may become convinced there is something wrong with him or her, or that no one understands his or her situation. Such a person may feel reluctant to attempt to change or to try new things. In extreme cases, a person may feel a sense of emptiness, which may become a state of clinical depression.
# In modern society
Loneliness frequently occurs in heavily populated cities; in these cities many people feel utterly alone and cut off, even when surrounded by throngs of other people. They experience a loss of identifiable community in an anonymous crowd. It is unclear whether loneliness is a condition aggravated by high population density itself, or simply part of the human condition brought on by this social milieu. Certainly, loneliness occurs even in societies with much smaller populations, but the sheer number of random people that one comes into contact with daily in a city, even if only briefly, may raise barriers to actually interacting more deeply with them and increase the feeling of being cut off and alone. Quantity of contact does not translate into quality of contact.
Loneliness appears to have become particularly prevalent in modern times. At the beginning of the last century families were typically larger and more stable, divorce was rarer and relatively few people lived alone. Today, the trend has reversed direction: over a quarter of the U.S. population lived alone in 1998. In 1995, 24 million Americans lived in single-person households; by 2010, it is estimated that number will have increased to around 31 million.
A 2006 study in the American Sociological Review found that Americans on average had only two close friends to confide in, down from an average of three in 1985. The percentage of people who noted having no such confidant rose from 10 percent to almost 25 percent; and 19 additional percent said they had only a single confidant (often their spouse), raising the risk of serious loneliness in case the relationship ended.
# As human condition
The existentialist school of thought views loneliness as the essence of being human. Each human being comes into the world alone, travels through life as a separate person, and ultimately dies alone. Coping with this, accepting it, and learning how to direct our own lives with some degree of grace and satisfaction is the human condition.. Some philosophers, such as Sartre, believe in a epistemic loneliness in which loneliness is a fundamental part of the human condition because of the paradox between the desire of man's consciousness to have meaning met with the isolation and nothingness of the universe. However, other existentialist thinkers argue the opposite. Human beings might be said to actively "engage" each other and the universe as they communicate and create, and loneliness is merely the feeling of being cut off from this process.
# Effects
Chronic loneliness (as opposed to the normal loneliness everyone feels from time to time), is a serious, life-threatening condition. At least one study has empirically correlated it with an increased risk of cancer, especially for those who hide their loneliness from the outside world. It is associated with increased risk of stroke and cardiovascular disease. People who are socially isolated also report poor sleep quality and thus have diminished restorative processes. Loneliness is also linked with depression, a risk factor for suicide. Émile Durkheim also described loneliness, specifically the inability or unwillingness to live for others (i.e. for friendships or altruistic ideas), as the main reason for what he called "egoistic" suicide.
Loneliness can play a part in alcoholism. In children, a lack of social connections is directly linked to several forms of antisocial and self-destructive behavior, most notably hostile and delinquent behavior. In both children and adults, loneliness often has a negative impact on learning and memory. Its effect on sleep patterns, as well as the above-mentioned other effects can have a devastating effect on the ability to function in everyday life.
Some other effects may not be symptomatic for years. In 2005, results from the U.S. Framingham Heart Study demonstrated that lonely men had raised levels of IL-6, a blood chemical linked to heart disease. A 2006 study conducted by the Center for Cognitive and Social Neuroscience at the University of Chicago found loneliness can add 30 points to a blood pressure reading for adults over the age of 50. Another remarkable finding, from a survey conducted by John Cacioppo, a psychologist at the University of Chicago, is that doctors say they provide better medical care to patients who have a strong network of family and friends than they do to patients who are alone.
Cacioppo's 2008 book, Loneliness: Human Nature and the Need for Social Connection, outlines five distinct pathways through which social isolation contributes to increased illness and early death. He also offers an evolutionary rationale for why the subjective sense of social isolation—loneliness—is so profoundly disruptive to human physiology that it impairs cognition and will power, alters DNA transcription in immune cells, and leads over time to high blood pressure.
Enforced loneliness (solitary confinement) has been a punishment method throughout history. It is often considered a form of tortureTemplate:Bywhom.
# Treatments
There are many different ways used to treat loneliness or clinical depression. The first step that most doctors recommend to patients is therapy. Therapy is a common and effective way of treating loneliness and is often successful. Short term therapy, the most common form for lonely or depressed patients, typically occurs over a period of 10 to 20 weeks. During therapy, emphasis is put on understanding the cause of the problem; reversing the negative thoughts, feelings, and attitudes resulting from the problem; and exploring ways to cure the patient. Some doctors also recommend group therapy as a means to connect with other sufferers and establish a support system. Doctors also frequently prescribe anti-depressants to patients as a stand-alone treatment or in conjunction with therapy. It usually takes a few tries before a patient finds the correct anti-depressant medication. Some patients may also develop a resistance to a certain type of medication and need to switch periodically.
Alternative approaches to treating depression are suggested by many doctors. These treatments may include exercise, dieting, hypnosis, electro-shock therapy, acupuncture, herbs, and many others. Many patients find that participating in these activities fully or partially alleviate symptoms related to depression. Another treatment for both loneliness and depression is pet therapy, or animal-assisted therapy, as it is more formally known. Some studies and surveys, as well as anecdotal evidence provided by volunteer and community organizations, indicate that the presence of animal companions—dogs, cats, and even rabbits or guinea pigs—can ease feelings of depression and loneliness among some sufferers. According to the Centers for Disease Control, there are a number of health benefits associated with pet ownership. In addition to easing feelings of loneliness (because of the increased opportunities for socializing with other pet owners, beyond the companionship the animal provides), having a pet is associated with lowered blood pressure and decreased levels of cholesterol and triglycerides. | Loneliness
Template:Otheruses4
Template:Worldwide
Loneliness is a feeling where people experience a powerful surge of emptiness and solitude. Loneliness is more than the feeling of wanting company or wanting to do something with another person. Someone who is lonely may find it hard to form human contact.
One of the first recorded uses of the word "lonely" was in William Shakespeare's Coriolanus, Act IV Scene 1.
# Distinction from solitude
Loneliness is not the same as being alone. Many people have times when they are alone through circumstances or choice. Being alone can be experienced as positive, pleasurable, and emotionally refreshing if it is under the individual's control. Solitude is the state of being alone and secluded from other people, and often implies having made a conscious choice to be alone. Loneliness does not require aloneness and is often experienced even in crowded places. It can be described as the absence of identifaction, understanding or compassion.
In their growth as individuals, humans start a separation process at birth, which continues with growing independence towards adulthood. As such, feeling alone can be a healthy emotion and, indeed, choosing to be alone for a period of solitude can be enriching. To experience loneliness, however, can be to feel overwhelmed by an unbearable feeling of separateness at a profound level. This can manifest in feelings of abandonment, rejection, depression, insecurity, anxiety, hopelessness, unworthiness, meaninglessness, and resentment. If these feelings are prolonged they may become debilitating and prevent the affected individual from developing healthy relationships and lifestyles. If the individual is convinced he or she is unlovable, this will increase the experience of suffering and the likelihood of avoiding social contact. Low self-esteem will often trigger the social disconnection which can lead to loneliness.
In some people, temporary or prolonged loneliness can lead to notable artistic and creative expression, for example, as was the case with Emily Dickinson. This is not to imply that loneliness itself ensures this creativity; rather, it may have an influence on the subject matter of the artist.
# Common causes
People can experience loneliness for many reasons, and many life events are associated with it. The lack of friendship relations during childhood and adolescence, or the physical absence of meaningful people around a person are causes for loneliness, depression, and involuntary celibacy. At the same time loneliness may be a symptom of another social or psychological problem (for example chronic depression) which should be analyzed.
Many people experience loneliness for the first time when they are left alone as an infant. It is also a very common though normally temporary consequence of divorce or the breakup or loss of any important long-term relationship. In these cases, it may stem both from the loss of a specific person and from the withdrawal from social circles caused by the event or the associated sadness.
Loss of a significant person in one's life will typically initiate a grief response; here, one might feel lonely, even in the company of others. Loneliness may also occur after the birth of a child, after marriage or any socially disruptive event, such as moving from one's home town to a university campus. Loneliness can occur within marriages or similar close relationships where there is anger, resentment, or where love cannot be given or received. It may represent a dysfunction of communication. Learning to cope with changes in life patterns is essential in overcoming loneliness.
# Typology
## Common types
Loneliness can be summarized as falling into these categories:
- Situational / circumstantial - loss of a relationship, move to a new city
- Developmental - a need for intimacy balanced by a need for individualism
- Internal - often including feelings of low self-esteem and vulnerability
## Common symptoms
Loneliness can evoke feelings that 'everyone else' has friends, or that one is socially inadequate and socially unskilled. A lonely person may become convinced there is something wrong with him or her, or that no one understands his or her situation. Such a person may feel reluctant to attempt to change or to try new things. In extreme cases, a person may feel a sense of emptiness, which may become a state of clinical depression.
# In modern society
Loneliness frequently occurs in heavily populated cities; in these cities many people feel utterly alone and cut off, even when surrounded by throngs of other people. They experience a loss of identifiable community in an anonymous crowd. It is unclear whether loneliness is a condition aggravated by high population density itself, or simply part of the human condition brought on by this social milieu. Certainly, loneliness occurs even in societies with much smaller populations, but the sheer number of random people that one comes into contact with daily in a city, even if only briefly, may raise barriers to actually interacting more deeply with them and increase the feeling of being cut off and alone. Quantity of contact does not translate into quality of contact.[1]
Loneliness appears to have become particularly prevalent in modern times. At the beginning of the last century families were typically larger and more stable, divorce was rarer and relatively few people lived alone. Today, the trend has reversed direction: over a quarter of the U.S. population lived alone in 1998. In 1995, 24 million Americans lived in single-person households; by 2010, it is estimated that number will have increased to around 31 million.[2]
A 2006 study in the American Sociological Review found that Americans on average had only two close friends to confide in, down from an average of three in 1985. The percentage of people who noted having no such confidant rose from 10 percent to almost 25 percent; and 19 additional percent said they had only a single confidant (often their spouse), raising the risk of serious loneliness in case the relationship ended.[3]
# As human condition
The existentialist school of thought views loneliness as the essence of being human. Each human being comes into the world alone, travels through life as a separate person, and ultimately dies alone. Coping with this, accepting it, and learning how to direct our own lives with some degree of grace and satisfaction is the human condition.[4]. Some philosophers, such as Sartre, believe in a epistemic loneliness in which loneliness is a fundamental part of the human condition because of the paradox between the desire of man's consciousness to have meaning met with the isolation and nothingness of the universe. However, other existentialist thinkers argue the opposite. Human beings might be said to actively "engage" each other and the universe as they communicate and create, and loneliness is merely the feeling of being cut off from this process.
# Effects
Chronic loneliness (as opposed to the normal loneliness everyone feels from time to time), is a serious, life-threatening condition. At least one study has empirically correlated it with an increased risk of cancer, especially for those who hide their loneliness from the outside world.[5] It is associated with increased risk of stroke and cardiovascular disease.[2] People who are socially isolated also report poor sleep quality and thus have diminished restorative processes.[6] Loneliness is also linked with depression, a risk factor for suicide.[7] Émile Durkheim also described loneliness, specifically the inability or unwillingness to live for others (i.e. for friendships or altruistic ideas), as the main reason for what he called "egoistic" suicide.[8]
Loneliness can play a part in alcoholism. In children, a lack of social connections is directly linked to several forms of antisocial and self-destructive behavior, most notably hostile and delinquent behavior. In both children and adults, loneliness often has a negative impact on learning and memory. Its effect on sleep patterns, as well as the above-mentioned other effects can have a devastating effect on the ability to function in everyday life.[7]
Some other effects may not be symptomatic for years. In 2005, results from the U.S. Framingham Heart Study demonstrated that lonely men had raised levels of IL-6, a blood chemical linked to heart disease. A 2006 study conducted by the Center for Cognitive and Social Neuroscience at the University of Chicago found loneliness can add 30 points to a blood pressure reading for adults over the age of 50. Another remarkable finding, from a survey conducted by John Cacioppo, a psychologist at the University of Chicago, is that doctors say they provide better medical care to patients who have a strong network of family and friends than they do to patients who are alone.
Cacioppo's 2008 book, Loneliness: Human Nature and the Need for Social Connection, outlines five distinct pathways through which social isolation contributes to increased illness and early death. He also offers an evolutionary rationale for why the subjective sense of social isolation—loneliness—is so profoundly disruptive to human physiology that it impairs cognition and will power, alters DNA transcription in immune cells, and leads over time to high blood pressure.[9]
Enforced loneliness (solitary confinement) has been a punishment method throughout history. It is often considered a form of tortureTemplate:Bywhom.
# Treatments
There are many different ways used to treat loneliness or clinical depression. The first step that most doctors recommend to patients is therapy. Therapy is a common and effective way of treating loneliness and is often successful. Short term therapy, the most common form for lonely or depressed patients, typically occurs over a period of 10 to 20 weeks. During therapy, emphasis is put on understanding the cause of the problem; reversing the negative thoughts, feelings, and attitudes resulting from the problem; and exploring ways to cure the patient. Some doctors also recommend group therapy as a means to connect with other sufferers and establish a support system.[10] Doctors also frequently prescribe anti-depressants to patients as a stand-alone treatment or in conjunction with therapy. It usually takes a few tries before a patient finds the correct anti-depressant medication. Some patients may also develop a resistance to a certain type of medication and need to switch periodically.[11]
Alternative approaches to treating depression are suggested by many doctors. These treatments may include exercise, dieting, hypnosis, electro-shock therapy, acupuncture, herbs, and many others. Many patients find that participating in these activities fully or partially alleviate symptoms related to depression.[12] Another treatment for both loneliness and depression is pet therapy, or animal-assisted therapy, as it is more formally known. Some studies and surveys, as well as anecdotal evidence provided by volunteer and community organizations, indicate that the presence of animal companions—dogs, cats, and even rabbits or guinea pigs—can ease feelings of depression and loneliness among some sufferers. According to the Centers for Disease Control, there are a number of health benefits associated with pet ownership. In addition to easing feelings of loneliness (because of the increased opportunities for socializing with other pet owners, beyond the companionship the animal provides), having a pet is associated with lowered blood pressure and decreased levels of cholesterol and triglycerides.[13] | https://www.wikidoc.org/index.php/Loneliness | |
1240bb28cee5bd3219b42a5a34b6588280199f86 | wikidoc | Lonidamine | Lonidamine
# Overview
Lonidamine is a derivative of indazole-3-carboxylic acid, which for a long time, has been known to inhibit aerobic glycolysis in cancer cells. It seems to enhance aerobic glycolysis in normal cells, but suppress glycolysis in cancer cells. This is most likely through the inhibition of the mitochondrially bound hexokinase. Later studies in Ehrlich ascites tumor cells showed that lonidamine inhibits both respiration and glycolysis leading to a decrease in cellular ATP.
Clinical trials of lonidamine in combination with other anticancer agents for a variety of cancers has begun. This is due to its proven ability to inhibit energy metabolism in cancer cells, and to enhance the activity of anticancer agents.
Lonidamine has been used in the treatment of brain tumours in combination with radiotherapy and temozolomide. Results showed that a combination of temozolomide and lonidamine at clinically achievable, low plasma concentrations, could inhibit tumour growth, and lonidamine could reduce the dose of temozolomide required for radiosensitization of brain tumours.
A derivative of lonidamine, gamendazole, is in testing as a possible male contraceptive pill. | Lonidamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lonidamine is a derivative of indazole-3-carboxylic acid, which for a long time, has been known to inhibit aerobic glycolysis in cancer cells. It seems to enhance aerobic glycolysis in normal cells, but suppress glycolysis in cancer cells. This is most likely through the inhibition of the mitochondrially bound hexokinase. Later studies in Ehrlich ascites tumor cells showed that lonidamine inhibits both respiration and glycolysis leading to a decrease in cellular ATP.[1]
Clinical trials of lonidamine in combination with other anticancer agents for a variety of cancers has begun. This is due to its proven ability to inhibit energy metabolism in cancer cells, and to enhance the activity of anticancer agents.[1]
Lonidamine has been used in the treatment of brain tumours in combination with radiotherapy and temozolomide. Results showed that a combination of temozolomide and lonidamine at clinically achievable, low plasma concentrations, could inhibit tumour growth, and lonidamine could reduce the dose of temozolomide required for radiosensitization of brain tumours.[2]
A derivative of lonidamine, gamendazole, is in testing as a possible male contraceptive pill.[3] | https://www.wikidoc.org/index.php/Lonidamine | |
792d3902c8edae35e36e87e15779a7cbddb4a5c2 | wikidoc | Lophophine | Lophophine
Lophophine, homomyristicylamine, (or 3-methoxy-4,5-methylendioxyphenethylamine) is an homologue of MMDA. It is also related to mescaline and Alexander Shulgin suggests it could be a natural component in the peyote cactus because it is the only logical chemical intermediate for the biosynthesis of several of tetrahydroisoquinolines known to be present in the cactus. Lophophine produces hallucinogenic, psychedelic, and entheogenic effects that are similar to mescaline.
# Chemistry
Lophophine is in a class of compounds commonly known as phenethylamines, and the full chemical name is 2-(7-methoxy-1,3-benzodioxol-5-yl)ethanamine.
# Effects
Little is known about the psychopharmacological effects of lophophine, but it does appear to have qualitative and quantitative effects that resemble mescaline. Shulgin reports in Mescaline: The Chemistry and Pharmacology of its Analogs that lophophine is active at 150-250 mg. He states at these dosages that the action of this base is quite similar to that of mescaline; there is a peaceful elevation of mood, euphoria, enhancement of visual perception, and the generation of eyes-closed imagery. At dosages above 300 mg, visual distortions that resemble those of mescaline begin to appear. He also notes that in contrast to mescaline, little nausea is produced from lophophine ingestion.
# Pharmacology
The mechanism that produces the hallucinogenic and entheogenic effects of lophophine is unknown. Although structure-activity relationships mean that it is likely to be caused by 5-HT2A receptor agonism - similar to other psychedelic drugs such as LSD and Mescaline.
# Dangers
The toxicity of lophophine is not known.
# Legality
Lophophine is unscheduled and unregulated in the United States, however because of its close similarity in structure and effects to MDA and MMDA, possession and sale of lophophine may be subject to prosecution under the Federal Analog Act. | Lophophine
Lophophine, homomyristicylamine, (or 3-methoxy-4,5-methylendioxyphenethylamine) is an homologue of MMDA. It is also related to mescaline and Alexander Shulgin suggests it could be a natural component in the peyote cactus because it is the only logical chemical intermediate for the biosynthesis of several of tetrahydroisoquinolines known to be present in the cactus. Lophophine produces hallucinogenic, psychedelic, and entheogenic effects that are similar to mescaline.
# Chemistry
Lophophine is in a class of compounds commonly known as phenethylamines, and the full chemical name is 2-(7-methoxy-1,3-benzodioxol-5-yl)ethanamine.
# Effects
Little is known about the psychopharmacological effects of lophophine, but it does appear to have qualitative and quantitative effects that resemble mescaline. Shulgin reports in Mescaline: The Chemistry and Pharmacology of its Analogs that lophophine is active at 150-250 mg. He states at these dosages that the action of this base is quite similar to that of mescaline; there is a peaceful elevation of mood, euphoria, enhancement of visual perception, and the generation of eyes-closed imagery. At dosages above 300 mg, visual distortions that resemble those of mescaline begin to appear. He also notes that in contrast to mescaline, little nausea is produced from lophophine ingestion.
# Pharmacology
The mechanism that produces the hallucinogenic and entheogenic effects of lophophine is unknown. Although structure-activity relationships mean that it is likely to be caused by 5-HT2A receptor agonism - similar to other psychedelic drugs such as LSD and Mescaline.
# Dangers
The toxicity of lophophine is not known.
# Legality
Lophophine is unscheduled and unregulated in the United States, however because of its close similarity in structure and effects to MDA and MMDA, possession and sale of lophophine may be subject to prosecution under the Federal Analog Act. | https://www.wikidoc.org/index.php/Lophophine | |
c1451584a357b9a48de4e434205beb26f7f88d18 | wikidoc | Loprazolam | Loprazolam
# Overview
Loprazolam marketed under the band names Dormonoct®, Havlane®, Sonin®, Somnovit®, is a drug which is an imidazole benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It is available in 1mg tablets. It is licensed and marketed for the short term treatment of severe insomnia.
# Indications
Insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is an intermediate acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.
# Dose
The dose of Loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half life is much more prolonged in the elderly than in younger patients. A half life of 19.8 hours has been reported in elderly patients.
Patients and prescribing physicians should however bear in mind that higher doses of loprazolam may impair long term memory functions.
# Mechanism of Action
Loprazolam is a benzodiazepine, which acts via positively modulating the GABAa receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAa receptors. This action enhances the effect of the neurotransmitter GABA on the GABAa receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces the following properties: muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant. These properties can be used for therapeutic benefit in clinical practise. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.
# Pharmacokinetics
After oral administration of loprazolam on an empty stomach it takes 2 hours for serum concentration levels to reach their peak which is a significantly longer time than other benzodiazepine hypnotics. The delay in the time for peak plasma levels to reach their maximum brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics, although studies have shown that the sleep inducing properties of loprazolam occur within 0.5 hours, which may indicate rapid penetration into the brain and thus the peak plasma delay of loprazolam may not be sigificantly relevant to loprazolams benefit as a hypnotic agent for the treatment of insomnia. If loprazolam is taken after a meal the time for plasma levels to reach their peak may be delayed even further. Loprazolam induces significant changes in the electrical activity of the brain as measured by an EEG, these changes are more pronounced, the higher the dosage. Metabolism of loprazolam in humans produces an active metabolite which is similar in potency to loprazolam, in levels of about half that of parent compound, the other half is excreted unchanged as loprazolam. The half life of the active metabolite is about the same as the parent compound loprazolam.
# Cognitive behavioural therapy
Chronic users of sedative hypnotic drugs who took part in a large scale clinical trial were found to have very high levels of insomnia and very low levels of sleep quality at trial intake. Those who received cognitive behavioural therapy and sleep hygiene, stimulus control, relaxation therapies had improved sleep quality, increased vitality, increased physical functioning and improved mental health. Reduced sedative hypnotic drug use also occurred in CBT treated patients with 33% at 6 month follow up reporting zero sedative hypnotic use. Clinical improvements were still apparent at 12 month follow-up. The patients age was not a barrier to successful outcome. It was concluded that psychological treatment can improve sleep quality, reduce hypnotic drug use and thus improve health related quality of life and is cost effective treatment for long term hypnotic users with chronic insomnia. CBT should be considered by healthcare providers and practitioners for insomnia management and to reduce benzodiazepine use in those with chronic insomnia.
# Side Effects
Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam Valium. The only main difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half life of loprazolam is considered to be intermediate whereas diazepam has a very long half life. The side effects of loprazolam are the following:
List of Side Effects
- drowsiness
- paradoxical increase in aggression
- lightheadedness
- confusion
- muscle weakness
- ataxia (particularly in the elderly)
- amnesia
- headache
- vertigo
- hypotension
- salivation changes
- gastro-intestinal disturbances
- visual disturbances
- dysarthria
- tremor
- changes in libido
- incontinence
- urinary retention
- blood disorders and jaundice
- skin reactions
- dependence and withdrawal reactions
Residual 'hangover' effects after nighttime administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.
# Tolerance, Dependence and Withdrawal
Loprazolam as with all other benzodiazepines is recommended for only short term management of insomnia in the UK due to the serious concerns of adverse affects of long term usage of benzodiazepines such as tolerance, dependency and withdrawal phenomenon as well as adverse effects on mood and cognition. Prolonged usage of benzodiazepines also is not recommended due to a lack of efficacy in there therapeutic actions due to tolerance to their effects and concerns of increasing physical and psychological adverse effects of some patients on long term benzodiazepines, eg agorophobia, gastrointestinal and peripheral nerve abnormalities such as burning and tingling sensations.
Loprazolam however has a low risk of dependence (addiction) and withdrawal phenomenon if it is used for less than 4 weeks or very occasionally. However in one placebo controlled study comparing 3 week treatment for insomnia of either loprazolam or triazolam rebound anxiety and insomnia occurred 3 days after discontinuing loprazolam therapy whereas with triazolam the rebound anxiety and insomnia was seen the next day. The difference between the two benzodiazepines in time for rebound or withdrawal phenomenon to appear is likely due to the difference in the elimination half life of the two drugs. These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1 - 2 weeks rather than 2 - 4 weeks to reduce the risk of physical dependence or and withdrawal or rebound phenomenon.
Withdrawal Symptoms
It should be noted that slow reduction of the dosage over a period of months at a rate which the individual can tolerate greatly minimises the severity of the withdrawal symptoms. It is usually recommended for individuals dependent on benzodiazepines cross to an equivalent dose of diazepam to gradually taper as diazepam has a longer half life and small dose reductions can be achieved compared to other benzodiazepines.
- anxiety and panic attacks
- sweating
- nightmares
- insomnia
- headache
- tremor
- nausea and vomiting
- feelings of unreality
- abnormal sensation of movement
- hypersensitivity to stimuli
- hyperventilation
- flushing
- sweating
- palpitations
- dimensional distortions of rooms and television pictures
- paranoid thoughts and feelings of persecution
- depersonalisation
- fears of 'going mad
- heightened perception of taste, smell, sound, and light; photophobia
- agoraphobia
- clinical depression
- poor memory and concentration
- aggression
- excitability
- Somatic Symptoms
- numbness
- altered sensations of the skin
- pain
- stiffness
- weakness in the neck, head, jaw, and limbs
- muscle fasciculation ranging from twitches to jerks affecting the legs or shoulders
- ataxia
- paraesthesiae
- influenza-like symptoms
- blurred double vision
- menorrhagia
- loss of or dramatic gain in appetite
- thirst with polyuria
- urinary incontinence
- dysphagia
- abdominal pain
- diarrhoea
- constipation
Major complications can occur after abrupt or over rapid withdrawal especially from high doses producing symptoms such as:
- psychosis
- confusion
- visual and auditory hallucinations
- delusions
- epileptic seizures (which may be fatal)
It has been estimated that between 30% and 50% of long term users of benzodiazepines will experience withdrawal symptoms. However up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, however the rate of taper was very fast at 25% of dose per week. Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10 - 15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasional several years. | Loprazolam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Loprazolam marketed under the band names Dormonoct®, Havlane®, Sonin®, Somnovit®, is a drug which is an imidazole benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It is available in 1mg tablets. It is licensed and marketed for the short term treatment of severe insomnia.
# Indications
Insomnia. Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is an intermediate acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.[1]
# Dose
The dose of Loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half life is much more prolonged in the elderly than in younger patients. A half life of 19.8 hours has been reported in elderly patients.[2]
Patients and prescribing physicians should however bear in mind that higher doses of loprazolam may impair long term memory functions.[3]
# Mechanism of Action
Loprazolam is a benzodiazepine, which acts via positively modulating the GABAa receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAa receptors. This action enhances the effect of the neurotransmitter GABA on the GABAa receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces the following properties: muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant. These properties can be used for therapeutic benefit in clinical practise. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.[4] [5]
# Pharmacokinetics
After oral administration of loprazolam on an empty stomach it takes 2 hours for serum concentration levels to reach their peak which is a significantly longer time than other benzodiazepine hypnotics. The delay in the time for peak plasma levels to reach their maximum brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics, although studies have shown that the sleep inducing properties of loprazolam occur within 0.5 hours, which may indicate rapid penetration into the brain and thus the peak plasma delay of loprazolam may not be sigificantly relevant to loprazolams benefit as a hypnotic agent for the treatment of insomnia. If loprazolam is taken after a meal the time for plasma levels to reach their peak may be delayed even further. Loprazolam induces significant changes in the electrical activity of the brain as measured by an EEG, these changes are more pronounced, the higher the dosage. Metabolism of loprazolam in humans produces an active metabolite which is similar in potency to loprazolam, in levels of about half that of parent compound, the other half is excreted unchanged as loprazolam. The half life of the active metabolite is about the same as the parent compound loprazolam.[6]
# Cognitive behavioural therapy
Chronic users of sedative hypnotic drugs who took part in a large scale clinical trial were found to have very high levels of insomnia and very low levels of sleep quality at trial intake. Those who received cognitive behavioural therapy and sleep hygiene, stimulus control, relaxation therapies had improved sleep quality, increased vitality, increased physical functioning and improved mental health. Reduced sedative hypnotic drug use also occurred in CBT treated patients with 33% at 6 month follow up reporting zero sedative hypnotic use. Clinical improvements were still apparent at 12 month follow-up. The patients age was not a barrier to successful outcome. It was concluded that psychological treatment can improve sleep quality, reduce hypnotic drug use and thus improve health related quality of life and is cost effective treatment for long term hypnotic users with chronic insomnia. CBT should be considered by healthcare providers and practitioners for insomnia management and to reduce benzodiazepine use in those with chronic insomnia.[7]
# Side Effects
Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam Valium.[8] The only main difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half life of loprazolam is considered to be intermediate whereas diazepam has a very long half life. The side effects of loprazolam are the following:
List of Side Effects
- drowsiness
- paradoxical increase in aggression
- lightheadedness
- confusion
- muscle weakness
- ataxia (particularly in the elderly)
- amnesia
- headache
- vertigo
- hypotension
- salivation changes
- gastro-intestinal disturbances
- visual disturbances
- dysarthria
- tremor
- changes in libido
- incontinence
- urinary retention
- blood disorders and jaundice
- skin reactions
- dependence and withdrawal reactions
Residual 'hangover' effects after nighttime administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.[9]
# Tolerance, Dependence and Withdrawal
Loprazolam as with all other benzodiazepines is recommended for only short term management of insomnia in the UK due to the serious concerns of adverse affects of long term usage of benzodiazepines such as tolerance, dependency and withdrawal phenomenon as well as adverse effects on mood and cognition. Prolonged usage of benzodiazepines also is not recommended due to a lack of efficacy in there therapeutic actions due to tolerance to their effects and concerns of increasing physical and psychological adverse effects of some patients on long term benzodiazepines, eg agorophobia, gastrointestinal and peripheral nerve abnormalities such as burning and tingling sensations.[10][11]
Loprazolam however has a low risk of dependence (addiction) and withdrawal phenomenon if it is used for less than 4 weeks or very occasionally. However in one placebo controlled study comparing 3 week treatment for insomnia of either loprazolam or triazolam rebound anxiety and insomnia occurred 3 days after discontinuing loprazolam therapy whereas with triazolam the rebound anxiety and insomnia was seen the next day. The difference between the two benzodiazepines in time for rebound or withdrawal phenomenon to appear is likely due to the difference in the elimination half life of the two drugs.[12] [13] These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1 - 2 weeks rather than 2 - 4 weeks to reduce the risk of physical dependence or and withdrawal or rebound phenomenon.
Withdrawal Symptoms
It should be noted that slow reduction of the dosage over a period of months at a rate which the individual can tolerate greatly minimises the severity of the withdrawal symptoms. It is usually recommended for individuals dependent on benzodiazepines cross to an equivalent dose of diazepam to gradually taper as diazepam has a longer half life and small dose reductions can be achieved compared to other benzodiazepines. [14] [15]
- anxiety and panic attacks
- sweating
- nightmares
- insomnia
- headache
- tremor
- nausea and vomiting
- feelings of unreality
- abnormal sensation of movement
- hypersensitivity to stimuli
- hyperventilation
- flushing
- sweating
- palpitations
- dimensional distortions of rooms and television pictures
- paranoid thoughts and feelings of persecution
- depersonalisation
- fears of 'going mad
- heightened perception of taste, smell, sound, and light; photophobia
- agoraphobia
- clinical depression
- poor memory and concentration
- aggression
- excitability
- Somatic Symptoms
- numbness
- altered sensations of the skin
- pain
- stiffness
- weakness in the neck, head, jaw, and limbs
- muscle fasciculation ranging from twitches to jerks affecting the legs or shoulders
- ataxia
- paraesthesiae
- influenza-like symptoms
- blurred double vision
- menorrhagia
- loss of or dramatic gain in appetite
- thirst with polyuria
- urinary incontinence
- dysphagia
- abdominal pain
- diarrhoea
- constipation
Major complications can occur after abrupt or over rapid withdrawal especially from high doses producing symptoms such as:
- psychosis
- confusion
- visual and auditory hallucinations
- delusions
- epileptic seizures (which may be fatal)
It has been estimated that between 30% and 50% of long term users of benzodiazepines will experience withdrawal symptoms. [16] However up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, however the rate of taper was very fast at 25% of dose per week. [17] Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10 - 15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasional several years.[18] | https://www.wikidoc.org/index.php/Loprazolam | |
b1762be13d3d3c8308b27be0650400430ce97d78 | wikidoc | Loracarbef | Loracarbef
# Overview
Loracarbef is a synthetic carbacephem antibiotic. Loracarbef has a spectrum of activity similar to that of the second generation cephalosporins. It is an analogue of cefaclor from which the sulfur atom is replaced with a methylene group. Therefore loracarbef has a greater stability in solution and may be stored at room temperature.
Diarrhea is the most common adverse effect. Side effects are more frequently seen with children under the age of twelve. It received FDA approval in 1991. Its use was discontinued in 2006.
# Category
Carbacephem
# Brand Names
LORABID® (DISCONTINUED)
# Mechanism of Action
Loracarbef is an oral, synthetic beta-lactam antibiotic of the carbacephem class. Loracarbef, like all beta-lactams and cephalosporins, inhibits penicillin binding proteins, enzymes that create the cross-linkage of the peptidoglycan polymer. This binding leads to interference with the formation and remodeling of the cell wall structure. | Loracarbef
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Loracarbef is a synthetic carbacephem antibiotic.[1] Loracarbef has a spectrum of activity similar to that of the second generation cephalosporins. It is an analogue of cefaclor from which the sulfur atom is replaced with a methylene group. Therefore loracarbef has a greater stability in solution and may be stored at room temperature.
Diarrhea is the most common adverse effect. Side effects are more frequently seen with children under the age of twelve. It received FDA approval in 1991. Its use was discontinued in 2006.
# Category
Carbacephem
# Brand Names
LORABID® (DISCONTINUED)
# Mechanism of Action
Loracarbef is an oral, synthetic beta-lactam antibiotic of the carbacephem class. Loracarbef, like all beta-lactams and cephalosporins, inhibits penicillin binding proteins, enzymes that create the cross-linkage of the peptidoglycan polymer. This binding leads to interference with the formation and remodeling of the cell wall structure. | https://www.wikidoc.org/index.php/Loracarbef | |
388242e8c23c06da76aeb181f31e3c4be40ad5f8 | wikidoc | Lorcainide | Lorcainide
# Overview
Lorcainide (Lorcainide hydrochloride) is a Class 1c antiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardiac and Wolff-Parkinson-White syndrome. Lorcainide was developed by Janssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001. It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease .
# Arrhythmia
Cardiac dysrhythmia is a heart rate disorder that manifests as an altered cardiac rhythm. It results from either abnormal pacemaker activity or a disturbance in impulse propagation, or both. Arrhythmias can be caused by various conditions including ischemia, hypoxia, pH disruptions, B adrenergic activation, drug interactions or the presence of diseased tissue. These events can trigger the development of ectopic pacemaker in the heart, which emit abnormal impulses at random times during the cardiac cycle. An arrhythmia can present itself as either bradycardia or tachycardia. Untreated arrhythmias may progress to atrial fibrillation or ventricular fibrillation. Treatment is aimed at normalizing cardiac rhythm by altering ion flow across the membrane. Antiarrhythmic agents can reduce arrhythmia related symptoms such as palpitations or syncope; however, they often have a narrow therapeutic index and can also be proarrhythmic.
# Wolff-Parkinson-White syndrome
Wolff-Parkinson-White syndrome (WPW) is a pre-excitation syndrome in which individuals are predisposed to supraventricular tachyarrhythmias (rapid and irregular heart beats). People with this condition have an extra or accessory atrioventricular conduction pathway that causes re-entry tachycardia. WPW is characterized by a short PR interval (0.12 seconds).
# Class 1c activity
Fast-acting voltage-gated sodium channels (Nav1.5) found in high concentrations in the ventricular myocytes, open at a membrane potential of −80 mv in typical cardiac rhythm. This will result in a rapid upstroke of an action potential that leads to contraction of the ventricles. Class 1c drugs have local anesthetic properties and have a high affinity for open Nav1.5 (but not closed or inactive Nav1.5), thus irreversibly binding and reducing the fast Na+ influx. Interactions of Lorcainide with Nav1.5 are time and voltage dependent. Class 1c drugs have a characteristically slow dissociation rate, which will slow the upstroke duration and amplitude of ventricular myocytes’ action potential and prolong the PR, QRS and QT intervals of an ECG. Lorcainide also increases the ventricular fibrillation threshold in a dose-dependent fashion. Overall, Lorcainide causes a decrease in tachycardiac events, but also reduced ventricular contractility ejection fraction.
The effect on sinus node function is controversial, as some researchers have noted a decreased sinus cycle length and increase in sinus node recovery, whereas others have observed no change.
# Other Activities
Lorcainide inhibits adenosine 5’-triphosphate (ATP)-hydrolytic action of myocardial Na+K+ATPase in-vitro in a concentration dependent manner. The mode of action and the implications of this finding are not well known.
# Benefits And Risks
Lorcainide exhibits a prolonged duration of action (approximately 8-10 hrs), is well absorbed when taken orally and has a good safety profile as well as a good drug efficacy. Hematologic, biochemical and urinary analysis of Lorcainide revealed no significant abnormalities. However, an increased prevalence of central nervous system effects, including headache, dizziness and sleep disturbances have been associated with oral dosages of Lorcainide when compared to intravenous administration. This could be due to a greater accumulation of plasma Noriorcainide when exposed to oral Lorcainide. Noriorcainide, an N-dealkylated derivative, is an active metabolite of Lorcainide. It is as potent as its parent compound with similar antiarrhythmic efficacy, wherein it suppresses chronic premature ventricular complexes. It has a half life of 26.5 +-7.2 hrs. | Lorcainide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lorcainide (Lorcainide hydrochloride) is a Class 1c antiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardiac [7] and Wolff-Parkinson-White syndrome. [9] Lorcainide was developed by Janssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001. [2] It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease [9].
# Arrhythmia
Cardiac dysrhythmia is a heart rate disorder that manifests as an altered cardiac rhythm. It results from either abnormal pacemaker activity or a disturbance in impulse propagation, or both. [6] Arrhythmias can be caused by various conditions including ischemia, hypoxia, pH disruptions, B adrenergic activation, drug interactions or the presence of diseased tissue. [5] These events can trigger the development of ectopic pacemaker in the heart, which emit abnormal impulses at random times during the cardiac cycle. An arrhythmia can present itself as either bradycardia or tachycardia. [5] Untreated arrhythmias may progress to atrial fibrillation or ventricular fibrillation. [5] Treatment is aimed at normalizing cardiac rhythm by altering ion flow across the membrane. Antiarrhythmic agents can reduce arrhythmia related symptoms such as palpitations or syncope; however, they often have a narrow therapeutic index and can also be proarrhythmic[6].
# Wolff-Parkinson-White syndrome
Wolff-Parkinson-White syndrome (WPW) is a pre-excitation syndrome in which individuals are predisposed to supraventricular tachyarrhythmias (rapid and irregular heart beats). [1] People with this condition have an extra or accessory atrioventricular conduction pathway that causes re-entry tachycardia. [1] WPW is characterized by a short PR interval (<0.12 second) and a prolonged, slurred QRS complex (>0.12 seconds). [1]
# Class 1c activity
Fast-acting voltage-gated sodium channels (Nav1.5) found in high concentrations in the ventricular myocytes, open at a membrane potential of −80 mv in typical cardiac rhythm. This will result in a rapid upstroke of an action potential that leads to contraction of the ventricles.[8] Class 1c drugs have local anesthetic properties and have a high affinity for open Nav1.5 (but not closed or inactive Nav1.5), thus irreversibly binding and reducing the fast Na+ influx. Interactions of Lorcainide with Nav1.5 are time and voltage dependent. Class 1c drugs have a characteristically slow dissociation rate, which will slow the upstroke duration and amplitude of ventricular myocytes’ action potential and prolong the PR, QRS and QT intervals of an ECG.[4] Lorcainide also increases the ventricular fibrillation threshold in a dose-dependent fashion.[4] Overall, Lorcainide causes a decrease in tachycardiac events, but also reduced ventricular contractility ejection fraction.
The effect on sinus node function is controversial, as some researchers have noted a decreased sinus cycle length and increase in sinus node recovery, whereas others have observed no change. [4]
# Other Activities
Lorcainide inhibits adenosine 5’-triphosphate (ATP)-hydrolytic action of myocardial Na+K+ATPase in-vitro in a concentration dependent manner. The mode of action and the implications of this finding are not well known. [3]
# Benefits And Risks
Lorcainide exhibits a prolonged duration of action (approximately 8-10 hrs), is well absorbed when taken orally and has a good safety profile as well as a good drug efficacy. [6] Hematologic, biochemical and urinary analysis of Lorcainide revealed no significant abnormalities. [9] However, an increased prevalence of central nervous system effects, including headache, dizziness and sleep disturbances have been associated with oral dosages of Lorcainide when compared to intravenous administration. This could be due to a greater accumulation of plasma Noriorcainide when exposed to oral Lorcainide. Noriorcainide, an N-dealkylated derivative, is an active metabolite of Lorcainide. It is as potent as its parent compound with similar antiarrhythmic efficacy, wherein it suppresses chronic premature ventricular complexes. [4] It has a half life of 26.5 +-7.2 hrs. [9] | https://www.wikidoc.org/index.php/Lorcainide | |
344b045f86c2b4b510826c97360cd0b6005a825c | wikidoc | Lorlatinib | Lorlatinib
# 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
Lorlatinib is a Antineoplastic Agents that is FDA approved for the treatment of The treatment of patients with lung cancer
- Should not be given to patients who are pregnant or are trying to get pregnant
- This medication is only to be used after confirming the cancer has a ALK gene marker
- The doctor will test for that gene. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Edema, Peripheral Neuropathy, Cognitive Effects, Dyspnea (shortness of breath), fatigue, weight gain, arthralgia, mood effects, diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Lorlatinib is indicated for:
- The treatment of patients with anaplastic lymphoma kinase- aggressive, wide-spread lung cancer
- It is indicated for with:
Crizonitib and another ALK inhibitor, or Alectinib, the first therapy for metastatic disease, or Ceritinib as the first ALK inhibitor for this type of disease
- Crizonitib and another ALK inhibitor, or Alectinib, the first therapy for metastatic disease, or Ceritinib as the first ALK inhibitor for this type of disease
### Limitations of Use
- See adverse reactions
- See specific populations
### Dosing Considerations
- Some dose reductions if the patients have adverse reactions include:
Swallow Lorlatinib orally in a recommended dosage of 75 mg once daily
If there is need for more reduction, take Lorlatinib 50 mg once daily orally
- Swallow Lorlatinib orally in a recommended dosage of 75 mg once daily
- If there is need for more reduction, take Lorlatinib 50 mg once daily orally
### Administration of Lorlatinib
- It is recommended that the patient take 100 mg of Lorlatinib, no matter if they have or have not eaten
- The tablets are meant to be swallowed whole: it is unacceptable to chew, break, split tablets because it will not have the same effect and it could be dangerous
Make sure to not to take them if they are broken, cracked, not in packaging etc
- Make sure to not to take them if they are broken, cracked, not in packaging etc
- It is important that the patient takes the medication the same time each day
The patient may take the forgotten dose if it is more that 4 hours from their next dose
It is really important that they do not take multiple doses at once
- The patient may take the forgotten dose if it is more that 4 hours from their next dose
- It is really important that they do not take multiple doses at once
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Lorlatinib 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 Lorlatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- It is crucial to withhold ingesting Lorlatinib for three plasma half lives for patients taking strong CYP3A inducers
- Mixing them together could lead to serious hepatotoxicity or chemical-driven liver damage
# Warnings
### Serious Central Nervous System Effects
- Seizures, Hallucinations, changes in mood, sleep, mental health are all examples of the side effects
- Reduce the dosage of Lorlatinib depending on the severity of the side effect
- For patients requiring first time reduction, give them 75 mg daily through mouth
- For patients requiring second time reduction, give them 50 mg daily through mouth
- About 54% of patients acquiring this drug may experience Central Nervous system side effects listed above
- Patients will be monitored for the first 1-2 months ingesting Lorbrena, and followed up on after the initial period
- Patients may experience an increase in serum cholesterol and triglycerides
- About 7% of patients in the Study B7461001 required to discontinue the drug for a short period of time, and another 3% of the patients required a dose reduction
- In the same study, 80% of the patients required to instigate lipid-lowering medications because they were not responding to reduction and temporary pause
This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
- This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
# Adverse Reactions
## Clinical Trials Experience
Severe Adverse Reactions (32% of 295 Patients)
- Some serious reactions reported in the study were: pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%)
- There were some fatal adverse reactions that occurred in about 2.7% of the patients. Those reactions include pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%)
## Postmarketing Experience
There is limited information regarding Lobrena Postmarketing Experience in the drug label.
# Drug Interactions
- Effects of CYP3A Inducers: Combining CYP3A inducers with Lobrena can decrease plasma concentrations that may dull the effects of the medication.
- It is important to discontinue CYP3A inducers for “3 plasma half-lives” before initiating the use of Lorlatinib. Interaction between CYP3A inducers and Lobrena can heighten the severity of the present adverse reactions
- In a study, Lobrena mixed with the CYP3A inducer rifampin shows results of severe hepatoxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
This drug can result in major birth defects or fetal harm during animal studies. It is not clear if it can cause fetal harm in human pregnancies. It is important to note that it should be prohibited to have pregnant women or women who want to carry out a pregnancy take Lobrena. In animal studies, fetal harm includes gastroschisis, rotated limbs, supernumerary digits, vessel abnormalities etc. It should be noted that the effects of this medication for pregnant human women is not listed in the FDA label.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lorlatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lorlatinib during labor and delivery.
### Nursing Mothers
There is not data from studies that indicate the presence of active metabolites or Lorlatinib in breast-fed milk. Patients should consult their medical professional on how to proceed.
### Pediatric Use
Lorlatinib has not been tested on pediatric patients, so the saftey and well-being of children administered Lorlatinib is unknown.
### Geriatic Use
Based on the limited trial data present, patients over the age of 65 do not require a different dose of Lorlatinib.
### Gender
There is no FDA guidance on the use of Lorlatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lorlatinib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lorlatinib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lorlatinib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Advise males who have female reproductive partners to wear contraception for the duration of ingesting this medication and for 3 months after the final dose. Additionally, there has been data that indicates lower testicular, epididymal, and prostate weights. There is a possibility for male fertility impairment after using Lobrena.
### Immunocompromised Patients
There is no FDA guidance one the use of Lorlatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- It is recommended that the patient take 100 mg of Lorlatinib, no matter if they have or have not eaten
- The tablets are meant to be swallowed whole: it is unacceptable to chew, break, split tablets because it will not have the same effect and it could be dangerous
Make sure to not to take them if they are broken, cracked, not in packaging etc
- Make sure to not to take them if they are broken, cracked, not in packaging etc
- It is important that the patient takes the medication the same time each day
The patient may take the forgotten dose if it is more that 4 hours from their next dose
It is really important that they do not take multiple doses at once
- The patient may take the forgotten dose if it is more that 4 hours from their next dose
- It is really important that they do not take multiple doses at once
### Monitoring
There is limited information regarding Lorlatinib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Lorlatinib and IV administrations.
# Overdosage
- If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Lorlatinib is a kinase inhibitor that reverses the activity of Anaplastic lymphoma kinase and other tyrosine kinase inhibitors including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. It also reversed the activity of several mutants of the ALK enzyme. Lolrlatinib is capable of crossing the blood-brain barrier which enebles it to treat spreading metasteses in the brain. The effectiveness of Lorlatinib activity has shown to be dose-dependent and associated with the inhibition of ALK phosphorylation. Patients using Lorlatinib have shown a new control to stop tumor regression despite having used tyrosine kinase inhibitors like crizontinib, alectinib, and/or ceritinib.
## Structure
There is limited information regarding Lorlatinib Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Lorlatinib Pharmacodynamics in the drug label.
## Pharmacokinetics
The Lorlatinib plasma concentration increased proportionally over the dose range of 10 mg or Lobrena to 200 mg. The mean Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ng·h/mL (39%) in patients with small cell lung cancer.
- This data is for intravenous dosage of Lobrena
Lorlatinib distributed and bound to 66% of plasma proteins, around a concentration of 2.4 micro M
- Lorlatinib distributed and bound to 66% of plasma proteins, around a concentration of 2.4 micro M
- The CV% was 305 L or 28% following a single dose intravenously
- The resulting blood to plasma ratio was 0.99
- Studies showed that the half-life of Lorlatinib plasma was 24 hours after one oral dose
- The oral clearance that resulted was 11 L/h and it eventually increased to 18 L/h which could mean auto-induction, or certain enzymes increased to help faster metabolize the agent
- Pregnancy= This drug can result in major birth defects or fetal harm during animal studies. It is not clear if it can cause fetal harm in human pregnancies. It is important to note that it should be prohibited to have pregnant women or women who want to carry out a pregnancy take Lobrena. In animal studies, fetal harm includes gastroschisis, rotated limbs, supernumerary digits, vessel abnormalities etc. It should be noted that the effects of this medication for pregnant human women is not listed in the FDA label.
- Lactation= Lobrena or any of its metabolites will not contaminate human milk, and it will not effect the production of breastfeeding milk. However, there could be serious adverse reactions for the infants receiving the breastfed milk. Therefore, women should be instructed to abstain from breastfeeding until 7 days after their final dose of Lobrena.
- Geriatric Use= Through the study B7461001, there has been no discrepancies of the effects between patients 65 and older (18 % of the test patients) and patients younger than that
- Pediatric Use: The efficiency and safety of this medication has not been established in pediatric patients.
## Nonclinical Toxicology
There is limited information regarding Lorlatinib Nonclinical Toxicology in the drug label.
# Clinical Studies
### Study in Adult Patients with Anaplastic Lymphoma Kinase
Study B7461001
- This study was a multinational, multi-cohort trial that welcomed finding the correct dose sizes and the amount of activity of this medication
- It included 295 patients with “ALK-positive or ROS1-positive metastatic” NSCLC or non-small cell lung cancer
- The patients were given 100 mg of Lorlatinib orally everyday and were monitored for 12.5 months. More than 52% of the patients were exposed to medication for more than 12 months
- The demographics of the patients: 19-85 year old patients- wide range- with the median age being 53 years. 58% of the patients were female. The races were: 49% Caucasian, 37% Asian.
- There were many adverse reactions that were reported in more than 20% of the patients were “edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea”
- There were soem abnormalities that occurred in the lab including “ hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase”
### Study in Pediatric Patients with Anaplastic Lymphoma Kinase
- There is limited information regarding Lorlatinib Studies in Pediatric Patients
# How Supplied
- It is supplied in a child-resistant vial that contains 25 or 100 mg worth of tablets. There will be 30 tablets in the bottle. Some of the inactive ingredients in the tablet include microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
The 25 mg bottles will contain tablets that appear as 8mm round, tan-colored, film-coated, and has 25 on one side and LLN on the other side
The 100 mg bottles will contain tablets that appear as 8.5 by 17 mm round, lavender-colored, film-coated, contains Pfizer on on side, and 100 and LLn on the other
- The 25 mg bottles will contain tablets that appear as 8mm round, tan-colored, film-coated, and has 25 on one side and LLN on the other side
- The 100 mg bottles will contain tablets that appear as 8.5 by 17 mm round, lavender-colored, film-coated, contains Pfizer on on side, and 100 and LLn on the other
## Storage
- Lorbrena is stored in a temperature of 20-25 degrees Celsius (68-77 degrees Fahrenheit)
- It is allowed to be exposed to temperatures from 15-30 degrees Celsius for some time
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be aware that utilizing Lobrena concurrent to CYP3A inducers can lead to serious cases of hepatotoxicity
- Patients should check with a doctor to confirm the compatibility of certain medications with Lobrena
### Serious Central Nervous System Effects
- Seizures, Hallucinations, changes in mood, sleep, mental health are all examples of the side effects
- Reduce the dosage of Lorlatinib depending on the severity of the side effect
- For patients requiring first time reduction, give them 75 mg daily through mouth
- For patients requiring second time reduction, give them 50 mg daily through mouth
- About 54% of patients acquiring this drug may experience Central Nervous system side effects listed above
- Patients will be monitored for the first 1-2 months ingesting Lorbrena, and followed up on after the initial period
- Patients may experience an increase in serum cholesterol and triglycerides
- About 7% of patients in the Study B7461001 required to discontinue the drug for a short period of time, and another 3% of the patients required a dose reduction
- In the same study, 80% of the patients required to instigate lipid-lowering medications because they were not responding to reduction and temporary pause
This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
- This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
### Discontinuation
- Patients ingesting Lobrena having serious adverse reactions had to discontinue the drug
- About 1.5% of patients experiencing Central Nervous system adverse effects had to completely discontinue this medication
- Overall, about 8% of patients had to discontinue the drug due to serious side effects like pneumonia, dyspnea, pyrexia, respiratory failure, myocardial infarction, acute pulmonary edema, embolism, peripheral artery occlusion, mental status change to name a few
Some of these reactions led to permanent discontinuation including respiratory failure and dyspnea included at the top
- Some of these reactions led to permanent discontinuation including respiratory failure and dyspnea included at the top
### Infusion reactions
- There is limited information on Lobrena infusion reactions
# Precautions with Alcohol
Alcohol-Lorlatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Lorbrena
# Look-Alike Drug Names
There is limited information regarding Lorlatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Lorlatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Uma Maveli[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
Lorlatinib is a Antineoplastic Agents that is FDA approved for the treatment of The treatment of patients with lung cancer
- Should not be given to patients who are pregnant or are trying to get pregnant
- This medication is only to be used after confirming the cancer has a ALK gene marker
- The doctor will test for that gene. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Edema, Peripheral Neuropathy, Cognitive Effects, Dyspnea (shortness of breath), fatigue, weight gain, arthralgia, mood effects, diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Lorlatinib is indicated for:
- The treatment of patients with anaplastic lymphoma kinase- aggressive, wide-spread lung cancer
- It is indicated for with:
Crizonitib and another ALK inhibitor, or Alectinib, the first therapy for metastatic disease, or Ceritinib as the first ALK inhibitor for this type of disease
- Crizonitib and another ALK inhibitor, or Alectinib, the first therapy for metastatic disease, or Ceritinib as the first ALK inhibitor for this type of disease
### Limitations of Use
- See adverse reactions
- See specific populations
### Dosing Considerations
- Some dose reductions if the patients have adverse reactions include:
Swallow Lorlatinib orally in a recommended dosage of 75 mg once daily
If there is need for more reduction, take Lorlatinib 50 mg once daily orally
- Swallow Lorlatinib orally in a recommended dosage of 75 mg once daily
- If there is need for more reduction, take Lorlatinib 50 mg once daily orally
### Administration of Lorlatinib
- It is recommended that the patient take 100 mg of Lorlatinib, no matter if they have or have not eaten
- The tablets are meant to be swallowed whole: it is unacceptable to chew, break, split tablets because it will not have the same effect and it could be dangerous
Make sure to not to take them if they are broken, cracked, not in packaging etc
- Make sure to not to take them if they are broken, cracked, not in packaging etc
- It is important that the patient takes the medication the same time each day
The patient may take the forgotten dose if it is more that 4 hours from their next dose
It is really important that they do not take multiple doses at once
- The patient may take the forgotten dose if it is more that 4 hours from their next dose
- It is really important that they do not take multiple doses at once
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Lorlatinib 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 Lorlatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- It is crucial to withhold ingesting Lorlatinib for three plasma half lives for patients taking strong CYP3A inducers
- Mixing them together could lead to serious hepatotoxicity or chemical-driven liver damage
# Warnings
### Serious Central Nervous System Effects
- Seizures, Hallucinations, changes in mood, sleep, mental health are all examples of the side effects
- Reduce the dosage of Lorlatinib depending on the severity of the side effect
- For patients requiring first time reduction, give them 75 mg daily through mouth
- For patients requiring second time reduction, give them 50 mg daily through mouth
- About 54% of patients acquiring this drug may experience Central Nervous system side effects listed above
- Patients will be monitored for the first 1-2 months ingesting Lorbrena, and followed up on after the initial period
- Patients may experience an increase in serum cholesterol and triglycerides
- About 7% of patients in the Study B7461001 required to discontinue the drug for a short period of time, and another 3% of the patients required a dose reduction
- In the same study, 80% of the patients required to instigate lipid-lowering medications because they were not responding to reduction and temporary pause
This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
- This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
# Adverse Reactions
## Clinical Trials Experience
Severe Adverse Reactions (32% of 295 Patients)
- Some serious reactions reported in the study were: pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%)
- There were some fatal adverse reactions that occurred in about 2.7% of the patients. Those reactions include pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%)
## Postmarketing Experience
There is limited information regarding Lobrena Postmarketing Experience in the drug label.
# Drug Interactions
- Effects of CYP3A Inducers: Combining CYP3A inducers with Lobrena can decrease plasma concentrations that may dull the effects of the medication.
- It is important to discontinue CYP3A inducers for “3 plasma half-lives” before initiating the use of Lorlatinib. Interaction between CYP3A inducers and Lobrena can heighten the severity of the present adverse reactions
- In a study, Lobrena mixed with the CYP3A inducer rifampin shows results of severe hepatoxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
This drug can result in major birth defects or fetal harm during animal studies. It is not clear if it can cause fetal harm in human pregnancies. It is important to note that it should be prohibited to have pregnant women or women who want to carry out a pregnancy take Lobrena. In animal studies, fetal harm includes gastroschisis, rotated limbs, supernumerary digits, vessel abnormalities etc. It should be noted that the effects of this medication for pregnant human women is not listed in the FDA label.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lorlatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lorlatinib during labor and delivery.
### Nursing Mothers
There is not data from studies that indicate the presence of active metabolites or Lorlatinib in breast-fed milk. Patients should consult their medical professional on how to proceed.
### Pediatric Use
Lorlatinib has not been tested on pediatric patients, so the saftey and well-being of children administered Lorlatinib is unknown.
### Geriatic Use
Based on the limited trial data present, patients over the age of 65 do not require a different dose of Lorlatinib.
### Gender
There is no FDA guidance on the use of Lorlatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lorlatinib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lorlatinib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lorlatinib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Advise males who have female reproductive partners to wear contraception for the duration of ingesting this medication and for 3 months after the final dose. Additionally, there has been data that indicates lower testicular, epididymal, and prostate weights. There is a possibility for male fertility impairment after using Lobrena.
### Immunocompromised Patients
There is no FDA guidance one the use of Lorlatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- It is recommended that the patient take 100 mg of Lorlatinib, no matter if they have or have not eaten
- The tablets are meant to be swallowed whole: it is unacceptable to chew, break, split tablets because it will not have the same effect and it could be dangerous
Make sure to not to take them if they are broken, cracked, not in packaging etc
- Make sure to not to take them if they are broken, cracked, not in packaging etc
- It is important that the patient takes the medication the same time each day
The patient may take the forgotten dose if it is more that 4 hours from their next dose
It is really important that they do not take multiple doses at once
- The patient may take the forgotten dose if it is more that 4 hours from their next dose
- It is really important that they do not take multiple doses at once
### Monitoring
There is limited information regarding Lorlatinib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Lorlatinib and IV administrations.
# Overdosage
- If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Lorlatinib is a kinase inhibitor that reverses the activity of Anaplastic lymphoma kinase and other tyrosine kinase inhibitors including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. It also reversed the activity of several mutants of the ALK enzyme. Lolrlatinib is capable of crossing the blood-brain barrier which enebles it to treat spreading metasteses in the brain. The effectiveness of Lorlatinib activity has shown to be dose-dependent and associated with the inhibition of ALK phosphorylation. Patients using Lorlatinib have shown a new control to stop tumor regression despite having used tyrosine kinase inhibitors like crizontinib, alectinib, and/or ceritinib.
## Structure
There is limited information regarding Lorlatinib Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Lorlatinib Pharmacodynamics in the drug label.
## Pharmacokinetics
The Lorlatinib plasma concentration increased proportionally over the dose range of 10 mg or Lobrena to 200 mg. The mean Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ng·h/mL (39%) in patients with small cell lung cancer.
- This data is for intravenous dosage of Lobrena
Lorlatinib distributed and bound to 66% of plasma proteins, around a concentration of 2.4 micro M
- Lorlatinib distributed and bound to 66% of plasma proteins, around a concentration of 2.4 micro M
- The CV% was 305 L or 28% following a single dose intravenously
- The resulting blood to plasma ratio was 0.99
- Studies showed that the half-life of Lorlatinib plasma was 24 hours after one oral dose
- The oral clearance that resulted was 11 L/h and it eventually increased to 18 L/h which could mean auto-induction, or certain enzymes increased to help faster metabolize the agent
- Pregnancy= This drug can result in major birth defects or fetal harm during animal studies. It is not clear if it can cause fetal harm in human pregnancies. It is important to note that it should be prohibited to have pregnant women or women who want to carry out a pregnancy take Lobrena. In animal studies, fetal harm includes gastroschisis, rotated limbs, supernumerary digits, vessel abnormalities etc. It should be noted that the effects of this medication for pregnant human women is not listed in the FDA label.
- Lactation= Lobrena or any of its metabolites will not contaminate human milk, and it will not effect the production of breastfeeding milk. However, there could be serious adverse reactions for the infants receiving the breastfed milk. Therefore, women should be instructed to abstain from breastfeeding until 7 days after their final dose of Lobrena.
- Geriatric Use= Through the study B7461001, there has been no discrepancies of the effects between patients 65 and older (18 % of the test patients) and patients younger than that
- Pediatric Use: The efficiency and safety of this medication has not been established in pediatric patients.
## Nonclinical Toxicology
There is limited information regarding Lorlatinib Nonclinical Toxicology in the drug label.
# Clinical Studies
### Study in Adult Patients with Anaplastic Lymphoma Kinase [ALXN1210-aHUS-311; NCT02949128]
Study B7461001
- This study was a multinational, multi-cohort trial that welcomed finding the correct dose sizes and the amount of activity of this medication
- It included 295 patients with “ALK-positive or ROS1-positive metastatic” NSCLC or non-small cell lung cancer
- The patients were given 100 mg of Lorlatinib orally everyday and were monitored for 12.5 months. More than 52% of the patients were exposed to medication for more than 12 months
- The demographics of the patients: 19-85 year old patients- wide range- with the median age being 53 years. 58% of the patients were female. The races were: 49% Caucasian, 37% Asian.
- There were many adverse reactions that were reported in more than 20% of the patients were “edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea”
- There were soem abnormalities that occurred in the lab including “ hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase”
### Study in Pediatric Patients with Anaplastic Lymphoma Kinase[ALXN1210-aHUS-312; NCT03131219]
- There is limited information regarding Lorlatinib Studies in Pediatric Patients
# How Supplied
- It is supplied in a child-resistant vial that contains 25 or 100 mg worth of tablets. There will be 30 tablets in the bottle. Some of the inactive ingredients in the tablet include microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
The 25 mg bottles will contain tablets that appear as 8mm round, tan-colored, film-coated, and has 25 on one side and LLN on the other side
The 100 mg bottles will contain tablets that appear as 8.5 by 17 mm round, lavender-colored, film-coated, contains Pfizer on on side, and 100 and LLn on the other
- The 25 mg bottles will contain tablets that appear as 8mm round, tan-colored, film-coated, and has 25 on one side and LLN on the other side
- The 100 mg bottles will contain tablets that appear as 8.5 by 17 mm round, lavender-colored, film-coated, contains Pfizer on on side, and 100 and LLn on the other
## Storage
- Lorbrena is stored in a temperature of 20-25 degrees Celsius (68-77 degrees Fahrenheit)
- It is allowed to be exposed to temperatures from 15-30 degrees Celsius for some time
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be aware that utilizing Lobrena concurrent to CYP3A inducers can lead to serious cases of hepatotoxicity
- Patients should check with a doctor to confirm the compatibility of certain medications with Lobrena
### Serious Central Nervous System Effects
- Seizures, Hallucinations, changes in mood, sleep, mental health are all examples of the side effects
- Reduce the dosage of Lorlatinib depending on the severity of the side effect
- For patients requiring first time reduction, give them 75 mg daily through mouth
- For patients requiring second time reduction, give them 50 mg daily through mouth
- About 54% of patients acquiring this drug may experience Central Nervous system side effects listed above
- Patients will be monitored for the first 1-2 months ingesting Lorbrena, and followed up on after the initial period
- Patients may experience an increase in serum cholesterol and triglycerides
- About 7% of patients in the Study B7461001 required to discontinue the drug for a short period of time, and another 3% of the patients required a dose reduction
- In the same study, 80% of the patients required to instigate lipid-lowering medications because they were not responding to reduction and temporary pause
This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
- This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
### Discontinuation
- Patients ingesting Lobrena having serious adverse reactions had to discontinue the drug
- About 1.5% of patients experiencing Central Nervous system adverse effects had to completely discontinue this medication
- Overall, about 8% of patients had to discontinue the drug due to serious side effects like pneumonia, dyspnea, pyrexia, respiratory failure, myocardial infarction, acute pulmonary edema, embolism, peripheral artery occlusion, mental status change to name a few
Some of these reactions led to permanent discontinuation including respiratory failure and dyspnea included at the top
- Some of these reactions led to permanent discontinuation including respiratory failure and dyspnea included at the top
### Infusion reactions
- There is limited information on Lobrena infusion reactions
# Precautions with Alcohol
Alcohol-Lorlatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Lorbrena
# Look-Alike Drug Names
There is limited information regarding Lorlatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Lorlatinib | |
bf03ebf3ef948f9c7171202f928a26773fa05e76 | wikidoc | Lornoxicam | Lornoxicam
# Overview
Lornoxicam (INN, or chlortenoxicam; trade name Xefo, among others) is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic (pain relieving), anti-inflammatory and antipyretic (fever reducing) properties. It is available in oral and parenteral formulations.
# Indications
Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other inflammations.
# Contraindications
The drug is contraindicated in patients that must not take other NSAIDs, possible reasons including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and severe impairment of heart, liver or kidney function. Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy.
# Adverse effects
Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like gastrointestinal disorders (nausea and diarrhea) and headache. Severe but seldom side effects include bleeding, bronchospasms and the extremely rare Stevens–Johnson syndrome.
# Interactions
Interactions with other drugs are typical of NSAIDs. Combination with vitamin K antagonists like warfarin increases the risk of bleeding. Combination with ciclosporin can lead to reduced kidney function, and to acute renal failure in rare cases. Lornoxicam can also increase the adverse effects of lithium, methotrexate and digoxin and its derivatives. The effect of diuretics, ACE inhibitors and angiotensin II receptor antagonists can be reduced, but this is only relevant in patients with special risks like heart failure. As with piroxicam, cimetidine can increase plasma levels but is unlikely to cause relevant interactions. | Lornoxicam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lornoxicam (INN, or chlortenoxicam; trade name Xefo, among others) is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic (pain relieving), anti-inflammatory and antipyretic (fever reducing) properties. It is available in oral and parenteral formulations.
# Indications
Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other inflammations.[1]
# Contraindications
The drug is contraindicated in patients that must not take other NSAIDs, possible reasons including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and severe impairment of heart, liver or kidney function. Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy.[1]
# Adverse effects
Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like gastrointestinal disorders (nausea and diarrhea) and headache. Severe but seldom side effects include bleeding, bronchospasms and the extremely rare Stevens–Johnson syndrome.[1]
# Interactions
Interactions with other drugs are typical of NSAIDs. Combination with vitamin K antagonists like warfarin increases the risk of bleeding. Combination with ciclosporin can lead to reduced kidney function, and to acute renal failure in rare cases. Lornoxicam can also increase the adverse effects of lithium, methotrexate and digoxin and its derivatives. The effect of diuretics, ACE inhibitors and angiotensin II receptor antagonists can be reduced, but this is only relevant in patients with special risks like heart failure. As with piroxicam, cimetidine can increase plasma levels but is unlikely to cause relevant interactions.[2] | https://www.wikidoc.org/index.php/Lornoxicam | |
f22720712dfbe66e927008a4362335bd8e4cce16 | wikidoc | Magaldrate | Magaldrate
# Overview
Magaldrate (INN) is a common antacid drug that is used for the treatment of duodenal and gastric ulcers, esophagitis from gastroesophageal reflux.
# Available forms
Magaldrate is available in the form of oral suspension or tablets.
# Pharmacology
Magaldrate is a hydroxymagnesium aluminate complex that is converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3, which are absorbed poorly and thus provide a sustained antacid effect.
# Interactions and adverse reactions
Magaldrate may negatively influence drugs like tetracyclines, benzodiazepines, and indomethacin. High doses or prolonged usage may lead to an increment of defecation and a reduction in feces consistence. In some cases it can alter the functionality of the gastrointestinal tract, occasionally provoking constipation or diarrhea.
# Brand names
The drug is sold with the following brand names: Digecid Plus (Beximco Pharma, Bangladesh), Marlox Plus (Incepta pharma Bangladesh), Gastid (SK+F, Bangladesh), Novelta (Bangladesh), Gadral (Italy); Magaltop (Italy); Magralibi (Italy); Mylanta (Australia); Riopan (Argentina, Austria, Brazil, Egypt, Germany, Italy, Mexico, Belgium, Switzerland, Greece). | Magaldrate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Magaldrate (INN) is a common antacid drug that is used for the treatment of duodenal and gastric ulcers, esophagitis from gastroesophageal reflux.
# Available forms
Magaldrate is available in the form of oral suspension or tablets.
# Pharmacology
Magaldrate is a hydroxymagnesium aluminate complex that is converted rapidly in gastric acid to Mg(OH)2 and Al(OH)3, which are absorbed poorly and thus provide a sustained antacid effect.[1]
# Interactions and adverse reactions
Magaldrate may negatively influence drugs like tetracyclines, benzodiazepines, and indomethacin. High doses or prolonged usage may lead to an increment of defecation and a reduction in feces consistence. In some cases it can alter the functionality of the gastrointestinal tract, occasionally provoking constipation or diarrhea.
# Brand names
The drug is sold with the following brand names: Digecid Plus (Beximco Pharma, Bangladesh), Marlox Plus (Incepta pharma Bangladesh), Gastid (SK+F, Bangladesh), Novelta (Bangladesh), Gadral (Italy); Magaltop (Italy); Magralibi (Italy); Mylanta (Australia); Riopan (Argentina, Austria, Brazil, Egypt, Germany, Italy, Mexico, Belgium, Switzerland, Greece). | https://www.wikidoc.org/index.php/Losospan | |
0d9b4f709bddf527b3125730a387dd40ad2417aa | wikidoc | Loxoprofen | Loxoprofen
Loxoprofen (INN) is a non-steroidal anti-inflammatory drug in the propionic acid derivatives group, which also includes ibuprofen and naproxen among others. It is marketed in Brazil, Mexico and Japan by Sankyo as its sodium salt, loxoprofen sodium, under the trade name Loxonin, and in Argentina as Oxeno. It is available in these countries for oral administration, and a transdermal preparation was approved for sale in Japan on January 2006.
# Pharmacokinetics
Loxoprofen is a prodrug. It is quickly converted to its active trans-alcohol metabolite following oral administration, and reaches its peak plasma concentration within 30 to 50 minutes.
# Mechanism of action
As most NSAIDs, loxoprofen is a non-selective cyclooxygenase inhibitor, and works by reducing the synthesis of prostaglandins from arachidonic acid.
# Interactions
Loxoprofen should not be administered concomitantly with second-generation quinolone antibiotics such as ciprofloxacin and norfloxacin, as it increases their inhibition of GABA and this may cause seizures.
It may also increase the plasma concentration of warfarin, methotrexate, sulfonylurea derivatives and lithium salts, so care should be taken when loxoprofen is administered to patients taking any of these drugs. | Loxoprofen
Loxoprofen (INN) is a non-steroidal anti-inflammatory drug in the propionic acid derivatives group, which also includes ibuprofen and naproxen among others. It is marketed in Brazil, Mexico and Japan by Sankyo as its sodium salt, loxoprofen sodium, under the trade name Loxonin, and in Argentina as Oxeno. It is available in these countries for oral administration, and a transdermal preparation was approved for sale in Japan on January 2006.[1]
# Pharmacokinetics
Loxoprofen is a prodrug. It is quickly converted to its active trans-alcohol metabolite following oral administration, and reaches its peak plasma concentration within 30 to 50 minutes.
# Mechanism of action
As most NSAIDs, loxoprofen is a non-selective cyclooxygenase inhibitor, and works by reducing the synthesis of prostaglandins from arachidonic acid.
# Interactions
Loxoprofen should not be administered concomitantly with second-generation quinolone antibiotics such as ciprofloxacin and norfloxacin, as it increases their inhibition of GABA and this may cause seizures.[2]
It may also increase the plasma concentration of warfarin, methotrexate, sulfonylurea derivatives and lithium salts, so care should be taken when loxoprofen is administered to patients taking any of these drugs.[2] | https://www.wikidoc.org/index.php/Loxoprofen | |
c9e895724330395384a0107646a780733063486a | wikidoc | Lujo virus | Lujo virus
# Overview
Lujo is a bisegmented RNA virus — a member of the family Arenaviridae — and a known cause of viral hemorrhagic fever (VHF) in humans. Its name was suggested by the Special Pathogens Unit of the National Institute for Communicable Diseases of the National Health Laboratory Service (NICD-NHLS) by using the first two letters of the names of the cities involved in the 2008 outbreak of the disease, Lusaka (Zambia) and Johannesburg (Republic of South Africa). It is the second pathogenic arenavirus to be described from the African continent — the first being Lassa virus — and since 2012 has been classed as a "Select Agent" under U.S. law.
# History
The discovery of this novel virus was described following a highly fatal nosocomial (hospital) outbreak of VHF in Johannesburg.
The first case was a female travel agent who lived in the outskirts of Lusaka. She suffered from fever which grew worse with time. She was evacuated to Johannesburg for medical treatment. Almost two weeks later, the paramedic that nursed the patient on the flight to South Africa, also fell ill and was also brought to Johannesburg for medical treatment. At this time the connection between these two patients was recognized by the attending physician in the Johannesburg hospital. Together with the NICD-NHLS the clinical syndrome of VHF was recognized and specimens from the second patient were submitted for laboratory confirmation. In addition, a cleaner and a nurse that had contact with the first patient also fell ill. A second nurse was infected through contact with the paramedic. The outbreak had a high case fatality rate with 4 of 5 identified cases resulting in death.
The Special Pathogens Unit of the NICD-NHLS together with colleagues from the Special Pathogens Unit of the U.S. Centers for Disease Control and Prevention (CDC) identified the etiological agent of the outbreak as an Old World arenavirus using molecular and serological tests. Sequencing and phylogenetic investigation of partial genome sequencing indicated that this virus was not Lassavirus and likely a previously unreported arenavirus. This was corroborated by full genome sequencing that was conducted by the NICD-NHLS, CDC and collaborators from Columbia University in New York.
# Distribution
The distribution of this newly described arenavirus is uncertain. To date this virus has only been reported from a patient from Zambia and a subsequent nosocomial outbreak in South Africa.
# Phylogenetics
Sequencing of the viral genome has shown that this virus belongs to the Old World arenavirus group. Comparisons with other viral genome sequences showed that this virus is equidistant from other Old World and New World arenaviruses. It is distantly similar to the other pathogenic African arenavirus, Lassa fever virus.
# Clinical
This virus has been associated with an outbreak of five cases of VHF in September and October 2008. In four cases (80% of total known infections) the infection was fatal. The fifth case was treated with ribavirin early after onset of clinical disease (was detected through active contact tracing), an antiviral drug which is effective in treating Lassa fever, and survived; however, ribavirin's effectiveness against Lujo virus remains unknown. | Lujo virus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lujo is a bisegmented RNA virus — a member of the family Arenaviridae — and a known cause of viral hemorrhagic fever (VHF) in humans. Its name was suggested by the Special Pathogens Unit of the National Institute for Communicable Diseases of the National Health Laboratory Service (NICD-NHLS) by using the first two letters of the names of the cities involved in the 2008 outbreak of the disease, Lusaka (Zambia) and Johannesburg (Republic of South Africa). It is the second pathogenic arenavirus to be described from the African continent — the first being Lassa virus — and since 2012 has been classed as a "Select Agent" under U.S. law.
# History
The discovery of this novel virus was described following a highly fatal nosocomial (hospital) outbreak of VHF in Johannesburg.[1]
The first case was a female travel agent who lived in the outskirts of Lusaka. She suffered from fever which grew worse with time. She was evacuated to Johannesburg for medical treatment. Almost two weeks later, the paramedic that nursed the patient on the flight to South Africa, also fell ill and was also brought to Johannesburg for medical treatment. At this time the connection between these two patients was recognized by the attending physician in the Johannesburg hospital. Together with the NICD-NHLS the clinical syndrome of VHF was recognized and specimens from the second patient were submitted for laboratory confirmation.[2] In addition, a cleaner and a nurse that had contact with the first patient also fell ill. A second nurse was infected through contact with the paramedic. The outbreak had a high case fatality rate with 4 of 5 identified cases resulting in death.
The Special Pathogens Unit of the NICD-NHLS together with colleagues from the Special Pathogens Unit of the U.S. Centers for Disease Control and Prevention (CDC) identified the etiological agent of the outbreak as an Old World arenavirus using molecular and serological tests.[1] Sequencing and phylogenetic investigation of partial genome sequencing indicated that this virus was not Lassavirus and likely a previously unreported arenavirus. This was corroborated by full genome sequencing that was conducted by the NICD-NHLS, CDC and collaborators from Columbia University in New York.[3]
# Distribution
The distribution of this newly described arenavirus is uncertain. To date this virus has only been reported from a patient from Zambia and a subsequent nosocomial outbreak in South Africa.
# Phylogenetics
Sequencing of the viral genome has shown that this virus belongs to the Old World arenavirus group. Comparisons with other viral genome sequences showed that this virus is equidistant from other Old World and New World arenaviruses. It is distantly similar to the other pathogenic African arenavirus, Lassa fever virus.[3]
# Clinical
This virus has been associated with an outbreak of five cases of VHF in September and October 2008.[1] In four cases (80% of total known infections) the infection was fatal. The fifth case was treated with ribavirin early after onset of clinical disease (was detected through active contact tracing), an antiviral drug which is effective in treating Lassa fever, and survived; however, ribavirin's effectiveness against Lujo virus remains unknown. | https://www.wikidoc.org/index.php/Lujo | |
c085a1aeef13e304b8178ad18485e451a1d24a42 | wikidoc | Lurasidone | Lurasidone
- LATUDA is not approved for use in patients with dementia-related psychosis.
- Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
- In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
- LATUDA is indicated for the treatment of patients with schizophrenia.
- The efficacy of LATUDA in schizophrenia was established in five 6-week controlled studies of adult patients with schizophrenia.
- The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
# Depressive Episodes Associated with Bipolar I Disorder
- Monotherapy: LATUDA is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA was established in a 6-week monotherapy study in adult patients with bipolar depression.
- Adjunctive Therapy with Lithium or Valproate: LATUDA is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA as adjunctive therapy was established in a 6-week study in adult patients with bipolar depression who were treated with lithium or valproate.
- The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- The efficacy of LATUDA in the treatment of mania associated withbipolar disorder has not been established.
# Dosing Information
- The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg per day . The maximum recommended dose is 160 mg per day.
- The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day)
- Concomitant Use with CYP3A4 Inhibitors
- LATUDA should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.)
- If LATUDA is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the LATUDA dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and LATUDA is added to the therapy, the recommended starting dose of LATUDA is 20 mg per day, and the maximum recommended dose of LATUDA is 80 mg per day.
- Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations.
- Concomitant Use with CYP3A4 Inducers
- LATUDA should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) . If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (7 days or more) with the CYP3A4 inducer.
# DOSAGE FORMS AND STRENGTHS
- LATUDA tablets are available in the following shape and color (Table 1) with respective one-sided debossing:
- Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.).
- StrongCYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.).
# Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. LATUDA is not approved for the treatment of patients with dementia-related psychosis .
# Suicidal Thoughts and Behaviors in Adolescents and Young Adults
- Patients withmajor depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
- Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidal thoughts and behaviors, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for LATUDA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
# Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis.
# Neuroleptic Malignant Syndrome
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA.
- Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure,tachycardia, diaphoresis, andcardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
- The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.
# Tardive Dyskinesia
- Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to causetardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome.
# Metabolic Changes
- Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria' polyphagia, and weakness. Patients who develop symptoms ofhyperglycemiaduring treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
- Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3
- In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307).
- Monotherapy
- Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).
- Adjunctive Therapy with Lithium or Valproate
- Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).
- Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
- Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6.
- In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively.
- Monotherapy
Data from the short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively.
- Adjunctive Therapy with Lithium or Valproate
- Data from the short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.
- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
- Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9. The mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 , respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for LATUDA-treated patients versus 3.3% for placebo-treated patients.
- In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377).
- Monotherapy
- Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean weight gain was +0.29 kg for LATUDA-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).
- Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean weight gain was +0.11 kg for LATUDA-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).
# Hyperprolactinemia
- As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels.
- Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea,amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients.
- Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a LATUDA carcinogenicity study conducted in rats and mice . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
- In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 12.
- The proportion of patients with prolactin elevations ≥ 5× upper limit of normal (ULN) was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 1.6% versus 0.6% for placebo-treated male patients.
- In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).
- Monotherapy
- The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 13.
- The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).
- Adjunctive Therapy with Lithium or Valproate
- The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 14
- The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).
# Leukopenia, Neutropenia and Agranulocytosis
- Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue LATUDA and have their WBC followed until recovery.
# Orthostatic Hypotension and Syncope
- LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.
- Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥ 10 bpm increase in pulse from sitting to standing or supine to standing position.
- The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic hypotension and syncope .
- In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo.
- Monotherapy
- In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.
- Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 120 mg compared to 0.9% with placebo
# Seizures
- As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
- In short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients.
- Monotherapy
- In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, no patient experienced seizures/convulsions.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.
# Potential for Cognitive and Motor Impairment
- LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely.
- In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.
- In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg, 15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to 7.1% (50/708) of placebo patients.
- Monotherapy
- In the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and 80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients.
# Body Temperature Dysregulation
- Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
# Suicide
- The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
- In short-term, placebo-controlled schizophrenia studies, the incidence of treatment-emergent suicidal ideation was 0.4% (6/1508) for LATUDA-treated patients compared to 0.8% (6/708) on placebo. No suicide attempts or completed suicides were reported in these studies.
- Monotherapy
- In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the incidence of treatment-emergent suicidal ideation was 0.0% (0/331) with LATUDA-treated patients compared to 0.0% (0/168) with placebo-treated patients. No suicide attempts or completed suicides were reported in this study.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, the incidence of treatment-emergent suicidal ideation was 1.1% (4/360) for LATUDA-treated patients compared to 0.3% (1/334) on placebo. No suicide attempts or completed suicides were reported in these studies.
# Activation of Mania/Hypomania
- Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.
- In the bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes.
# Dysphagia
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
# Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies
- Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
- The information below is derived from an integrated clinical study database for LATUDA consisting of 3799 patients exposed to one or more doses of LATUDA for the treatment of schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure.
- Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
# Schizophrenia
- The following findings are based on the short-term, placebo-controlled premarketing studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508).
- Commonly Observed Adverse Reactions:
- The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea.
- Adverse Reactions Associated with Discontinuation of Treatment:
- A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
- Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: :*Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 15.
- Dose-Related Adverse Reactions in the Schizophrenia Studies
- Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg).
# Bipolar Depression (Monotherapy)
- The following findings are based on the short-term, placebo-controlled premarketing study for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n=331).
- Commonly Observed Adverse Reactions:
- The most common adverse reactions (incidence ≥ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with LATUDA were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.
- Adverse Reactions Associated with Discontinuation of Treatment:
- A total of 6.0% (20/331) LATUDA-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
- Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: :*Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 16.
Table 16: Adverse Reactions in 2% or More of LATU
- Dose-Related Adverse Reactions in the Monotherapy Study:
- In the short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively.
# Bipolar Depression
- The following findings are based on two short-term, placebo-controlled premarketing studies for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360).
- Commonly Observed Adverse Reactions:
- The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in subjects treated with LATUDA were akathisia and somnolence.
- Adverse Reactions Associated with Discontinuation of Treatment:
- A total of 5.8% (21/360) LATUDA-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
- Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: :*Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 17.
- Extrapyramidal Symptoms
- Schizophrenia
In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 18.
- Bipolar Depression
- Monotherapy
In the short-term, placebo-controlled monotherapy bipolar depression study, for LATUDA-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 19
- Adjunctive Therapy with Lithium or Valproate
In the short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDA-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. The incidence of akathisia for LATUDA-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 20.
In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.
- Schizophrenia
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 14.4%; placebo, 7.1%), the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%).
- Bipolar Depression
- Monotherapy
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.4%; placebo, 5.6%), the SAS (LATUDA, 3.7%; placebo, 1.9%) and the AIMS (LATUDA, 3.4%; placebo, 1.2%).
- Adjunctive Therapy with Lithium or Valproate
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.7%; placebo, 2.1%), the SAS (LATUDA, 2.8%; placebo, 2.1%) and the AIMS (LATUDA, 2.8%; placebo, 0.6%).
- Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Schizophrenia
In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day.
- Bipolar Depression
Monotherapy
In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.
- Adjunctive Therapy with Lithium or Valproate
In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of LATUDA-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.
- Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).
- Frequent: tachycardia;
- Infrequent: AV block 1st degree, angina pectoris, bradycardia.
- Frequent: abdominal pain, diarrhea;
- Infrequent: gastritis.
- Infrequent: anemia
- Frequent: decreased appetite
- Rare: rhabdomyolysis
- Infrequent: cerebrovascular accident, dysarthria
- Infrequent: abnormal dreams, panic attack, sleep disorder
- Frequent: rash, pruritus;
- Rare: angioedema
- Infrequent: vertigo
- Frequent: blurred vision
- Infrequent: dysuria;
- Rare: renal failure
- Infrequent: amenorrhea, dysmenorrhea;
- Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction
- Frequent: hypertension
- Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 21).
- Monotherapy
- Serum Creatinine: In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for LATUDA-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of LATUDA-treated patients and 0.6% (1/162) on placebo (Table 22)
- Adjunctive Therapy with Lithium or Valproate
- Serum Creatinine: In short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for LATUDA-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of LATUDA-treated patients and 1.6% (5/334) on placebo (Table 23).
- LATUDA is predominantly metabolized by CYP3A4. LATUDA should not be used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) or strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) . The LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 (e.g., diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc.). If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose.
- It is not necessary to adjust the LATUDA dose when used concomitantly with lithium.
- It is not necessary to adjust the LATUDA dose when used concomitantly with valproate. A dedicated drug-drug interaction study has not been conducted with valproate and LATUDA. Based on pharmacokinetic data from the bipolar depression studies valproate levels were not affected by lurasidone, and lurasidone concentrations were not affected by valproate.
- Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations.
# Potential for LATUDA to Affect Other Drugs
- No dose adjustment is needed for lithium, substrates of P-gp, CYP3A4 (Figure 2) or valproate when coadministered with LATUDA. ).
- There are no adequate and well controlled studies of LATUDA use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- LATUDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Safe use of LATUDA during pregnancy or lactation has not been established; therefore, use of LATUDA in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.
- No adverse developmental effects were observed in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day, which is approximately half of the maximum recommended human dose (MRHD) of 160 mg/day, based on mg/m2 body surface area.
- No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 1.5- and 6-times, in rats and rabbits, respectively, the MRHD of 160 mg/day based on mg/m2 body surface area.
- Elderly patients with dementia-related psychosis treated with LATUDA are at an increased risk of death compared to placebo. LATUDA is not approved for the treatment of patients with dementia-related psychosis
- LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, LATUDA was administered with food
- Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring.
- Clinical monitoring of weight is recommended.
- In management of overdosage Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias.
- In premarketing clinical studies, accidental or intentional overdosage of LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months.
- Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to LATUDA, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consider the possibility of multiple-drug overdose.
- Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of LATUDA. Similarly, the alpha-blocking properties of bretylium might be additive to those of LATUDA, resulting in problematic hypotension.
- Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of LATUDA-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
- The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
- Its chemical name is (3aR,4S,7R,7aS)-2-(1R,2R)-2-4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl cyclohexylmethylhexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N4O2S·HCl and its molecular weight is 529.14.
- The chemical structure is:
- Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.
- LATUDA tablets are intended for oral administration only. Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.
- Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake.
- The effects of LATUDA on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.
- In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo.
- Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 (7) hours.
- LATUDA is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. LATUDA is highly bound (~99%) to serum proteins.
- In a food effect study, LATUDA mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. LATUDA exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content .
- In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food.
- LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. LATUDA is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA.
- Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of -labeled LATUDA.
- Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.
- LATUDA increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14-times those in humans receiving the MRHD.
- LATUDA increased the incidence of mammary gland carcinomas in females rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4-times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-times those in humans receiving the MRHD.
- Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents to humans is unknown .
- LATUDA did not cause mutation or chromosomal aberration when tested in vitro and in vivo. LATUDA was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg (61 times the MRHD of 160 mg/day based on mg/m2 body surface area).
- Estrus cycle irregularities were seen in rats orally administered LATUDA at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. The no-effect dose is 0.1 mg/kg which is approximately 0.006-times the MRHD of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose, which was reversible after a 14-day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is approximately equal to the MRHD based on body surface area.
- LATUDA had no effect on fertility in male rats treated orally with LATUDA for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (9-times the MRHD based on mg/m2 body surface area).
- The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity.
- Several instruments were used for assessing psychiatric signs and symptoms in these studies:
- Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
- Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
- The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject's current illness state on a 1- to 7-point scale.
- The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups.
- The results of the studies follow:
- Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
- Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
- Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
- Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.
- Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
- Thus, the efficacy of LATUDA at doses of 40, 80, 120 and 160 mg/day has been established (Table 24).
- Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.
# Depressive Episodes Associated with Bipolar I Disorder
- The efficacy of LATUDA, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of LATUDA (20 to 60 mg/day, or 80 to 120 mg/day) or placebo.
- The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject's current illness state on a 7-point scale, where a higher score is associated with greater illness severity.
- For both dose groups, LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 25. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).
- The efficacy of LATUDA, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo.
- The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.
- LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 25).
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- LATUDA is not approved for use in patients with dementia-related psychosis.
- Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
- In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
- LATUDA is indicated for the treatment of patients with schizophrenia.
- The efficacy of LATUDA in schizophrenia was established in five 6-week controlled studies of adult patients with schizophrenia.
- The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
### Depressive Episodes Associated with Bipolar I Disorder
- Monotherapy: LATUDA is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA was established in a 6-week monotherapy study in adult patients with bipolar depression.
- Adjunctive Therapy with Lithium or Valproate: LATUDA is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA as adjunctive therapy was established in a 6-week study in adult patients with bipolar depression who were treated with lithium or valproate.
- The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- The efficacy of LATUDA in the treatment of mania associated withbipolar disorder has not been established.
### Dosing Information
- The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies (14.1)]. The maximum recommended dose is 160 mg per day.
- The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day)
- Concomitant Use with CYP3A4 Inhibitors
- LATUDA should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.)
- If LATUDA is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the LATUDA dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and LATUDA is added to the therapy, the recommended starting dose of LATUDA is 20 mg per day, and the maximum recommended dose of LATUDA is 80 mg per day.
- Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations.
- Concomitant Use with CYP3A4 Inducers
- LATUDA should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) . If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (7 days or more) with the CYP3A4 inducer.
### DOSAGE FORMS AND STRENGTHS
- LATUDA tablets are available in the following shape and color (Table 1) with respective one-sided debossing:
- Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.).
- StrongCYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.).
### Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].
### Suicidal Thoughts and Behaviors in Adolescents and Young Adults
- Patients withmajor depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
- Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidal thoughts and behaviors, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for LATUDA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
### Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis.
### Neuroleptic Malignant Syndrome
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA.
- Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure,tachycardia, diaphoresis, andcardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
- The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.
### Tardive Dyskinesia
- Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to causetardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome.
### Metabolic Changes
- Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria' polyphagia, and weakness. Patients who develop symptoms ofhyperglycemiaduring treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
- Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3
- In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307).
- Monotherapy
- Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).
- Adjunctive Therapy with Lithium or Valproate
- Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).
- Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
- Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6.
- In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively.
- Monotherapy
Data from the short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dL at week 24, respectively.
- Adjunctive Therapy with Lithium or Valproate
- Data from the short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.
- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
- Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9. The mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 , respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for LATUDA-treated patients versus 3.3% for placebo-treated patients.
- In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377).
- Monotherapy
- Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 10. The mean weight gain was +0.29 kg for LATUDA-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).
- Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 11. The mean weight gain was +0.11 kg for LATUDA-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).
### Hyperprolactinemia
- As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels.
- Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea,amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients.
- Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a LATUDA carcinogenicity study conducted in rats and mice . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
- In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 12.
- The proportion of patients with prolactin elevations ≥ 5× upper limit of normal (ULN) was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 1.6% versus 0.6% for placebo-treated male patients.
- In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).
- Monotherapy
- The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 13.
- The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).
- Adjunctive Therapy with Lithium or Valproate
- The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 14
- The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% versus 0% for placebo-treated male patients.
- In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).
### Leukopenia, Neutropenia and Agranulocytosis
- Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.
- Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue LATUDA and have their WBC followed until recovery.
### Orthostatic Hypotension and Syncope
- LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.
- Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥ 10 bpm increase in pulse from sitting to standing or supine to standing position.
- The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)].
- In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo.
- Monotherapy
- In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.
- Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 120 mg compared to 0.9% with placebo
### Seizures
- As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
- In short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients.
- Monotherapy
- In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, no patient experienced seizures/convulsions.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.
### Potential for Cognitive and Motor Impairment
- LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely.
- In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.
- In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg, 15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to 7.1% (50/708) of placebo patients.
- Monotherapy
- In the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and 80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients.
### Body Temperature Dysregulation
- Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
### Suicide
- The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
- In short-term, placebo-controlled schizophrenia studies, the incidence of treatment-emergent suicidal ideation was 0.4% (6/1508) for LATUDA-treated patients compared to 0.8% (6/708) on placebo. No suicide attempts or completed suicides were reported in these studies.
- Monotherapy
- In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the incidence of treatment-emergent suicidal ideation was 0.0% (0/331) with LATUDA-treated patients compared to 0.0% (0/168) with placebo-treated patients. No suicide attempts or completed suicides were reported in this study.
- Adjunctive Therapy with Lithium or Valproate
- In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, the incidence of treatment-emergent suicidal ideation was 1.1% (4/360) for LATUDA-treated patients compared to 0.3% (1/334) on placebo. No suicide attempts or completed suicides were reported in these studies.
### Activation of Mania/Hypomania
- Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.
- In the bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes.
### Dysphagia
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
### Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies
- Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
- The information below is derived from an integrated clinical study database for LATUDA consisting of 3799 patients exposed to one or more doses of LATUDA for the treatment of schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure.
- Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
### Schizophrenia
- The following findings are based on the short-term, placebo-controlled premarketing studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508).
- Commonly Observed Adverse Reactions:
- The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea.
- Adverse Reactions Associated with Discontinuation of Treatment:
- A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
- Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: :*Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 15.
- Dose-Related Adverse Reactions in the Schizophrenia Studies
- Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg).
### Bipolar Depression (Monotherapy)
- The following findings are based on the short-term, placebo-controlled premarketing study for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n=331).
- Commonly Observed Adverse Reactions:
- The most common adverse reactions (incidence ≥ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with LATUDA were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.
- Adverse Reactions Associated with Discontinuation of Treatment:
- A total of 6.0% (20/331) LATUDA-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
- Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: :*Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 16.
Table 16: Adverse Reactions in 2% or More of LATU
- Dose-Related Adverse Reactions in the Monotherapy Study:
- In the short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively.
### Bipolar Depression
- The following findings are based on two short-term, placebo-controlled premarketing studies for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360).
- Commonly Observed Adverse Reactions:
- The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in subjects treated with LATUDA were akathisia and somnolence.
- Adverse Reactions Associated with Discontinuation of Treatment:
- A total of 5.8% (21/360) LATUDA-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
- Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: :*Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 17.
- Extrapyramidal Symptoms
- Schizophrenia
In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 18.
- Bipolar Depression
- Monotherapy
In the short-term, placebo-controlled monotherapy bipolar depression study, for LATUDA-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 19
- Adjunctive Therapy with Lithium or Valproate
In the short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDA-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. The incidence of akathisia for LATUDA-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 20.
In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.
- Schizophrenia
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 14.4%; placebo, 7.1%), the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%).
- Bipolar Depression
- Monotherapy
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.4%; placebo, 5.6%), the SAS (LATUDA, 3.7%; placebo, 1.9%) and the AIMS (LATUDA, 3.4%; placebo, 1.2%).
- Adjunctive Therapy with Lithium or Valproate
The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 8.7%; placebo, 2.1%), the SAS (LATUDA, 2.8%; placebo, 2.1%) and the AIMS (LATUDA, 2.8%; placebo, 0.6%).
- Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- Schizophrenia
In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day.
- Bipolar Depression
Monotherapy
In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.
- Adjunctive Therapy with Lithium or Valproate
In the short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of LATUDA-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.
- Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).
- Frequent: tachycardia;
- Infrequent: AV block 1st degree, angina pectoris, bradycardia.
- Frequent: abdominal pain, diarrhea;
- Infrequent: gastritis.
- Infrequent: anemia
- Frequent: decreased appetite
- Rare: rhabdomyolysis
- Infrequent: cerebrovascular accident, dysarthria
- Infrequent: abnormal dreams, panic attack, sleep disorder
- Frequent: rash, pruritus;
- Rare: angioedema
- Infrequent: vertigo
- Frequent: blurred vision
- Infrequent: dysuria;
- Rare: renal failure
- Infrequent: amenorrhea, dysmenorrhea;
- Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction
- Frequent: hypertension
- Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 21).
- Monotherapy
- Serum Creatinine: In the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for LATUDA-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of LATUDA-treated patients and 0.6% (1/162) on placebo (Table 22)
- Adjunctive Therapy with Lithium or Valproate
- Serum Creatinine: In short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for LATUDA-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of LATUDA-treated patients and 1.6% (5/334) on placebo (Table 23).
- LATUDA is predominantly metabolized by CYP3A4. LATUDA should not be used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) or strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see Contraindications (4)]. The LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 (e.g., diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc.). If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose.
- It is not necessary to adjust the LATUDA dose when used concomitantly with lithium.
- It is not necessary to adjust the LATUDA dose when used concomitantly with valproate. A dedicated drug-drug interaction study has not been conducted with valproate and LATUDA. Based on pharmacokinetic data from the bipolar depression studies valproate levels were not affected by lurasidone, and lurasidone concentrations were not affected by valproate.
- Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations.
### Potential for LATUDA to Affect Other Drugs
- No dose adjustment is needed for lithium, substrates of P-gp, CYP3A4 (Figure 2) or valproate when coadministered with LATUDA. ).
- There are no adequate and well controlled studies of LATUDA use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- LATUDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Safe use of LATUDA during pregnancy or lactation has not been established; therefore, use of LATUDA in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.
- No adverse developmental effects were observed in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day, which is approximately half of the maximum recommended human dose (MRHD) of 160 mg/day, based on mg/m2 body surface area.
- No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 1.5- and 6-times, in rats and rabbits, respectively, the MRHD of 160 mg/day based on mg/m2 body surface area.
- Elderly patients with dementia-related psychosis treated with LATUDA are at an increased risk of death compared to placebo. LATUDA is not approved for the treatment of patients with dementia-related psychosis
- LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, LATUDA was administered with food
- Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring.
- Clinical monitoring of weight is recommended.
- In management of overdosage Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias.
- In premarketing clinical studies, accidental or intentional overdosage of LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months.
- Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to LATUDA, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consider the possibility of multiple-drug overdose.
- Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of LATUDA. Similarly, the alpha-blocking properties of bretylium might be additive to those of LATUDA, resulting in problematic hypotension.
- Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of LATUDA-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
- The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
- Its chemical name is (3aR,4S,7R,7aS)-2-(1R,2R)-2-4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl cyclohexylmethylhexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N4O2S·HCl and its molecular weight is 529.14.
- The chemical structure is:
- Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.
- LATUDA tablets are intended for oral administration only. Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.
- Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake.
- The effects of LATUDA on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.
- In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo.
- Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 (7) hours.
- LATUDA is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. LATUDA is highly bound (~99%) to serum proteins.
- In a food effect study, LATUDA mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. LATUDA exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [see Dosage and Administration (2.3)].
- In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food.
- LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. LATUDA is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA.
- Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of [14C]-labeled LATUDA.
- Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.
- LATUDA increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14-times those in humans receiving the MRHD.
- LATUDA increased the incidence of mammary gland carcinomas in females rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4-times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-times those in humans receiving the MRHD.
- Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents to humans is unknown [see Warnings and Precautions (5.7)].
- LATUDA did not cause mutation or chromosomal aberration when tested in vitro and in vivo. LATUDA was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg (61 times the MRHD of 160 mg/day based on mg/m2 body surface area).
- Estrus cycle irregularities were seen in rats orally administered LATUDA at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. The no-effect dose is 0.1 mg/kg which is approximately 0.006-times the MRHD of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose, which was reversible after a 14-day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is approximately equal to the MRHD based on body surface area.
- LATUDA had no effect on fertility in male rats treated orally with LATUDA for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (9-times the MRHD based on mg/m2 body surface area).
- The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity.
- Several instruments were used for assessing psychiatric signs and symptoms in these studies:
- Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
- Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
- The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject's current illness state on a 1- to 7-point scale.
- The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups.
- The results of the studies follow:
- Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
- Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
- Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
- Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.
- Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
- Thus, the efficacy of LATUDA at doses of 40, 80, 120 and 160 mg/day has been established (Table 24).
- Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.
### Depressive Episodes Associated with Bipolar I Disorder
- The efficacy of LATUDA, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of LATUDA (20 to 60 mg/day, or 80 to 120 mg/day) or placebo.
- The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject's current illness state on a 7-point scale, where a higher score is associated with greater illness severity.
- For both dose groups, LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 25. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).
- The efficacy of LATUDA, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo.
- The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.
- LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 25).
- ↑ Jump up to: 1.0 1.1 1.2 1.3 "PRODUCT INFORMATION LATUDA (lurasidone hydrochloride)" (PDF). TGA eBusiness Services. Therapeutic Goods Administration. 16 April 2014. Retrieved 1 May 2014..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}
- ↑ Empty citation (help)
- ↑ "http://www.ismp.org". External link in |title= (help) | https://www.wikidoc.org/index.php/Lurasidone | |
0d98cabe8c3f4f1da8c73dc486e1250cd8bfef72 | wikidoc | Lymphocyte | Lymphocyte
# Overview
A lymphocyte is a type of white blood cell in the vertebrate immune system. By their appearance under the light microscope, there are two broad categories of lymphocytes, namely the large granular lymphocytes and the small lymphocytes. Functionally distinct subsets of lymphocytes correlate with their appearance. Most, but not all large granular lymphocytes are more commonly known as the natural killer cells (NK cells). The small lymphocytes are the T cells and B cells. Lymphocytes play an important and integral role in the body's defenses. An average human body contains about 10^12 lymphoid cells, and the lymphoid tissue as a whole represents about 2% of the total body weight.
# Types of lymphocytes
The three major types of lymphocyte are T cells, B cells and natural killer (Nk) cells
NK cells are a part of innate immune system and play a major role in defending the host from both tumours and virally infected cells. NK cells distinguish infected cells and tumours from normal and uninfected cells by recognizing alterations in levels of a surface molecule called MHC (major histocompatibility complex) class I. NK cells are activated in response to a family of cytokines called interferons. Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells. They were named "natural killer" because of the initial notion that they do not require prior activation in order to kill cells which are missing MHC class I.
T cells and B-cells are the major cellular components of the adaptive immune response. T cells are involved in cell-mediated immunity whereas B cells are primarily responsible for humoral immunity (relating to antibodies). The function of T cells and B cells is to recognize specific “non-self” antigens, during a process known as antigen presentation. Once they have identified an invader, the cells generate specific responses that are tailored to maximally eliminate specific pathogens or pathogen infected cells. B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses. In response to pathogens some T cells, called helper T cells produce cytokines that direct the immune response whilst other T cells, called cytotoxic T cells, produce toxic granules that induce the death of pathogen infected cells. Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of memory cells. Throughout the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again.
# Lymphocyte development
Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow. This process is called haematopoiesis. All lymphocytes originate, during this process, from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes follows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation of lymphocytes is known as lymphopoiesis. B cells remain in the bone marrow to mature, while T cells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g the spleen and lymph nodes) where they survey for invading pathogens and/or tumour cells.
The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate the antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or by signaling to other cells of the immune system (helper T cells). Memory cells remain in the peripheral tissues and circulation for an extended time ready to respond to the same antigen upon future exposure.
# Characteristics
Microscopically, in a Wright's stained peripheral blood smear, a normal lymphocyte has a large, dark-staining nucleus with little to no basophilic cytoplasm. In normal situations, the coarse, dense nucleus of a lymphocyte is approximately the size of a red blood cell (about 7 micrometres in diameter). Some lymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clear zone to one side of the nucleus. Polyribosomes are a prominent feature in the lymphocytes and can be viewed with an electron microscope. The ribosomes are involved in protein synthesis allowing the generation of large quantities of cytokines and immunoglobulins by these cells.
It is impossible to distinguish between T cells and B cells in a peripheral blood smear. Normally, flow cytometry testing is used for specific lymphocyte population counts. This can be used to specifically determine the percentage of lymphocytes that contain a particular combination of specific cell surface proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular proteins (for example, cytokines). In order to study the function of a lymphocyte by virtue of the proteins it generates, other scientific techniques like the ELISPOT or secretion assay techniques can be used.
# Lymphocytes and disease
A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as percentage of lymphocytes to total white blood cells counted. An increase in lymphocytes is usually a sign of a viral infection (in some rare cases, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal person). A general increase in the number of lymphocytes is known as lymphocytosis whereas a decrease is lymphocytopenia.
A decrease in lymphocytes occurs when the human immunodeficiency virus (HIV) hijacks and destroys T cells (specifically, the CD4+ subgroup of T lymphocytes). Without the key defense that these T cells provide, the body becomes susceptible to opportunistic infections that otherwise would not affect healthy people. The extent of HIV progression is typically determined by measuring the percentage of CD4+ T cells in the patient's blood. The effects of other viruses or lymphocyte disorders can also often be estimated by counting the numbers of lymphocytes present in the blood. | Lymphocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A lymphocyte is a type of white blood cell in the vertebrate immune system. By their appearance under the light microscope, there are two broad categories of lymphocytes, namely the large granular lymphocytes and the small lymphocytes. Functionally distinct subsets of lymphocytes correlate with their appearance. Most, but not all large granular lymphocytes are more commonly known as the natural killer cells (NK cells). The small lymphocytes are the T cells and B cells. Lymphocytes play an important and integral role in the body's defenses. An average human body contains about 10^12 lymphoid cells, and the lymphoid tissue as a whole represents about 2% of the total body weight.
# Types of lymphocytes
The three major types of lymphocyte are T cells, B cells and natural killer (Nk) cells
NK cells are a part of innate immune system and play a major role in defending the host from both tumours and virally infected cells. NK cells distinguish infected cells and tumours from normal and uninfected cells by recognizing alterations in levels of a surface molecule called MHC (major histocompatibility complex) class I. NK cells are activated in response to a family of cytokines called interferons. Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells.[1] They were named "natural killer" because of the initial notion that they do not require prior activation in order to kill cells which are missing MHC class I.
T cells and B-cells are the major cellular components of the adaptive immune response. T cells are involved in cell-mediated immunity whereas B cells are primarily responsible for humoral immunity (relating to antibodies). The function of T cells and B cells is to recognize specific “non-self” antigens, during a process known as antigen presentation. Once they have identified an invader, the cells generate specific responses that are tailored to maximally eliminate specific pathogens or pathogen infected cells. B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses. In response to pathogens some T cells, called helper T cells produce cytokines that direct the immune response whilst other T cells, called cytotoxic T cells, produce toxic granules that induce the death of pathogen infected cells. Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of memory cells. Throughout the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again.
# Lymphocyte development
Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow.[2] This process is called haematopoiesis. All lymphocytes originate, during this process, from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes follows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation of lymphocytes is known as lymphopoiesis. B cells remain in the bone marrow to mature, while T cells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g the spleen and lymph nodes) where they survey for invading pathogens and/or tumour cells.
The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate the antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or by signaling to other cells of the immune system (helper T cells). Memory cells remain in the peripheral tissues and circulation for an extended time ready to respond to the same antigen upon future exposure.
# Characteristics
Microscopically, in a Wright's stained peripheral blood smear, a normal lymphocyte has a large, dark-staining nucleus with little to no basophilic cytoplasm. In normal situations, the coarse, dense nucleus of a lymphocyte is approximately the size of a red blood cell (about 7 micrometres in diameter).[2] Some lymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clear zone to one side of the nucleus. Polyribosomes are a prominent feature in the lymphocytes and can be viewed with an electron microscope.[2] The ribosomes are involved in protein synthesis allowing the generation of large quantities of cytokines and immunoglobulins by these cells.
It is impossible to distinguish between T cells and B cells in a peripheral blood smear.[2] Normally, flow cytometry testing is used for specific lymphocyte population counts. This can be used to specifically determine the percentage of lymphocytes that contain a particular combination of specific cell surface proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular proteins (for example, cytokines). In order to study the function of a lymphocyte by virtue of the proteins it generates, other scientific techniques like the ELISPOT or secretion assay techniques can be used.[1]
# Lymphocytes and disease
A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as percentage of lymphocytes to total white blood cells counted. An increase in lymphocytes is usually a sign of a viral infection (in some rare cases, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal person). A general increase in the number of lymphocytes is known as lymphocytosis whereas a decrease is lymphocytopenia.
A decrease in lymphocytes occurs when the human immunodeficiency virus (HIV) hijacks and destroys T cells (specifically, the CD4+ subgroup of T lymphocytes). Without the key defense that these T cells provide, the body becomes susceptible to opportunistic infections that otherwise would not affect healthy people. The extent of HIV progression is typically determined by measuring the percentage of CD4+ T cells in the patient's blood. The effects of other viruses or lymphocyte disorders can also often be estimated by counting the numbers of lymphocytes present in the blood. | https://www.wikidoc.org/index.php/Lymphocyte | |
cd104f41f86cbef2407fa69b4b7714326164ca05 | wikidoc | M2 protein | M2 protein
The M2 protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helixes stabilized by two disulfide bonds. It is activated by low pH.
# Structure
The M2 protein unit consists of three protein domains: the 24 amino acids on the N-terminal end, exposed to the outside environment, the 19 hydrophobic aminoacids on the transmembrane region, and the 54 aminoacids on the C-terminal end, oriented towards the inside of the viral particle.
# Function
The M2 protein has an important role in the life cycle of the influenza A virus. It is located in the viral envelope. It enables hydrogen ions to enter the viral particle (virion) from the endosome, thus lowering pH of the inside of the virus, which causes dissociation of the viral matrix protein M1 from the ribonucleoprotein RNP. This is a crucial step in uncoating of the virus and exposing its content to the cytoplasm of the host cell.
# Inhibition and resistance
The function of the M2 channel can be inhibited by antiviral drugs amantadine and rimantadine, which then blocks the virus from taking over the host cell. The molecule of the drug binds to the transmembrane region, sterically blocking the channel. This stops the protons from entering the virion, which then does not disintegrate.
However, the M2 gene is susceptible to mutations. When one of five aminoacids in the transmembrane region gets suitably substituted, the virus gains resistance to the existing M2 inhibitors. As the mutations are relatively frequent, presence of the selection factors (eg. using amantadine for treatment of sick poultry) can lead to emergence of a resistant strain. | M2 protein
The M2 protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helixes stabilized by two disulfide bonds. It is activated by low pH.
# Structure
The M2 protein unit consists of three protein domains: the 24 amino acids on the N-terminal end, exposed to the outside environment, the 19 hydrophobic aminoacids on the transmembrane region, and the 54 aminoacids on the C-terminal end, oriented towards the inside of the viral particle.
# Function
The M2 protein has an important role in the life cycle of the influenza A virus. It is located in the viral envelope. It enables hydrogen ions to enter the viral particle (virion) from the endosome, thus lowering pH of the inside of the virus, which causes dissociation of the viral matrix protein M1 from the ribonucleoprotein RNP. This is a crucial step in uncoating of the virus and exposing its content to the cytoplasm of the host cell.
# Inhibition and resistance
The function of the M2 channel can be inhibited by antiviral drugs amantadine and rimantadine, which then blocks the virus from taking over the host cell. The molecule of the drug binds to the transmembrane region, sterically blocking the channel. This stops the protons from entering the virion, which then does not disintegrate.
However, the M2 gene is susceptible to mutations. When one of five aminoacids in the transmembrane region gets suitably substituted, the virus gains resistance to the existing M2 inhibitors. As the mutations are relatively frequent, presence of the selection factors (eg. using amantadine for treatment of sick poultry) can lead to emergence of a resistant strain. | https://www.wikidoc.org/index.php/M2_protein | |
d62dc93622834755d53cf91cbc0ddb628fffd49f | wikidoc | MAX (gene) | MAX (gene)
MAX (also known as myc-associated factor X) is a gene that in humans encodes the MAX transcription factor.
# Function
The protein product of MAX contains the basic helix-loop-helix and leucine zipper motifs. It is therefore included in the bHLHZ family of transcription factors. It is able to form homodimers with other MAX proteins and heterodimers with other transcription factors, including Mad, Mxl1 and Myc. The homodimers and heterodimers compete for a common DNA target site (the E-box) in a gene promoter zone. Rearrangement of dimers (e.g., Mad:Max, Max:Myc) provides a system of transcriptional regulation with greater diversity of gene targets. Max must dimerise in order to be biologically active.
Transcriptionally active hetero- and homodimers involving Max can promote cell proliferation as well as apoptosis.
# Interactions
The protein product of Max has been shown to interact with:
- Myc,
- MNT,
- MSH2,
- MXD1,
- MXI1,
- MYCL1,
- N-Myc,
- SPAG9,
- TEAD1, and
- Transformation/transcription domain-associated protein.
# Clinical relevance
This gene has been shown mutated in cases of hereditary pheochromocytoma. More recently the Max gene becomes mutated and becomes inactivated in small cell lung cancer (SCLC). This is mutually exclusive with alterations at Myc and BRG1, the latter coding for an ATPase of the SWI/SNF complex. It was demonstrated that the BRG1 product regulates the expression of Max through direct recruitment to the Max promoter region, and that depletion of BRG1 strongly hinders cell growth, specifically in Max-deficient cells, suggesting that the two together cause synthetic lethality. Furthermore, Max required BRG1 to activate neuroendocrine transcriptional programs and to up-regulate Myc targets, such as glycolytic-related genes. | MAX (gene)
MAX (also known as myc-associated factor X) is a gene that in humans encodes the MAX transcription factor.[1][2]
# Function
The protein product of MAX contains the basic helix-loop-helix and leucine zipper motifs. It is therefore included in the bHLHZ family of transcription factors. It is able to form homodimers with other MAX proteins and heterodimers with other transcription factors, including Mad, Mxl1 and Myc. The homodimers and heterodimers compete for a common DNA target site (the E-box) in a gene promoter zone. Rearrangement of dimers (e.g., Mad:Max, Max:Myc) provides a system of transcriptional regulation with greater diversity of gene targets. Max must dimerise in order to be biologically active.[3]
Transcriptionally active hetero- and homodimers involving Max can promote cell proliferation as well as apoptosis.[4]
# Interactions
The protein product of Max has been shown to interact with:
- Myc,[5][6][7][8][9][10][11][12][13][14][15][16][17]
- MNT,[14]
- MSH2,[9]
- MXD1,[11][13][15][18]
- MXI1,[12][14][16][19]
- MYCL1,[10][16]
- N-Myc,[10][16]
- SPAG9,[11]
- TEAD1,[20] and
- Transformation/transcription domain-associated protein.[6][7]
# Clinical relevance
This gene has been shown mutated in cases of hereditary pheochromocytoma.[21] More recently the Max gene becomes mutated and becomes inactivated in small cell lung cancer (SCLC). This is mutually exclusive with alterations at Myc and BRG1, the latter coding for an ATPase of the SWI/SNF complex. It was demonstrated that the BRG1 product regulates the expression of Max through direct recruitment to the Max promoter region, and that depletion of BRG1 strongly hinders cell growth, specifically in Max-deficient cells, suggesting that the two together cause synthetic lethality. Furthermore, Max required BRG1 to activate neuroendocrine transcriptional programs and to up-regulate Myc targets, such as glycolytic-related genes.[22] | https://www.wikidoc.org/index.php/MAX_(gene) | |
11017ccecb72f14cdb057a71799b07bec4a6bd43 | wikidoc | MEGA Trial | MEGA Trial
# Objective
To assess whether evidence for treatment of hypercholesterolemia with statins derived from western populations can be extrapolated to the Japanese population.
# Methods
Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study) was a prospective, randomized, open-labelled, blinded study which enrolled 8214 Japanese men and postmenopausal women aged 40 to 70 years and with a serum total cholesterol concentration of 220 to 270 mg/dL. All the patients were randomly assigned to receive either diet therapy alone or diet therapy plus pravastatin 10 to 20 mg daily and followed-up for a mean period of 5.3 years.
# Results
The following results were obtained at the end of follow-up period:
- Mean total cholesterol was reduced by 2.1% and 11.5% in the patients treated with diet alone and diet plus pravastatin respectively.
- Similarly mean LDL-C reduced by 3.2% and 18.0%.
- Significantly lower CAD in patients treated with diet plus pravastatin than in those treated with diet alone.
# Conclusion
Treatment with a low dose of pravastatin reduces the risk of CAD in Japan by much the same amount as higher doses have shown in Europe and the USA. | MEGA Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for MEGA Trial.
# Objective
To assess whether evidence for treatment of hypercholesterolemia with statins derived from western populations can be extrapolated to the Japanese population.
# Methods
Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study) was a prospective, randomized, open-labelled, blinded study which enrolled 8214 Japanese men and postmenopausal women aged 40 to 70 years and with a serum total cholesterol concentration of 220 to 270 mg/dL. All the patients were randomly assigned to receive either diet therapy alone or diet therapy plus pravastatin 10 to 20 mg daily and followed-up for a mean period of 5.3 years.
# Results
The following results were obtained at the end of follow-up period:
- Mean total cholesterol was reduced by 2.1% and 11.5% in the patients treated with diet alone and diet plus pravastatin respectively.
- Similarly mean LDL-C reduced by 3.2% and 18.0%.
- Significantly lower CAD in patients treated with diet plus pravastatin than in those treated with diet alone.
# Conclusion
Treatment with a low dose of pravastatin reduces the risk of CAD in Japan by much the same amount as higher doses have shown in Europe and the USA.[1][2] | https://www.wikidoc.org/index.php/MEGA_Trial |
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