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a2e96073db1143ffaa79b4c5a75eacd8ee656e96 | wikidoc | Nefadozone | Nefadozone
Nefazodone hydrochloride (trade name Serzone) is an antidepressant drug marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries, due to the small possibility of hepatic (liver) injury, which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately one in 250,000 to 300,000 patient-years. On May 20, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States. Several generic formulations of nefazodone are still available.
# Structure and mode of action
Nefazodone is most closely related to trazodone (trade name Desyrel). Nefazodone is not considered to be an SSRI, MAOI or tricyclic antidepressant. It is not chemically related to either bupropion/amfebutamone or venlafaxine.
It operates by blocking post-synaptic serotonin type-2A receptors and, to a lesser extent, by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake. Nefazodone is also a relatively potent alpha-1 adrenoceptor antagonist.
# Dosing
Nefazodone doses for adults typically start at 50 mg twice daily uptitrated by 100 mg/day per week to a maximum of 600 mg (300 mg twice daily), according to Food and Drug Administration (FDA) regulations. Some patients with severe depression were treated with more than 600 mg/day. Most patients were treated with 300 mg–600 mg daily.
# Side effects
Unlike most other SNRIs and SSRIs, Nefazodone has no negative effects on libido or sexual functioning, and is actually sometimes used as an antidote to SSRI induced impotence and anorgasmia in men.
# Advantages
Nefazodone's claimed advantages over other antidepressants include reduced possibility of disturbed sleep or sexual dysfunction, and ability to treat some patients who did not respond to other antidepressant drugs.
# Notes
- ↑ Rxlist.com: "Nefazodone Prescribing Information", accessed 8 January 2007.]
- ↑ FDA Orange Book, accessed 15 January 2006.
- ↑ About.com: "Serzone Pulled from U.S. Market", accessed 15 January 2006.
- ↑ Sanchez, C (1999). "Comparison of the Effects of Antidepressants and Their Metabolites on Reuptake of Biogenic Amines and on Receptor Binding". Celular and Molecular Neurobiology. 19 (4): 467–89. Unknown parameter |coauthors= ignored (help).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}
de:Nefazodon
it:Nefazodone
sv:Nefazodon | Nefadozone
Nefazodone hydrochloride (trade name Serzone) is an antidepressant drug marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries, due to the small possibility of hepatic (liver) injury, which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately one in 250,000 to 300,000 patient-years.[1] On May 20, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States. Several generic formulations of nefazodone are still available.[2][3]
# Structure and mode of action
Nefazodone is most closely related to trazodone (trade name Desyrel). Nefazodone is not considered to be an SSRI, MAOI or tricyclic antidepressant. It is not chemically related to either bupropion/amfebutamone or venlafaxine.
It operates by blocking post-synaptic serotonin type-2A receptors and, to a lesser extent, by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake. Nefazodone is also a relatively potent alpha-1 adrenoceptor antagonist.[4]
# Dosing
Nefazodone doses for adults typically start at 50 mg twice daily uptitrated by 100 mg/day per week to a maximum of 600 mg (300 mg twice daily), according to Food and Drug Administration (FDA) regulations. Some patients with severe depression were treated with more than 600 mg/day. Most patients were treated with 300 mg–600 mg daily.
# Side effects
Unlike most other SNRIs and SSRIs, Nefazodone has no negative effects on libido or sexual functioning, and is actually sometimes used as an antidote to SSRI induced impotence and anorgasmia in men.[5]
# Advantages
Nefazodone's claimed advantages over other antidepressants include reduced possibility of disturbed sleep or sexual dysfunction, and ability to treat some patients who did not respond to other antidepressant drugs.
# Notes
- ↑ Rxlist.com: "Nefazodone Prescribing Information", accessed 8 January 2007.]
- ↑ FDA Orange Book, accessed 15 January 2006.
- ↑ About.com: "Serzone Pulled from U.S. Market", accessed 15 January 2006.
- ↑ Sanchez, C (1999). "Comparison of the Effects of Antidepressants and Their Metabolites on Reuptake of Biogenic Amines and on Receptor Binding". Celular and Molecular Neurobiology. 19 (4): 467–89. Unknown parameter |coauthors= ignored (help).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}
- ↑ [1]
Template:Antidepressants
de:Nefazodon
it:Nefazodone
sv:Nefazodon
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nefadozone | |
475087691cddf18eac1d9d0f1d543c2aa649f91c | wikidoc | Nelfinavir | Nelfinavir
# Disclaimer
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# Overview
Nelfinavir is an antiretroviral that is FDA approved for the treatment of HIV infection. Common adverse reactions include lipodystrophy, diarrhea, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV infection.
- In the clinical studies described below, efficacy was evaluated by the percent of patients with plasma HIV RNA < 400 copies/mL (Studies 511 and 542) or < 500 copies/mL (Study ACTG 364), using the Roche RT-PCR (Amplicor) HIV-1 Monitor or < 50 copies/mL, using the Roche HIV-1 Ultrasensitive assay (Study Avanti 3). In the analysis presented in each figure, patients who terminated the study early for any reason, switched therapy due to inadequate efficacy or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 400 copies/mL, above 500 copies/mL, or above 50 copies/mL at subsequent time points, depending on the assay that was used.
- Study 511: VIRACEPT + zidovudine + lamivudine versus zidovudine + lamivudine
- Study 511 was a double-blind, randomized, placebo-controlled trial comparing treatment with zidovudine (ZDV; 200 mg TID) and lamivudine (3TC; 150 mg BID) plus 2 doses of VIRACEPT (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naive HIV-1 infected patients (median age 35 years , 89% male and 78% Caucasian). Mean baseline CD4 cell count was 288 cells/mm3 and mean baseline plasma HIV RNA was 5.21 log10 copies/mL (160,394 copies/mL). The percent of patients with plasma HIV RNA < 400 copies/mL and mean changes in CD4 cell count are summarized in Figures 1 and 2, respectively.
- Figure 1
- Study 511: Percentage of Patients With HIV RNA Below 400 Copies/mL
- Study 542: VIRACEPT BID + stavudine + lamivudine compared to VIRACEPT TID + stavudine + lamivudine
- Study 542 is an ongoing, randomized, open-label trial comparing the HIV RNA suppression achieved by VIRACEPT 1250 mg BID versus VIRACEPT 750 mg TID in patients also receiving stavudine (d4T; 30–40 mg BID) and lamivudine (3TC; 150 mg BID). Patients had a median age of 36 years (range 18 to 83), were 84% male, and were 91% Caucasian. Patients had received less than 6 months of therapy with nucleoside transcriptase inhibitors and were naïve to protease inhibitors. Mean baseline CD4 cell count was 296 cells/mm3 and mean baseline plasma HIV RNA was 5.0 log10 copies/mL (100,706 copies/mL).
- Results showed that there was no significant difference in mean CD4 cell count among treatment groups; the mean increases from baseline for the BID and TID arms were 150 cells/mm3 at 24 weeks and approximately 200 cells/mm3 at 48 weeks.
- The percent of patients with HIV RNA < 400 copies/mL is summarized in Figure 3. The outcomes of patients through 48 weeks of treatment are summarized in Table 8.
- Figure 3
- Study 542: Percentage of Patients With HIV RNA Below 400 Copies/mL
- Study Avanti 3: VIRACEPT TID + zidovudine + lamivudine compared to zidovudine + lamivudine
- Study Avanti 3 was a placebo-controlled, randomized, double-blind study designed to evaluate the safety and efficacy of VIRACEPT (750 mg TID) in combination with zidovudine (ZDV; 300 mg BID) and lamivudine (3TC; 150 mg BID) (n=53) versus placebo in combination with ZDV and 3TC (n=52) administered to antiretroviral-naive patients with HIV infection and a CD4 cell count between 150 and 500 cells/µL. Patients had a mean age of 35 (range 22–59), were 89% male, and 88% Caucasian. Mean baseline CD4 cell count was 304 cells/mm3 and mean baseline plasma HIV RNA was 4.8 log10 copies/mL (57,887 copies/mL). The percent of patients with plasma HIV RNA < 50 copies/mL at 52 weeks was 54% for the VIRACEPT + ZDV + 3TC treatment group and 13% for the ZDV + 3TC treatment group.
- Study ACTG 364: VIRACEPT TID + 2NRTIs compared to efavirenz + 2NRTIs compared to VIRACEPT + efavirenz + 2NRTIs
- Study ACTG 364 was a randomized, double-blind study that evaluated the combination of VIRACEPT 750 mg TID and/or efavirenz 600 mg QD with 2 NRTIs (either didanosine + d4T, ddI + 3TC, or d4T + 3TC) in patients with prolonged prior nucleoside exposure who had completed 2 previous ACTG studies. Patients had a mean age of 41 years (range 18 to 75), were 88% male, and were 74% Caucasian. Mean baseline CD4 cell count was 389 cells/mm3 and mean baseline plasma HIV RNA was 3.9 log10 copies/mL (7,954 copies/mL).
- The percent of patients with plasma HIV RNA < 500 copies/mL at 48 weeks was 42%, 62%, and 72% for the VIRACEPT (n=66), EFV (n=65), and VIRACEPT + EFV (n=64) treatment groups, respectively. The 4-drug combination of VIRACEPT + EFV + 2 NRTIs was more effective in suppressing plasma HIV RNA in these patients than either 3-drug regimen.
- The recommended dose is 1250 mg (five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily. VIRACEPT should be taken with a meal. Patients unable to swallow the 250 or 625 mg tablets may dissolve the tablets in a small amount of water. Once dissolved, patients should mix the cloudy liquid well, and consume it immediately. The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed.
- In children 2 years of age and older, the recommended oral dose of VIRACEPT Oral Powder or 250 mg tablets is 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily. All doses should be taken with a meal. Doses higher than the adult maximum dose of 2500 mg per day have not been studied in children. For children unable to take tablets, VIRACEPT Oral Powder may be administered. The oral powder may be mixed with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements; once mixed, the entire contents must be consumed in order to obtain the full dose. If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours. Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended to be used in combination with VIRACEPT, because the combination may result in a bitter taste. VIRACEPT Oral Powder should not be reconstituted with water in its original container.
- The healthcare provider should assess appropriate formulation and dosage for each patient. Crushed 250 mg tablets can be used in lieu of powder. Tables 14 and 15 provide dosing guidelines for VIRACEPT tablets and powder based on age and body weight.
Hepatic Impairment
- Viracept can be used in patients with mild hepatic impairment without any dose adjustment. VIRACEPT should not be used in patients with either moderate or severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nelfinavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelfinavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nelfinavir in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nelfinavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelfinavir in pediatric patients.
# Contraindications
- VIRACEPT is contraindicated in patients with clinically significant hypersensitivity to any of its components.
- Coadministration of VIRACEPT is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 9.
# Warnings
- ALERT: Find out about medicines that should not be taken with VIRACEPT. This statement is included on the product's bottle label.
- Nelfinavir is an inhibitor of the CYP3A enzyme. Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Caution should be exercised when inhibitors of CYP3A, including VIRACEPT, are coadministered with drugs that are metabolized by CYP3A and that prolong the QT interval. Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19 may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations.
- Concomitant use of VIRACEPT with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including VIRACEPT, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A pathway (e.g., atorvastatin). (Also see TABLES 6 and 7: DRUG INTERACTIONS). The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including VIRACEPT, are used in combination with these drugs.
- Particular caution should be used when prescribing sildenafil, or other PDE5 inhibitors, in patients receiving protease inhibitors, including VIRACEPT. Coadministration of these drugs is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. (See PRECAUTIONS, DRUG INTERACTIONS and INFORMATION FOR PATIENTS, and the complete prescribing information for sildenafil and other PDE5 inhibitors.)
- Concomitant use of St. John's wort (hypericum perforatum) or St. John's wort-containing products and VIRACEPT is not recommended. Coadministration of St. John's wort with protease inhibitors, including VIRACEPT, is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of VIRACEPT and lead to loss of virologic response and possible resistance to VIRACEPT or to the class of protease inhibitors.
- Patients with Phenylketonuria: VIRACEPT Oral Powder contains 11.2 mg phenylalanine per gram of powder.
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
# Adverse Reactions
## Clinical Trials Experience
- The safety of VIRACEPT was studied in over 5000 patients who received drug either alone or in combination with nucleoside analogues. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients receiving VIRACEPT was diarrhea, which was generally of mild to moderate intensity.
- Drug-related clinical adverse experiences of moderate or severe intensity in ≥ 2% of patients treated with VIRACEPT coadministered with d4T and 3TC (Study 542) for up to 48 weeks or with ZDV plus 3TC (Study 511) for up to 24 weeks are presented in Table 12.
- Adverse events occurring in less than 2% of patients receiving VIRACEPT in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment and of at least moderate severity are listed below.
- Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, fever, headache, malaise, pain, and redistribution/accumulation of body fat.
- Digestive System: anorexia, dyspepsia, epigastric pain, gastrointestinal bleeding, hepatitis, mouth ulceration, pancreatitis, and vomiting.
- Hemic/Lymphatic System: anemia, leukopenia, and thrombocytopenia.
- Metabolic/Nutritional System: increases in alkaline phosphatase, amylase, creatine phosphokinase, lactic dehydrogenase, SGOT, SGPT, and gamma glutamyl transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, dehydration, and liver function tests abnormal.
- Musculoskeletal System: arthralgia, arthritis, cramps, myalgia, myasthenia, and myopathy.
- Nervous System: anxiety, depression, dizziness, emotional lability, hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep disorder, somnolence, and suicide ideation.
- Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis.
- Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating, and urticaria.
- Special Senses: acute iritis and eye disorder.
- Urogenital System: kidney calculus, sexual dysfunction, and urine abnormality.
## Postmarketing Experience
- The following additional adverse experiences have been reported from postmarketing surveillance as at least possibly related or of unknown relationship to VIRACEPT:
- Body as a Whole: hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever, and edema).
- Cardiovascular System: QTc prolongation, torsades de pointes.
- Digestive System: jaundice.
- Metabolic/Nutritional System: bilirubinemia, metabolic acidosis.
- The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 13. Marked laboratory abnormalities are defined as a Grade 3 or 4 abnormality in a patient with a normal baseline value, or a Grade 4 abnormality in a patient with a Grade 1 abnormality at baseline.
- VIRACEPT has been studied in approximately 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event profile seen during pediatric clinical trials was similar to that for adults.
- The most commonly reported drug-related, treatment-emergent adverse events reported in the pediatric studies included: diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. Diarrhea, regardless of assigned relationship to study drug, was reported in 39% to 47% of pediatric patients receiving VIRACEPT in 2 of the larger treatment trials. Leukopenia/neutropenia was the laboratory abnormality most commonly reported as a significant event across the pediatric studies.
# Drug Interactions
There is limited information regarding Nelfinavir Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There were no effects on fetal development or maternal toxicity when nelfinavir was administered to pregnant rats at systemic exposures (AUC) comparable to human exposure. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight decrease in maternal body weight was observed; however, even at the highest dose evaluated, systemic exposure in rabbits was significantly lower than human exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation had no effect on the survival, growth, and development of the offspring to weaning. Subsequent reproductive performance of these offspring was also not affected by maternal exposure to nelfinavir. However, there are no adequate and well-controlled studies in pregnant women taking VIRACEPT. Because animal reproduction studies are not always predictive of human response, VIRACEPT should be used during pregnancy only if clearly needed.
Antiretroviral Pregnancy Registry: (APR)
- To monitor maternal-fetal outcomes of pregnant women exposed to VIRACEPT and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nelfinavir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nelfinavir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats have demonstrated that nelfinavir is excreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIRACEPT.
### Pediatric Use
- The safety and effectiveness of VIRACEPT have been established in patients from 2 to 13 years of age. The use of VIRACEPT in these age groups is supported by evidence from adequate and well-controlled studies of VIRACEPT in adults and pharmacokinetic studies and studies supporting activity in pediatric patients. In patients less than 2 years of age, VIRACEPT was found to be safe at the doses studied, but a reliably effective dose could not be established.
- The following issues should be considered when initiating VIRACEPT in pediatric patients:
- In pediatric patients ≥ 2 years of age receiving VIRACEPT as part of triple combination antiretroviral therapy in randomized studies, the proportion of patients achieving a HIV RNA level <400 copies/mL through 48 weeks ranged from 26% to 42%.
- Response rates in children <2 years of age appeared to be poorer than those in patients ≥ 2 years of age in some studies.
- Highly variable drug exposure remains a significant problem in the use of VIRACEPT in pediatric patients. Unpredictable drug exposure may be exacerbated in pediatric patients because of increased clearance compared to adults and difficulties with compliance and adequate food intake with dosing. Pharmacokinetic results from the pediatric studies are reported in Table 5.
- Study 556 was a randomized, double-blind, placebo-controlled trial with VIRACEPT or placebo coadministered with ZDV and ddI in 141 HIV-positive children who had received minimal antiretroviral therapy. The mean age of the children was 3.9 years. Ninety four (67%) children were between 2–12 years, and 47 (33%) were < 2 years of age. The mean baseline HIV RNA value was 5.0 log for all patients and the mean CD4 cell count was 886 cells/mm3 for all patients. The efficacy of VIRACEPT measured by HIV RNA <400 at 48 weeks in children ≥ 2 years of age was 26% compared to 2% of placebo patients (p=0.0008). In the children < 2 years of age, only 1 of 27 and 2 of 20 maintained an undetectable HIV RNA level at 48 weeks for placebo and VIRACEPT patients, respectively.
- PACTG 377 was an open-label study that randomized 181 HIV treatment-experienced pediatric patients to receive: d4T+NVP+RTV, d4T+3TC+NFV, or d4T+3TC+NVP+NFV with NFV given on a TID schedule. The median age was 5.9 years and 46% were male. At baseline the median HIV RNA was 4.4 log and median CD4 cell count was 690 cells/mm3. Substudy PACTG 725 evaluated d4T+3TC+NFV with NFV given on a BID schedule. The proportion of patients with detectable viral load at baseline achieving HIV RNA <400 copies/mL at 48 weeks was: 41% for d4T+NVP+RTV, 42% for d4T+3TC+NFV, 30% for d4T+NVP+NFV, and 52% for d4T+3TC+NVP+NFV. No significant clinical differences were identified between patients receiving VIRACEPT in BID or TID schedules.
- VIRACEPT has been evaluated in 2 studies of young infants. The PENTA 7 study was an open-label study to evaluate the toxicity, tolerability, pharmacokinetics, and activity of NFV+d4T+ddI in 20 HIV-infected infants less than 12 weeks of age. PACTG 353 evaluated the pharmacokinetics and safety of VIRACEPT in infants born to HIV-infected women receiving NFV as part of combination therapy during pregnancy.
### Geriatic Use
- Clinical studies of VIRACEPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Nelfinavir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nelfinavir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nelfinavir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nelfinavir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nelfinavir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nelfinavir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Nelfinavir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Nelfinavir in the drug label.
# Overdosage
- Human experience of acute overdose with VIRACEPT is limited. There is no specific antidote for overdose with VIRACEPT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. Since nelfinavir is highly protein bound, dialysis is unlikely to significantly remove drug from blood.
# Pharmacology
There is limited information regarding Nelfinavir Pharmacology in the drug label.
## Mechanism of Action
## Structure
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nelfinavir in the drug label.
## Pharmacokinetics
- The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.
- Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state , peak plasma concentrations , morning and evening trough concentrations ) from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 1.
- The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.
- In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax was comparable for both formulations. In HIV-1 infected subjects (N = 21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (Cmax and AUC).
- Table 2 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 × 625 tablets) to HIV-infected patients (N = 21) for 14 days.
Nelfinavir exposure can be increased by increasing the calorie or fat content in meals taken with VIRACEPT.
- A food effect study has not been conducted with the 625 mg tablet. However, based on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of nelfinavir 1250 mg, the magnitude of the food effect for the 625 mg nelfinavir tablet appears comparable to that of the 250 mg tablets. VIRACEPT should be taken with a meal.
- The apparent volume of distribution following oral administration of nelfinavir was 2–7 L/kg. Nelfinavir in serum is extensively protein-bound (>98%).
- Unchanged nelfinavir comprised 82–86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.
- The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1–2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.
- The steady-state pharmacokinetics of nelfinavir (1250 mg BID for 2 weeks) was studied in HIV-seronegative subjects with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=6) hepatic impairment. When compared with subjects with normal hepatic function, the Cmax and AUC of nelfinavir were not significantly different in subjects with mild hepatic impairment but were increased by 22% and 62%, respectively, in subjects with moderate hepatic impairment. The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-seronegative subjects with severe hepatic impairment.
- The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-positive patients with any degree of hepatic impairment.
- The pharmacokinetics of nelfinavir have not been studied in patients with renal insufficiency; however, less than 2% of nelfinavir is excreted in the urine, so the impact of renal impairment on nelfinavir elimination should be minimal.
- No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated.
- The pharmacokinetics of nelfinavir have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving VIRACEPT three times or twice daily. The dosing regimens and associated AUC24 values are summarized in Table 5.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Nelfinavir in the drug label.
# Clinical Studies
There is limited information regarding Nelfinavir Clinical Studies in the drug label.
# How Supplied
- VIRACEPT (nelfinavir mesylate) 250 mg: Light blue, capsule-shaped tablets with a clear film coating engraved with "VIRACEPT" on one side and "250 mg" on the other.
- Bottles of 300, 250 mg tablets………………………………...NDC 63010-010-30
- VIRACEPT (nelfinavir mesylate) 625 mg: White oval tablet with a clear film coating engraved with "V" on one side and "625" on the other.
- Bottles of 120, 625 mg tablets………………………………...NDC 63010-027-70
- VIRACEPT (nelfinavir mesylate) Oral Powder is available as a 50 mg/g off-white powder containing 50 mg (as nelfinavir free base) in each level scoopful (1 gram).
- Multiple use bottles of 144 grams of powder with scoop …….NDC 63010-011-90
## Storage
- Viracept tablets and oral powder should be stored at 15° to 30°C (59° TO 86°F).
- Keep container tightly closed. Dispense in original container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Nelfinavir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Nelfinavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VIRACEPT ®
# Look-Alike Drug Names
There is limited information regarding Nelfinavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nelfinavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Overview
Nelfinavir is an antiretroviral that is FDA approved for the treatment of HIV infection. Common adverse reactions include lipodystrophy, diarrhea, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV infection.
- In the clinical studies described below, efficacy was evaluated by the percent of patients with plasma HIV RNA < 400 copies/mL (Studies 511 and 542) or < 500 copies/mL (Study ACTG 364), using the Roche RT-PCR (Amplicor) HIV-1 Monitor or < 50 copies/mL, using the Roche HIV-1 Ultrasensitive assay (Study Avanti 3). In the analysis presented in each figure, patients who terminated the study early for any reason, switched therapy due to inadequate efficacy or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 400 copies/mL, above 500 copies/mL, or above 50 copies/mL at subsequent time points, depending on the assay that was used.
- Study 511: VIRACEPT + zidovudine + lamivudine versus zidovudine + lamivudine
- Study 511 was a double-blind, randomized, placebo-controlled trial comparing treatment with zidovudine (ZDV; 200 mg TID) and lamivudine (3TC; 150 mg BID) plus 2 doses of VIRACEPT (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naive HIV-1 infected patients (median age 35 years [range 21 to 63], 89% male and 78% Caucasian). Mean baseline CD4 cell count was 288 cells/mm3 and mean baseline plasma HIV RNA was 5.21 log10 copies/mL (160,394 copies/mL). The percent of patients with plasma HIV RNA < 400 copies/mL and mean changes in CD4 cell count are summarized in Figures 1 and 2, respectively.
- Figure 1
- Study 511: Percentage of Patients With HIV RNA Below 400 Copies/mL
- Study 542: VIRACEPT BID + stavudine + lamivudine compared to VIRACEPT TID + stavudine + lamivudine
- Study 542 is an ongoing, randomized, open-label trial comparing the HIV RNA suppression achieved by VIRACEPT 1250 mg BID versus VIRACEPT 750 mg TID in patients also receiving stavudine (d4T; 30–40 mg BID) and lamivudine (3TC; 150 mg BID). Patients had a median age of 36 years (range 18 to 83), were 84% male, and were 91% Caucasian. Patients had received less than 6 months of therapy with nucleoside transcriptase inhibitors and were naïve to protease inhibitors. Mean baseline CD4 cell count was 296 cells/mm3 and mean baseline plasma HIV RNA was 5.0 log10 copies/mL (100,706 copies/mL).
- Results showed that there was no significant difference in mean CD4 cell count among treatment groups; the mean increases from baseline for the BID and TID arms were 150 cells/mm3 at 24 weeks and approximately 200 cells/mm3 at 48 weeks.
- The percent of patients with HIV RNA < 400 copies/mL is summarized in Figure 3. The outcomes of patients through 48 weeks of treatment are summarized in Table 8.
- Figure 3
- Study 542: Percentage of Patients With HIV RNA Below 400 Copies/mL
- Study Avanti 3: VIRACEPT TID + zidovudine + lamivudine compared to zidovudine + lamivudine
- Study Avanti 3 was a placebo-controlled, randomized, double-blind study designed to evaluate the safety and efficacy of VIRACEPT (750 mg TID) in combination with zidovudine (ZDV; 300 mg BID) and lamivudine (3TC; 150 mg BID) (n=53) versus placebo in combination with ZDV and 3TC (n=52) administered to antiretroviral-naive patients with HIV infection and a CD4 cell count between 150 and 500 cells/µL. Patients had a mean age of 35 (range 22–59), were 89% male, and 88% Caucasian. Mean baseline CD4 cell count was 304 cells/mm3 and mean baseline plasma HIV RNA was 4.8 log10 copies/mL (57,887 copies/mL). The percent of patients with plasma HIV RNA < 50 copies/mL at 52 weeks was 54% for the VIRACEPT + ZDV + 3TC treatment group and 13% for the ZDV + 3TC treatment group.
- Study ACTG 364: VIRACEPT TID + 2NRTIs compared to efavirenz + 2NRTIs compared to VIRACEPT + efavirenz + 2NRTIs
- Study ACTG 364 was a randomized, double-blind study that evaluated the combination of VIRACEPT 750 mg TID and/or efavirenz 600 mg QD with 2 NRTIs (either didanosine [ddI] + d4T, ddI + 3TC, or d4T + 3TC) in patients with prolonged prior nucleoside exposure who had completed 2 previous ACTG studies. Patients had a mean age of 41 years (range 18 to 75), were 88% male, and were 74% Caucasian. Mean baseline CD4 cell count was 389 cells/mm3 and mean baseline plasma HIV RNA was 3.9 log10 copies/mL (7,954 copies/mL).
- The percent of patients with plasma HIV RNA < 500 copies/mL at 48 weeks was 42%, 62%, and 72% for the VIRACEPT (n=66), EFV (n=65), and VIRACEPT + EFV (n=64) treatment groups, respectively. The 4-drug combination of VIRACEPT + EFV + 2 NRTIs was more effective in suppressing plasma HIV RNA in these patients than either 3-drug regimen.
- The recommended dose is 1250 mg (five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily. VIRACEPT should be taken with a meal. Patients unable to swallow the 250 or 625 mg tablets may dissolve the tablets in a small amount of water. Once dissolved, patients should mix the cloudy liquid well, and consume it immediately. The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed.
- In children 2 years of age and older, the recommended oral dose of VIRACEPT Oral Powder or 250 mg tablets is 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily. All doses should be taken with a meal. Doses higher than the adult maximum dose of 2500 mg per day have not been studied in children. For children unable to take tablets, VIRACEPT Oral Powder may be administered. The oral powder may be mixed with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements; once mixed, the entire contents must be consumed in order to obtain the full dose. If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours. Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended to be used in combination with VIRACEPT, because the combination may result in a bitter taste. VIRACEPT Oral Powder should not be reconstituted with water in its original container.
- The healthcare provider should assess appropriate formulation and dosage for each patient. Crushed 250 mg tablets can be used in lieu of powder. Tables 14 and 15 provide dosing guidelines for VIRACEPT tablets and powder based on age and body weight.
Hepatic Impairment
- Viracept can be used in patients with mild hepatic impairment without any dose adjustment. VIRACEPT should not be used in patients with either moderate or severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nelfinavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelfinavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nelfinavir in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nelfinavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelfinavir in pediatric patients.
# Contraindications
- VIRACEPT is contraindicated in patients with clinically significant hypersensitivity to any of its components.
- Coadministration of VIRACEPT is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 9.
# Warnings
- ALERT: Find out about medicines that should not be taken with VIRACEPT. This statement is included on the product's bottle label.
- Nelfinavir is an inhibitor of the CYP3A enzyme. Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Caution should be exercised when inhibitors of CYP3A, including VIRACEPT, are coadministered with drugs that are metabolized by CYP3A and that prolong the QT interval. Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19 may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations.
- Concomitant use of VIRACEPT with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including VIRACEPT, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A pathway (e.g., atorvastatin). (Also see TABLES 6 and 7: DRUG INTERACTIONS). The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including VIRACEPT, are used in combination with these drugs.
- Particular caution should be used when prescribing sildenafil, or other PDE5 inhibitors, in patients receiving protease inhibitors, including VIRACEPT. Coadministration of these drugs is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. (See PRECAUTIONS, DRUG INTERACTIONS and INFORMATION FOR PATIENTS, and the complete prescribing information for sildenafil and other PDE5 inhibitors.)
- Concomitant use of St. John's wort (hypericum perforatum) or St. John's wort-containing products and VIRACEPT is not recommended. Coadministration of St. John's wort with protease inhibitors, including VIRACEPT, is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of VIRACEPT and lead to loss of virologic response and possible resistance to VIRACEPT or to the class of protease inhibitors.
- Patients with Phenylketonuria: VIRACEPT Oral Powder contains 11.2 mg phenylalanine per gram of powder.
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
# Adverse Reactions
## Clinical Trials Experience
- The safety of VIRACEPT was studied in over 5000 patients who received drug either alone or in combination with nucleoside analogues. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients receiving VIRACEPT was diarrhea, which was generally of mild to moderate intensity.
- Drug-related clinical adverse experiences of moderate or severe intensity in ≥ 2% of patients treated with VIRACEPT coadministered with d4T and 3TC (Study 542) for up to 48 weeks or with ZDV plus 3TC (Study 511) for up to 24 weeks are presented in Table 12.
- Adverse events occurring in less than 2% of patients receiving VIRACEPT in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment and of at least moderate severity are listed below.
- Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, fever, headache, malaise, pain, and redistribution/accumulation of body fat.
- Digestive System: anorexia, dyspepsia, epigastric pain, gastrointestinal bleeding, hepatitis, mouth ulceration, pancreatitis, and vomiting.
- Hemic/Lymphatic System: anemia, leukopenia, and thrombocytopenia.
- Metabolic/Nutritional System: increases in alkaline phosphatase, amylase, creatine phosphokinase, lactic dehydrogenase, SGOT, SGPT, and gamma glutamyl transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, dehydration, and liver function tests abnormal.
- Musculoskeletal System: arthralgia, arthritis, cramps, myalgia, myasthenia, and myopathy.
- Nervous System: anxiety, depression, dizziness, emotional lability, hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep disorder, somnolence, and suicide ideation.
- Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis.
- Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating, and urticaria.
- Special Senses: acute iritis and eye disorder.
- Urogenital System: kidney calculus, sexual dysfunction, and urine abnormality.
## Postmarketing Experience
- The following additional adverse experiences have been reported from postmarketing surveillance as at least possibly related or of unknown relationship to VIRACEPT:
- Body as a Whole: hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever, and edema).
- Cardiovascular System: QTc prolongation, torsades de pointes.
- Digestive System: jaundice.
- Metabolic/Nutritional System: bilirubinemia, metabolic acidosis.
- The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 13. Marked laboratory abnormalities are defined as a Grade 3 or 4 abnormality in a patient with a normal baseline value, or a Grade 4 abnormality in a patient with a Grade 1 abnormality at baseline.
- VIRACEPT has been studied in approximately 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event profile seen during pediatric clinical trials was similar to that for adults.
- The most commonly reported drug-related, treatment-emergent adverse events reported in the pediatric studies included: diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. Diarrhea, regardless of assigned relationship to study drug, was reported in 39% to 47% of pediatric patients receiving VIRACEPT in 2 of the larger treatment trials. Leukopenia/neutropenia was the laboratory abnormality most commonly reported as a significant event across the pediatric studies.
# Drug Interactions
There is limited information regarding Nelfinavir Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There were no effects on fetal development or maternal toxicity when nelfinavir was administered to pregnant rats at systemic exposures (AUC) comparable to human exposure. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight decrease in maternal body weight was observed; however, even at the highest dose evaluated, systemic exposure in rabbits was significantly lower than human exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation had no effect on the survival, growth, and development of the offspring to weaning. Subsequent reproductive performance of these offspring was also not affected by maternal exposure to nelfinavir. However, there are no adequate and well-controlled studies in pregnant women taking VIRACEPT. Because animal reproduction studies are not always predictive of human response, VIRACEPT should be used during pregnancy only if clearly needed.
Antiretroviral Pregnancy Registry: (APR)
- To monitor maternal-fetal outcomes of pregnant women exposed to VIRACEPT and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nelfinavir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nelfinavir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats have demonstrated that nelfinavir is excreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIRACEPT.
### Pediatric Use
- The safety and effectiveness of VIRACEPT have been established in patients from 2 to 13 years of age. The use of VIRACEPT in these age groups is supported by evidence from adequate and well-controlled studies of VIRACEPT in adults and pharmacokinetic studies and studies supporting activity in pediatric patients. In patients less than 2 years of age, VIRACEPT was found to be safe at the doses studied, but a reliably effective dose could not be established.
- The following issues should be considered when initiating VIRACEPT in pediatric patients:
- In pediatric patients ≥ 2 years of age receiving VIRACEPT as part of triple combination antiretroviral therapy in randomized studies, the proportion of patients achieving a HIV RNA level <400 copies/mL through 48 weeks ranged from 26% to 42%.
- Response rates in children <2 years of age appeared to be poorer than those in patients ≥ 2 years of age in some studies.
- Highly variable drug exposure remains a significant problem in the use of VIRACEPT in pediatric patients. Unpredictable drug exposure may be exacerbated in pediatric patients because of increased clearance compared to adults and difficulties with compliance and adequate food intake with dosing. Pharmacokinetic results from the pediatric studies are reported in Table 5.
- Study 556 was a randomized, double-blind, placebo-controlled trial with VIRACEPT or placebo coadministered with ZDV and ddI in 141 HIV-positive children who had received minimal antiretroviral therapy. The mean age of the children was 3.9 years. Ninety four (67%) children were between 2–12 years, and 47 (33%) were < 2 years of age. The mean baseline HIV RNA value was 5.0 log for all patients and the mean CD4 cell count was 886 cells/mm3 for all patients. The efficacy of VIRACEPT measured by HIV RNA <400 at 48 weeks in children ≥ 2 years of age was 26% compared to 2% of placebo patients (p=0.0008). In the children < 2 years of age, only 1 of 27 and 2 of 20 maintained an undetectable HIV RNA level at 48 weeks for placebo and VIRACEPT patients, respectively.
- PACTG 377 was an open-label study that randomized 181 HIV treatment-experienced pediatric patients to receive: d4T+NVP+RTV, d4T+3TC+NFV, or d4T+3TC+NVP+NFV with NFV given on a TID schedule. The median age was 5.9 years and 46% were male. At baseline the median HIV RNA was 4.4 log and median CD4 cell count was 690 cells/mm3. Substudy PACTG 725 evaluated d4T+3TC+NFV with NFV given on a BID schedule. The proportion of patients with detectable viral load at baseline achieving HIV RNA <400 copies/mL at 48 weeks was: 41% for d4T+NVP+RTV, 42% for d4T+3TC+NFV, 30% for d4T+NVP+NFV, and 52% for d4T+3TC+NVP+NFV. No significant clinical differences were identified between patients receiving VIRACEPT in BID or TID schedules.
- VIRACEPT has been evaluated in 2 studies of young infants. The PENTA 7 study was an open-label study to evaluate the toxicity, tolerability, pharmacokinetics, and activity of NFV+d4T+ddI in 20 HIV-infected infants less than 12 weeks of age. PACTG 353 evaluated the pharmacokinetics and safety of VIRACEPT in infants born to HIV-infected women receiving NFV as part of combination therapy during pregnancy.
### Geriatic Use
- Clinical studies of VIRACEPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Nelfinavir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nelfinavir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nelfinavir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nelfinavir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nelfinavir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nelfinavir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Nelfinavir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Nelfinavir in the drug label.
# Overdosage
- Human experience of acute overdose with VIRACEPT is limited. There is no specific antidote for overdose with VIRACEPT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. Since nelfinavir is highly protein bound, dialysis is unlikely to significantly remove drug from blood.
# Pharmacology
There is limited information regarding Nelfinavir Pharmacology in the drug label.
## Mechanism of Action
-
## Structure
-
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nelfinavir in the drug label.
## Pharmacokinetics
- The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.
- Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC24], peak plasma concentrations [Cmax], morning and evening trough concentrations [Ctrough]) from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 1.
- The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.
- In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax was comparable for both formulations. In HIV-1 infected subjects (N = 21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (Cmax and AUC).
- Table 2 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 × 625 tablets) to HIV-infected patients (N = 21) for 14 days.
Nelfinavir exposure can be increased by increasing the calorie or fat content in meals taken with VIRACEPT.
- A food effect study has not been conducted with the 625 mg tablet. However, based on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of nelfinavir 1250 mg, the magnitude of the food effect for the 625 mg nelfinavir tablet appears comparable to that of the 250 mg tablets. VIRACEPT should be taken with a meal.
- The apparent volume of distribution following oral administration of nelfinavir was 2–7 L/kg. Nelfinavir in serum is extensively protein-bound (>98%).
- Unchanged nelfinavir comprised 82–86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.
- The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1–2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.
- The steady-state pharmacokinetics of nelfinavir (1250 mg BID for 2 weeks) was studied in HIV-seronegative subjects with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=6) hepatic impairment. When compared with subjects with normal hepatic function, the Cmax and AUC of nelfinavir were not significantly different in subjects with mild hepatic impairment but were increased by 22% and 62%, respectively, in subjects with moderate hepatic impairment. The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-seronegative subjects with severe hepatic impairment.
- The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-positive patients with any degree of hepatic impairment.
- The pharmacokinetics of nelfinavir have not been studied in patients with renal insufficiency; however, less than 2% of nelfinavir is excreted in the urine, so the impact of renal impairment on nelfinavir elimination should be minimal.
- No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated.
- The pharmacokinetics of nelfinavir have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving VIRACEPT three times or twice daily. The dosing regimens and associated AUC24 values are summarized in Table 5.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Nelfinavir in the drug label.
# Clinical Studies
There is limited information regarding Nelfinavir Clinical Studies in the drug label.
# How Supplied
- VIRACEPT (nelfinavir mesylate) 250 mg: Light blue, capsule-shaped tablets with a clear film coating engraved with "VIRACEPT" on one side and "250 mg" on the other.
- Bottles of 300, 250 mg tablets………………………………...NDC 63010-010-30
- VIRACEPT (nelfinavir mesylate) 625 mg: White oval tablet with a clear film coating engraved with "V" on one side and "625" on the other.
- Bottles of 120, 625 mg tablets………………………………...NDC 63010-027-70
- VIRACEPT (nelfinavir mesylate) Oral Powder is available as a 50 mg/g off-white powder containing 50 mg (as nelfinavir free base) in each level scoopful (1 gram).
- Multiple use bottles of 144 grams of powder with scoop …….NDC 63010-011-90
## Storage
- Viracept tablets and oral powder should be stored at 15° to 30°C (59° TO 86°F).
- Keep container tightly closed. Dispense in original container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Nelfinavir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Nelfinavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VIRACEPT ®[1]
# Look-Alike Drug Names
There is limited information regarding Nelfinavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nelfinavir | |
1a3ab3bafbc6bbc350002009ac908652aee445d0 | wikidoc | Nerve root | Nerve root
A nerve root is the initial segment of a nerve leaving the central nervous system. It can refer to:
- A cranial nerve root, the beginning of one of the eleven pairs leaving the central nervous system from the brain stem or the highest levels of the spinal cord;
- A spinal nerve root, the beginning of one of the thirty-one pairs oleaving the central nervous system from the spinal cord. Each spinal nerve root consists of the union of a sensory dorsal root and a motor ventral root. | Nerve root
A nerve root is the initial segment of a nerve leaving the central nervous system. It can refer to:
- A cranial nerve root, the beginning of one of the eleven pairs leaving the central nervous system from the brain stem or the highest levels of the spinal cord;
- A spinal nerve root, the beginning of one of the thirty-one pairs oleaving the central nervous system from the spinal cord. Each spinal nerve root consists of the union of a sensory dorsal root and a motor ventral root.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nerve_root | |
66c4016862220109ecbc3666904f4946fc4c9c9d | wikidoc | Netarsudil | Netarsudil
# 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
Netarsudil is a Rho kinase inhibitor that is FDA approved for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Common adverse reactions include conjunctival hyperemia, corneal verticillata, instillation site pain, and conjunctival hemorrhage.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Netarsudil 0.02% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
- The recommended dosage is one drop in the affected eye(s) once daily in the evening.
- If one dose is missed, treatment should continue with the next dose in the evening. Twice a day dosing is not well tolerated and is not recommended. If Netarsudil is to be used concomitantly with other topical ophthalmic drug products to lower IOP, administer each drug product at least 5 minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Netarsudil Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Netarsudil 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 Netarsudil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Netarsudil Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Netarsudil Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
- Contact lenses should be removed prior to instillation of Netarsudil and may be reinserted 15 minutes following its administration.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- The most common ocular adverse reaction observed in controlled clinical studies with Netarsudil dosed once daily was conjunctival hyperemia which was reported in 53% of patients. Other common (approximately 20%) ocular adverse reactions reported were: corneal verticillata, instillation site pain, and conjunctival hemorrhage. Instillation site erythema, corneal staining, blurred vision, increased lacrimation, erythema of eyelid, and reduced visual acuity were reported in 5-10% of patients.
Corneal Verticillata
- Corneal verticillata occurred in approximately 20% of the patients in controlled clinical studies. The corneal verticillata seen in Netarsudil-treated patients were first noted at 4 weeks of daily dosing. This reaction did not result in any apparent visual functional changes in patients. Most corneal verticillata resolved upon discontinuation of treatment.
## Postmarketing Experience
There is limited information regarding Netarsudil Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Netarsudil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no available data on Netarsudil use in pregnant women to inform any drug associated risk; however, systemic exposure to Netarsudil from ocular administration is low. Intravenous administration of Netarsudil to pregnant rats and rabbits during organogenesis did not produce adverse embryofetal effects at clinically relevant systemic exposures.
Data (Animal)
- Netarsudil administered daily by intravenous injection to rats during organogenesis caused abortions and embryofetal lethality at doses ≥0.3 mg/kg/day (126-fold the plasma exposure at the recommended human ophthalmic dose , based on Cmax). The no-observed-adverse-effect-level (NOAEL) for embryofetal development toxicity was 0.1 mg/kg/day (40-fold the plasma exposure at the RHOD, based on Cmax).
- Netarsudil administered daily by intravenous injection to rabbits during organogenesis caused embryofetal lethality and decreased fetal weight at 5 mg/kg/day (1480-fold the plasma exposure at the RHOD, based on Cmax). Malformations were observed at ≥3 mg/kg/day (1330-fold the plasma exposure at the RHOD, based on Cmax), including thoracogastroschisis, umbilical hernia and absent intermediate lung lobe. The NOAEL for embryofetal development toxicity was 0.5 mg/kg/day (214-fold the plasma exposure at the RHOD, based on Cmax).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Netarsudil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Netarsudil during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of Netarsudil in human milk, the effects on the breastfed infant, or the effects on milk production. However, systemic exposure to Netarsudil following topical ocular administration is low, and it is not known whether measurable levels of Netarsudil would be present in maternal milk following topical ocular administration.
- The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Netarsudil and any potential adverse effects on the breast-fed child from Netarsudil.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
### Gender
There is no FDA guidance on the use of Netarsudil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Netarsudil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Netarsudil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Netarsudil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Netarsudil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Netarsudil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer in the evening.
- When used concomitantly with other ophthalmic products intended to lower intraocular pressure, separate administration of each product by at least 5 minutes.
### Monitoring
- A reduction in intraocular pressure indicates efficacy.
# IV Compatibility
There is limited information regarding the compatibility of Netarsudil and IV administrations.
# Overdosage
There is limited information regarding Netarsudil overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Netarsudil is a rho kinase inhibitor, which is believed to reduce IOP by increasing the outflow of aqueous humor through the trabecular meshwork route. The exact mechanism is unknown.
## Structure
## Pharmacodynamics
There is limited information regarding Netarsudil Pharmacodynamics in the drug label.
## Pharmacokinetics
Absorption
- The systemic exposures of Netarsudil and its active metabolite, AR-13503, were evaluated in 18 healthy subjects after topical ocular administration of Netarsudil 0.02% once daily (one drop bilaterally in the morning) for 8 days. There were no quantifiable plasma concentrations of Netarsudil (lower limit of quantitation (LLOQ) 0.100 ng/mL) post dose on Day 1 and Day 8. Only one plasma concentration at 0.11 ng/mL for the active metabolite was observed for one subject on Day 8 at 8 hours post-dose.
Metabolism
- After topical ocular dosing, Netarsudil is metabolized by esterases in the eye.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Netarsudil. Netarsudil was not mutagenic in the Ames test, in the mouse lymphoma test, or in the in vivo rat micronucleus test. Studies to evaluate the effects of Netarsudil on male or female fertility in animals have not been performed.
# Clinical Studies
- Netarsudil 0.02% was evaluated in three randomized and controlled clinical trials, namely AR-13324-CS301 (NCT 02207491, referred to as Study 301), AR-13324-CS302 (NCT 02207621, referred to as Study 302), and AR-13324-CS304 (NCT 02558374, referred to as Study 304), in patients with open-angle glaucoma or ocular hypertension. Studies 301 and 302 enrolled subjects with baseline IOP lower than 27 mmHg and Study 304 enrolled subjects with baseline IOP lower than 30 mmHg. The treatment duration was 3 months in Study 301, 12 months in Study 302, and 6 months in Study 304.
- The three studies demonstrated up to 5 mmHg reductions in IOP for subjects treated with Netarsudil 0.02% once daily in the evening. For patients with baseline IOP < 25 mmHg, the IOP reductions with Netarsudil 0.02% dosed once daily were similar to those with timolol 0.5% dosed twice daily (see Table 1). For patients with baseline IOP equal to or above 25 mmHg, however, Netarsudil 0.02% resulted in smaller mean IOP reductions at the morning time points than timolol 0.5% for study visits on Days 43 and 90; the difference in mean IOP reduction between the two treatment groups was as high as 3 mmHg, favoring timolol.
- This table was produced based on the observed data from all randomized subjects who did not have major protocol violations. The treatment differences and two-sided CIs for comparing Netarsudil QD vs Timolol BID 0.5% were based on Analysis of Covariance (ANCOVA) adjusted for baseline IOP.
# How Supplied
Netarsudil 0.02% (0.2 mg per mL) is supplied sterile in opaque white low density polyethylene bottles and tips with white polypropylene caps.
- 2.5 mL fill in a 4 mL container
- NDC # 70727-497-25
## Storage
- Storage: Store at 2°C to 8°C (36°F to 46°F) until opened. After opening, the product may be kept at 2°C to 25°C (36°F to 77°F) for up to 6 weeks. During shipment, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 14 days.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Handling the Container
- Instruct patients to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to minimize contamination of the solution. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
When to Seek Physician Advice
- Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of Netarsudil.
Use with Contact Lenses
- Advise patients that Netarsudil contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of Netarsudil and may be reinserted 15 minutes following its administration.
Use with Other Ophthalmic Drugs
- Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes between applications.
Missed Dose
- Advise patients that if one dose is missed, treatment should continue with the next dose in the evening.
# Precautions with Alcohol
Alcohol-Netarsudil interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Rhopressa
# Look-Alike Drug Names
There is limited information regarding Netarsudil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Netarsudil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[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
Netarsudil is a Rho kinase inhibitor that is FDA approved for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Common adverse reactions include conjunctival hyperemia, corneal verticillata, instillation site pain, and conjunctival hemorrhage.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Netarsudil 0.02% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
- The recommended dosage is one drop in the affected eye(s) once daily in the evening.
- If one dose is missed, treatment should continue with the next dose in the evening. Twice a day dosing is not well tolerated and is not recommended. If Netarsudil is to be used concomitantly with other topical ophthalmic drug products to lower IOP, administer each drug product at least 5 minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Netarsudil Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Netarsudil 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 Netarsudil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Netarsudil Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Netarsudil Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
- Contact lenses should be removed prior to instillation of Netarsudil and may be reinserted 15 minutes following its administration.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- The most common ocular adverse reaction observed in controlled clinical studies with Netarsudil dosed once daily was conjunctival hyperemia which was reported in 53% of patients. Other common (approximately 20%) ocular adverse reactions reported were: corneal verticillata, instillation site pain, and conjunctival hemorrhage. Instillation site erythema, corneal staining, blurred vision, increased lacrimation, erythema of eyelid, and reduced visual acuity were reported in 5-10% of patients.
Corneal Verticillata
- Corneal verticillata occurred in approximately 20% of the patients in controlled clinical studies. The corneal verticillata seen in Netarsudil-treated patients were first noted at 4 weeks of daily dosing. This reaction did not result in any apparent visual functional changes in patients. Most corneal verticillata resolved upon discontinuation of treatment.
## Postmarketing Experience
There is limited information regarding Netarsudil Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Netarsudil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no available data on Netarsudil use in pregnant women to inform any drug associated risk; however, systemic exposure to Netarsudil from ocular administration is low. Intravenous administration of Netarsudil to pregnant rats and rabbits during organogenesis did not produce adverse embryofetal effects at clinically relevant systemic exposures.
Data (Animal)
- Netarsudil administered daily by intravenous injection to rats during organogenesis caused abortions and embryofetal lethality at doses ≥0.3 mg/kg/day (126-fold the plasma exposure at the recommended human ophthalmic dose [RHOD], based on Cmax). The no-observed-adverse-effect-level (NOAEL) for embryofetal development toxicity was 0.1 mg/kg/day (40-fold the plasma exposure at the RHOD, based on Cmax).
- Netarsudil administered daily by intravenous injection to rabbits during organogenesis caused embryofetal lethality and decreased fetal weight at 5 mg/kg/day (1480-fold the plasma exposure at the RHOD, based on Cmax). Malformations were observed at ≥3 mg/kg/day (1330-fold the plasma exposure at the RHOD, based on Cmax), including thoracogastroschisis, umbilical hernia and absent intermediate lung lobe. The NOAEL for embryofetal development toxicity was 0.5 mg/kg/day (214-fold the plasma exposure at the RHOD, based on Cmax).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Netarsudil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Netarsudil during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of Netarsudil in human milk, the effects on the breastfed infant, or the effects on milk production. However, systemic exposure to Netarsudil following topical ocular administration is low, and it is not known whether measurable levels of Netarsudil would be present in maternal milk following topical ocular administration.
- The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Netarsudil and any potential adverse effects on the breast-fed child from Netarsudil.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
### Gender
There is no FDA guidance on the use of Netarsudil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Netarsudil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Netarsudil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Netarsudil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Netarsudil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Netarsudil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer in the evening.
- When used concomitantly with other ophthalmic products intended to lower intraocular pressure, separate administration of each product by at least 5 minutes.
### Monitoring
- A reduction in intraocular pressure indicates efficacy.
# IV Compatibility
There is limited information regarding the compatibility of Netarsudil and IV administrations.
# Overdosage
There is limited information regarding Netarsudil overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Netarsudil is a rho kinase inhibitor, which is believed to reduce IOP by increasing the outflow of aqueous humor through the trabecular meshwork route. The exact mechanism is unknown.
## Structure
## Pharmacodynamics
There is limited information regarding Netarsudil Pharmacodynamics in the drug label.
## Pharmacokinetics
Absorption
- The systemic exposures of Netarsudil and its active metabolite, AR-13503, were evaluated in 18 healthy subjects after topical ocular administration of Netarsudil 0.02% once daily (one drop bilaterally in the morning) for 8 days. There were no quantifiable plasma concentrations of Netarsudil (lower limit of quantitation (LLOQ) 0.100 ng/mL) post dose on Day 1 and Day 8. Only one plasma concentration at 0.11 ng/mL for the active metabolite was observed for one subject on Day 8 at 8 hours post-dose.
Metabolism
- After topical ocular dosing, Netarsudil is metabolized by esterases in the eye.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Netarsudil. Netarsudil was not mutagenic in the Ames test, in the mouse lymphoma test, or in the in vivo rat micronucleus test. Studies to evaluate the effects of Netarsudil on male or female fertility in animals have not been performed.
# Clinical Studies
- Netarsudil 0.02% was evaluated in three randomized and controlled clinical trials, namely AR-13324-CS301 (NCT 02207491, referred to as Study 301), AR-13324-CS302 (NCT 02207621, referred to as Study 302), and AR-13324-CS304 (NCT 02558374, referred to as Study 304), in patients with open-angle glaucoma or ocular hypertension. Studies 301 and 302 enrolled subjects with baseline IOP lower than 27 mmHg and Study 304 enrolled subjects with baseline IOP lower than 30 mmHg. The treatment duration was 3 months in Study 301, 12 months in Study 302, and 6 months in Study 304.
- The three studies demonstrated up to 5 mmHg reductions in IOP for subjects treated with Netarsudil 0.02% once daily in the evening. For patients with baseline IOP < 25 mmHg, the IOP reductions with Netarsudil 0.02% dosed once daily were similar to those with timolol 0.5% dosed twice daily (see Table 1). For patients with baseline IOP equal to or above 25 mmHg, however, Netarsudil 0.02% resulted in smaller mean IOP reductions at the morning time points than timolol 0.5% for study visits on Days 43 and 90; the difference in mean IOP reduction between the two treatment groups was as high as 3 mmHg, favoring timolol.
- This table was produced based on the observed data from all randomized subjects who did not have major protocol violations. The treatment differences and two-sided CIs for comparing Netarsudil QD vs Timolol BID 0.5% were based on Analysis of Covariance (ANCOVA) adjusted for baseline IOP.
# How Supplied
Netarsudil 0.02% (0.2 mg per mL) is supplied sterile in opaque white low density polyethylene bottles and tips with white polypropylene caps.
- 2.5 mL fill in a 4 mL container
- NDC # 70727-497-25
## Storage
- Storage: Store at 2°C to 8°C (36°F to 46°F) until opened. After opening, the product may be kept at 2°C to 25°C (36°F to 77°F) for up to 6 weeks. During shipment, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 14 days.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Handling the Container
- Instruct patients to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to minimize contamination of the solution. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
When to Seek Physician Advice
- Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of Netarsudil.
Use with Contact Lenses
- Advise patients that Netarsudil contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of Netarsudil and may be reinserted 15 minutes following its administration.
Use with Other Ophthalmic Drugs
- Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes between applications.
Missed Dose
- Advise patients that if one dose is missed, treatment should continue with the next dose in the evening.
# Precautions with Alcohol
Alcohol-Netarsudil interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Rhopressa
# Look-Alike Drug Names
There is limited information regarding Netarsudil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Netarsudil | |
b3bd81832efa2fdfcb8e8b6d89b11038cb288e83 | wikidoc | Netilmicin | Netilmicin
# Overview
Netilmicin is a member of the aminoglycoside family of antibiotics. These antibiotics have the ability to kill a wide variety of bacteria. Netilmicin is not absorbed from the gut and is therefore only given by injection or infusion. It is only used in the treatment of serious infections particularly those resistant to gentamicin.
# Available dosage forms
Available dosage forms include:
- UK: netilmicin (as sulfate):
10 mg/mL (1.5 mL amp)
50 mg/mL (1-mL amp)
100 mg/mL(1-mL,1.5-mL & 2-mL amp)
- 10 mg/mL (1.5 mL amp)
- 50 mg/mL (1-mL amp)
- 100 mg/mL(1-mL,1.5-mL & 2-mL amp)
- France: Nétilmicin sulfate:
Amp 25 mg/1 mL
50 mg/2 mL
100 mg/1 mL
150 mg/1.5 mL
- Amp 25 mg/1 mL
- 50 mg/2 mL
- 100 mg/1 mL
- 150 mg/1.5 mL
# Ingredients for 100 mg/mL vial
FDA approval date : February 28, 1983
# Comparison with drugs of the same therapeutic category
According to the British National Formulary (BNF), netilmicin has similar activity to gentamicin, but less ototoxicity in those needing treatment for longer than 10 days.Netilmicin is active against a number of gentamicin-resistant Gram-negative bacilli but is less active against Ps. Aeuroginosa than gentamicin or tobramycin.
However according to the below-mentioned studies, the above advantages are somehow controversial:
- Netilmicin (Netromycin, Schering-Plough, Netspan- Cipla): In summary, netilmicin has not been demonstrated to have significant advantages over other aminoglycosides (gentamicin, tobramycin, amikacin), and it is more expensive; thus, its potential value is limited. Drug Intelligence & Clinical Pharmacy: Vol. 17, No. 2, pp. 83-91.
- Once-daily gentamicin versus once-daily netilmicin in patients with serious infections—a randomized clinical trial: We conclude that with once-daily dosing no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated. Journal of Antimicrobial Chemotherapy (1994) 33, 823-835.
- Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial: We conclude that with once-daily treatment no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated. Clin Otolaryngol Allied Sci. 1995 Apr;20(2):118-23.
- Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients: We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin. Arch Intern Med. 1986 Dec;146(12):2329-34.
- Daily single-dose aminoglycoside administration. Therapeutic and economic benefits: Animal studies have shown that dosing aminoglycosides once daily is more efficient and less nephrotoxic than the conventional multiple daily dosing regimens. Netilmicin and amikacin are the drugs most often used in clinical trials of once-daily dosing regimens. Ugeskr Laeger. 1993 May 10;155(19):1436-41.
- Comparison of Netilmicin with Gentamicin in the Therapy of Experimental Escherichia coli Meningitis: Because of its reduced toxicity and greater in vivo bactericidal activity, netilmicin may offer an advantage over gentamicin in the therapy of gram-negative bacillary meningitis. Antimicrob Agents Chemother. 1978 June; 13(6): 899-904.
- A comparison of netilmicin and gentamicin in the treatment of pelvic infections: The microbacteria isolated by standard culture techniques before therapy revealed Neisseria gonorrhoeae in 69% and 51% of the netilmicin and gentamicin groups, respectively; anaerobic organisms were cultured in about 75% of each group. Obstetrics & Gynecology 1979;54:554-557.
- Netilmicin: a review of toxicity in laboratory animals: Presently available data suggest that netilmicin offers distinct advantages over older aminoglycosides. Final conclusions must await prospective randomized double-blind trials in man. J Int Med Res. 1978;6(4):286-99.
- Nonparallel nephrotoxicity dose-response curves of aminoglycosides: Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Antimicrob Agents Chemother. 1981 June; 19(6): 1024–1028.
- Comparative ototoxicity of netilmicin, gentamicin, and tobramycin in cats: Under the conditions of this study, at least a twofold (vestibular) to fourfold (cochlear) relative safety margin for ototoxicity was established in favor of netilmicin over tobramycin and gentamicin. Toxicol Appl Pharmacol. 1985 Mar 15;77(3):479-89.
- Comparison of Netilmicin and Gentamicin Pharmacokinetics in Humans: In a crossover study, single doses of netilmicin and gentamicin were administered intramuscularly, each at 1.0 and 2.5 mg/kg. No significant differences were observed between the two drugs in disposition half-life, rate of distribution and elimination, area under the serum concentration-time curve, urinary excretion, total body clearance, and renal clearance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1980, p. 184-187. Schering-Plough Research Division, Bloomfield, New Jersey 07003. | Netilmicin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Netilmicin is a member of the aminoglycoside family of antibiotics. These antibiotics have the ability to kill a wide variety of bacteria. Netilmicin is not absorbed from the gut and is therefore only given by injection or infusion. It is only used in the treatment of serious infections particularly those resistant to gentamicin.
# Available dosage forms
Available dosage forms include:
- UK: netilmicin (as sulfate):
10 mg/mL (1.5 mL amp)
50 mg/mL (1-mL amp)
100 mg/mL(1-mL,1.5-mL & 2-mL amp)
- 10 mg/mL (1.5 mL amp)
- 50 mg/mL (1-mL amp)
- 100 mg/mL(1-mL,1.5-mL & 2-mL amp)
- France: Nétilmicin sulfate:
Amp 25 mg/1 mL
50 mg/2 mL
100 mg/1 mL
150 mg/1.5 mL
- Amp 25 mg/1 mL
- 50 mg/2 mL
- 100 mg/1 mL
- 150 mg/1.5 mL
# Ingredients for 100 mg/mL vial
FDA approval date : February 28, 1983
# Comparison with drugs of the same therapeutic category
According to the British National Formulary (BNF), netilmicin has similar activity to gentamicin, but less ototoxicity in those needing treatment for longer than 10 days.Netilmicin is active against a number of gentamicin-resistant Gram-negative bacilli but is less active against Ps. Aeuroginosa than gentamicin or tobramycin.
However according to the below-mentioned studies, the above advantages are somehow controversial:
- Netilmicin (Netromycin, Schering-Plough, Netspan- Cipla): In summary, netilmicin has not been demonstrated to have significant advantages over other aminoglycosides (gentamicin, tobramycin, amikacin), and it is more expensive; thus, its potential value is limited. Drug Intelligence & Clinical Pharmacy: Vol. 17, No. 2, pp. 83-91.
- Once-daily gentamicin versus once-daily netilmicin in patients with serious infections—a randomized clinical trial: We conclude that with once-daily dosing no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated. Journal of Antimicrobial Chemotherapy (1994) 33, 823-835.
- Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial: We conclude that with once-daily treatment no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated. Clin Otolaryngol Allied Sci. 1995 Apr;20(2):118-23.
- Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients: We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin. Arch Intern Med. 1986 Dec;146(12):2329-34.
- Daily single-dose aminoglycoside administration. Therapeutic and economic benefits: Animal studies have shown that dosing aminoglycosides once daily is more efficient and less nephrotoxic than the conventional multiple daily dosing regimens. Netilmicin and amikacin are the drugs most often used in clinical trials of once-daily dosing regimens. Ugeskr Laeger. 1993 May 10;155(19):1436-41.
- Comparison of Netilmicin with Gentamicin in the Therapy of Experimental Escherichia coli Meningitis: Because of its reduced toxicity and greater in vivo bactericidal activity, netilmicin may offer an advantage over gentamicin in the therapy of gram-negative bacillary meningitis. Antimicrob Agents Chemother. 1978 June; 13(6): 899-904.
- A comparison of netilmicin and gentamicin in the treatment of pelvic infections: The microbacteria isolated by standard culture techniques before therapy revealed Neisseria gonorrhoeae in 69% and 51% of the netilmicin and gentamicin groups, respectively; anaerobic organisms were cultured in about 75% of each group. Obstetrics & Gynecology 1979;54:554-557.
- Netilmicin: a review of toxicity in laboratory animals: Presently available data suggest that netilmicin offers distinct advantages over older aminoglycosides. Final conclusions must await prospective randomized double-blind trials in man. J Int Med Res. 1978;6(4):286-99.
- Nonparallel nephrotoxicity dose-response curves of aminoglycosides: Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Antimicrob Agents Chemother. 1981 June; 19(6): 1024–1028.
- Comparative ototoxicity of netilmicin, gentamicin, and tobramycin in cats: Under the conditions of this study, at least a twofold (vestibular) to fourfold (cochlear) relative safety margin for ototoxicity was established in favor of netilmicin over tobramycin and gentamicin. Toxicol Appl Pharmacol. 1985 Mar 15;77(3):479-89.
- Comparison of Netilmicin and Gentamicin Pharmacokinetics in Humans: In a crossover study, single doses of netilmicin and gentamicin were administered intramuscularly, each at 1.0 and 2.5 mg/kg. No significant differences were observed between the two drugs in disposition half-life, rate of distribution and elimination, area under the serum concentration-time curve, urinary excretion, total body clearance, and renal clearance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1980, p. 184-187. Schering-Plough Research Division, Bloomfield, New Jersey 07003. | https://www.wikidoc.org/index.php/Netilmicin | |
47cb801b1f9443ad18cb5357e55b6677ae3f9546 | wikidoc | Oprelvekin | Oprelvekin
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# Black Box Warning
# Overview
Oprelvekin is a thrombopoietic growth factor that is FDA approved for the prophylaxis of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, candidiasis, nausea, oral candidiasis, vomiting, dizziness, fatigue, headache, blurred vision, conjunctival hyperemia and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Neumega in adults without severe renal impairment is 50 mcg/kg given once daily. Neumega should be administered subcutaneously as a single injection in either the abdomen, thigh, or hip (or upper arm if not self-injecting). A safe and effective dose has not been established in children.
- The recommended dose of Neumega in adults with severe renal impairment (creatinine clearance <30 mL/min) is 25 mcg/kg. An estimate of the patient's creatinine clearance (CLcr) in mL/min is required. CLcr in mL/min may be estimated from a spot serum creatinine (mg/dL) determination using the following formula:
- Dosing should be initiated six to 24 hours after the completion of chemotherapy. Platelet counts should be monitored periodically to assess the optimal duration of therapy. Dosing should be continued until the post-nadir platelet count is ≥50,000/μL. In controlled clinical trials, doses were administered in courses of 10 to 21 days. Dosing beyond 21 days per treatment course is not recommended.
- Treatment with Neumega should be discontinued at least two days before starting the next planned cycle of chemotherapy.
### Preparation of Neumega
- Neumega is a sterile, white, preservative-free, lyophilized powder for subcutaneous injection upon reconstitution. Reconstitute the Neumega 5 mg vial using the 1.0 mL of Sterile Water for Injection, USP (without preservative) contained in the pre-filled syringe included in the kit. The reconstituted Neumega solution is clear, colorless, isotonic, with a pH of 7.0, and contains 5 mg/mL of Neumega. Any unused portion of the reconstituted Neumega solution should be discarded.
- During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled. Excessive or vigorous agitation should be avoided.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is present or the solution is discolored, the vial should not be used.
- Administer Neumega within 3 hours following reconstitution. Reconstituted Neumega may be refrigerated or maintained at room temperature . Do not freeze or shake the reconstituted solution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oprelvekin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oprelvekin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Oprelvekin 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 Oprelvekin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oprelvekin in pediatric patients.
# Contraindications
- Oprelvekin is contraindicated in patients with a history of hypersensitivity to Oprelvekin or any component of the product.
# Warnings
### Allergic Reactions Including Anaphylaxis
- In the post-marketing setting, Oprelvekin has caused allergic or hypersensitivity reactions, including anaphylaxis. The administration of Oprelvekin should be attended by appropriate precautions in case allergic reactions occur. In addition, patients should be counseled about the symptoms for which they should seek medical attention. Signs and symptoms reported included edema of the face, tongue, or larynx; shortness of breath; wheezing; chest pain; hypotension (including shock); dysarthria; loss of consciousness; mental status changes; rash; urticaria; flushing and fever. Reactions occurred after the first dose or subsequent doses of Oprelvekin. Administration of Oprelvekin should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction.
### Increased Toxicity Following Myeloablative Therapy
- Oprelvekin is not indicated following myeloablative chemotherapy. In a randomized, placebo-controlled Phase 2 study, the effectiveness of Oprelvekin was not demonstrated. In this study, a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia was observed in patients receiving Oprelvekin as compared to placebo.
- The following severe or fatal adverse reactions have been reported in post-marketing use in patients who received Oprelvekin following bone marrow transplantation: fluid retention or overload (eg, facial edema, pulmonary edema), capillary leak syndrome, pleural and pericardial effusion, papilledema and renal failure.
### Fluid Retention
- Oprelvekin is known to cause serious fluid retention that can result in peripheral edema, dyspnea on exertion, pulmonary edema, capillary leak syndrome, atrial arrhythmias, and exacerbation of pre-existing pleural effusions. Severe fluid retention, some cases resulting in death, was reported following recent bone marrow transplantation in patients who have received Oprelvekin. Oprelvekin is not indicated following myeloablative chemotherapy. It should be used with caution in patients with clinically evident congestive heart failure, patients who may be susceptible to developing congestive heart failure, patients receiving aggressive hydration, patients with a history of heart failure who are well-compensated and receiving appropriate medical therapy, and patients who may develop fluid retention as a result of associated medical conditions or whose medical condition may be exacerbated by fluid retention.
- Fluid retention is reversible within several days following discontinuation of Oprelvekin During dosing with Oprelvekin fluid balance should be monitored and appropriate medical management is advised.
- Close monitoring of fluid and electrolyte status should be performed in patients receiving chronic diuretic therapy. Sudden deaths have occurred in oprelvekin-treated patients receiving chronic diuretic therapy and ifosfamide who developed severe hypokalemia.
- Pre-existing fluid collections, including pericardial effusions or ascites, should be monitored. Drainage should be considered if medically indicated.
### Dilutional Anemia
- Moderate decreases in hemoglobin concentration, hematocrit, and red blood cell count (~10% to 15%) without a decrease in red blood cell mass have been observed. These changes are predominantly due to an increase in plasma volume (dilutional anemia) that is primarily related to renal sodium and water retention. The decrease in hemoglobin concentration typically begins within three to five days of the initiation of Oprelvekin, and is reversible over approximately a week following discontinuation of Oprelvekin.
### Cardiovascular Events
- Oprelvekin use is associated with cardiovascular events including arrhythmias and pulmonary edema. Cardiac arrest has been reported, but the causal relationship to Oprelvekin is uncertain. Use with caution in patients with a history of atrial arrhythmias, and only after consideration of the potential risks in relation to anticipated benefit. In clinical trials, cardiac events including atrial arrhythmias (atrial fibrillation or atrial flutter) occurred in 15% (23/157) of patients treated with Oprelvekin at doses of 50 mcg/kg. Arrhythmias were usually brief in duration; conversion to sinus rhythm typically occurred spontaneously or after rate-control drug therapy. Approximately one-half (11/24) of the patients who were rechallenged had recurrent atrial arrhythmias. Clinical sequelae, including stroke, have been reported in patients who experienced atrial arrhythmias while receiving Oprelvekin.
- The mechanism for induction of arrhythmias is not known. Oprelvekin was not directly arrhythmogenic in animal models. In some patients, development of atrial arrhythmias may be due to increased plasma volume associated with fluid retention.
- In the post-marketing setting, ventricular arrhythmias have been reported, generally occurring within two to seven days of initiation of treatment.
### Nervous System Events
- Stroke has been reported in the setting of patients who develop atrial fibrillation/flutter while receiving Oprelvekin. Patients with a history of stroke or transient ischemic attack may also be at increased risk for these events.
### Papilledema
- Papilledema has been reported in 2% (10/405) of patients receiving Oprelvekin in clinical trials following repeated cycles of exposure. The incidence was higher, 16% (7/43) in children than in adults, 1% (3/362). Nonhuman primates treated with Oprelvekin at a dose of 1,000 mcg/kg SC once daily for four to 13 weeks developed papilledema that was not associated with inflammation or any other histologic abnormality and was reversible after dosing was discontinued. Oprelvekin should be used with caution in patients with pre-existing papilledema, or with tumors involving the central nervous system since it is possible that papilledema could worsen or develop during treatment. Changes in visual acuity and/or visual field defects ranging from blurred vision to blindness can occur in patients with papilledema taking Oprelvekin.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- Three hundred twenty-four subjects, with ages ranging from eight months to 75 years, have been exposed to Oprelvekin treatment in clinical studies. Subjects have received up to six (eight in pediatric patients) sequential courses of Oprelvekin treatment, with each course lasting from one to 28 days. Apart from the sequelae of the underlying malignancy or cytotoxic chemotherapy, most adverse events were mild or moderate in severity and reversible after discontinuation of Oprelvekin dosing.
- In general, the incidence and type of adverse events were similar between Oprelvekin 50 mcg/kg and placebo groups. The most frequently reported serious adverse events were neutropenic fever, syncope, atrial fibrillation, fever and pneumonia. The most commonly reported adverse events were edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, and pleural effusions. The most frequently reported adverse reactions resulting in clinical intervention (eg, discontinuation of Oprelvekin, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were atrial arrhythmias, syncope, dyspnea, congestive heart failure, and pulmonary edema. Selected adverse events that occurred in ≥10% of Oprelvekin-treated patients are listed in TABLE 3.
- The following adverse events also occurred more frequently in cancer patients receiving Oprelvekin than in those receiving placebo: blurred vision, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, and eye hemorrhage. Other than a higher incidence of severe asthenia in Oprelvekin treated patients (10 in Oprelvekin patients versus two in placebo patients), the incidence of severe or life-threatening adverse events was comparable in the Oprelvekin and placebo treatment groups.
- Two patients with cancer treated with Oprelvekin experienced sudden death that the investigator considered possibly or probably related to Oprelvekin Both deaths occurred in patients with severe hypokalemia (<3.0 mEq/L) who had received high doses of ifosfamide and were receiving daily doses of a diuretic.
- Other serious events associated with Oprelvekin were papilledema and cardiovascular events including atrial arrhythmias and stroke. In addition, cardiomegaly was reported in children.
- The following adverse events, occurring in ≥10% of patients, were observed at equal or greater frequency in placebo-treated patients: asthenia, pain, chills, abdominal pain, infection, anorexia, constipation, dyspepsia, ecchymosis, myalgia, bone pain, nervousness, and alopecia. The incidence of fever, neutropenic fever, flu-like symptoms, thrombocytosis, thrombotic events, the average number of units of red blood cells transfused per patient, and the duration of neutropenia <500 cells/μL were similar in the Oprelvekin 50 mcg/kg and placebo groups.
### Immunogenicity
- In clinical studies that evaluated the immunogenicity of Oprelvekin, two of 181 patients (1%) developed antibodies to Oprelvekin. In one of these two patients, neutralizing antibodies to Oprelvekin were detected in an unvalidated assay. The clinical relevance of the presence of these antibodies is unknown. In the post-marketing setting, cases of allergic reactions, including anaphylaxis have been reported. The presence of antibodies to Oprelvekin was not assessed in these patients.
- The data reflect the percentage of patients whose test results were considered positive for antibodies to Oprelvekin and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to Oprelvekin with incidence of antibodies to other products may be misleading.
### Abnormal Laboratory Values
- The most common laboratory abnormality reported in patients in clinical trials was a decrease in hemoglobin concentration predominantly as a result of expansion of the plasma volume. The increase in plasma volume is also associated with a decrease in the serum concentration of albumin and several other proteins (eg, transferrin and gamma globulins). A parallel decrease in calcium without clinical effects has been documented.
- After daily SC injections, treatment with Oprelvekin resulted in a two-fold increase in plasma fibrinogen. Other acute-phase proteins also increased. These protein levels returned to normal after dosing with Oprelvekin was discontinued. Von Willebrand factor (vWF) concentrations increased with a normal multimer pattern in healthy subjects receiving Oprelvekin.
## Postmarketing Experience
- 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reactions, (2) frequency of reporting, or (3) strength of causal connection to Oprelvekin.
- The following adverse reactions have been reported during the post-marketing use of Oprelvekin:
allergic reactions and anaphylaxis/anaphylactoid reactions
papilledema
visual disturbances ranging from blurred vision to blindness
-ptic neuropathy
ventricular arrhythmias
capillary leak syndrome
renal failure
injection site reactions (dermatitis, pain, and discoloration)
- allergic reactions and anaphylaxis/anaphylactoid reactions
- papilledema
- visual disturbances ranging from blurred vision to blindness
- optic neuropathy
- ventricular arrhythmias
- capillary leak syndrome
- renal failure
- injection site reactions (dermatitis, pain, and discoloration)
# Drug Interactions
- Most patients in trials evaluating Oprelvekin were treated concomitantly with filgrastim (G-CSF) with no adverse effect of Oprelvekin on the activity of G-CSF. No information is available on the clinical use of sargramostim (GM-CSF) with Oprelvekin in human subjects. However, in a study in nonhuman primates in which Oprelvekin and GM-CSF were coadministered, there were no adverse interactions between Oprelvekin and GM-CSF and no apparent difference in the pharmacokinetic profile of Oprelvekin.
- Drug interactions between Oprelvekin and other drugs have not been fully evaluated. Based on in vitro and nonclinical in vivo evaluations of Oprelvekin, drug-drug interactions with known substrates of P450 enzymes would not be predicted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Oprelvekin has been shown to have embryocidal effects in pregnant rats and rabbits when given in doses of 0.2 to 20 times the human dose. There are no adequate and well-controlled studies of Oprelvekin in pregnant women. Oprelvekin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oprelvekin has been tested in studies of fertility, early embryonic development, and pre- and postnatal development in rats and in studies of organogenesis (teratogenicity) in rats and rabbits. Parental toxicity has been observed when Oprelvekin is given at doses of two to 20 times the human dose (≥100 mcg/kg/day) in the rat and at 0.02 to 2.0 times the human dose (≥1 mcg/kg/day) in the rabbit. Findings in pregnant rats consisted of transient hypoactivity and dyspnea after administration (maternal toxicity), as well as prolonged estrus cycle, increased early embryonic deaths and decreased numbers of live fetuses. In addition, low fetal body weights and a reduced number of ossified sacral and caudal vertebrae (ie, retarded fetal development) occurred in rats at 20 times the human dose. Findings in pregnant rabbits consisted of decreased fecal/urine eliminations (the only toxicity noted at 1 mcg/kg/day in dams) as well as decreased food consumption, body weight loss, abortion, increased embryonic and fetal deaths, and decreased numbers of live fetuses. No teratogenic effects of Oprelvekin were observed in rabbits at doses up to 0.6 times the human dose (30 mcg/kg/day).
- Adverse effects in the first generation offspring of rats given Oprelvekin at maternally toxic doses ≥2 times the human dose (≥100 mcg/kg/day) during both gestation and lactation included increased newborn mortality, decreased viability index on day 4 of lactation, and decreased body weights during lactation. In rats given 20 times the human dose (1000 mcg/kg/day) during both gestation and lactation, maternal toxicity and growth retardation of the first generation offspring resulted in an increased rate of fetal death of the second generation offspring.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oprelvekin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oprelvekin during labor and delivery.
### Nursing Mothers
It is not known if Oprelvekin 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 Oprelvekin, a decision should be made whether to discontinue nursing or to discontinue Oprelvekin, taking into account the importance of the drug to the mother.
### Pediatric Use
A safe and effective dose of Oprelvekin has not been established in children. In a Phase 1, single arm, dose-escalation study, 43 pediatric patients were treated with Oprelvekin at doses ranging from 25 to 125 mcg/kg/day following ICE chemotherapy. All patients required platelet transfusions and the lack of a comparator arm made the study design inadequate to assess efficacy. The projected effective dose (based on comparable AUC observed for the effective dose in healthy adults) in children appears to exceed the maximum tolerated pediatric dose of 50 mcg/kg/day. Papilledema was dose-limiting and occurred in 16% of children.
- The most common adverse events seen in pediatric studies included tachycardia (84%), conjunctival injection (57%), radiographic and echocardiographic evidence of cardiomegaly (21%) and periosteal changes (11%). These events occurred at a higher frequency in children than adults. The incidence of other adverse events was generally similar to those observed using Oprelvekin at a dose of 50 mcg/kg in the randomized studies in adults receiving chemotherapy.
- Studies in animals were predictive of the effect of Oprelvekin on developing bone in children. In growing rodents treated with 100, 300, or 1000 mcg/kg/day for a minimum of 28 days, thickening of femoral and tibial growth plates was noted, which did not completely resolve after a 28-day non-treatment period. In a nonhuman primate toxicology study of Oprelvekin animals treated for two to 13 weeks at doses of 10 to 1000 mcg/kg showed partially reversible joint capsule and tendon fibrosis and periosteal hyperostosis. An asymptomatic, laminated periosteal reaction in the diaphyses of the femur, tibia, and fibula has been observed in one patient during pediatric studies involving multiple courses of Oprelvekin treatment. The relationship of these findings to treatment with Oprelvekin is unclear. No studies have been performed to assess the long-term effects of Oprelvekin on growth and development.
### Geriatic Use
- Clinical studies of Oprelvekin did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger subjects. In a controlled study, 141 adult patients with various nonmyeloid malignancies were randomized (2:1) to Oprelvekin 50 mcg/kg/day or placebo administered subcutaneously for 14 days after chemotherapy was completed. Among 106 patients less than 65 years of age, the proportion who did not require platelet transfusions was higher among Oprelvekin-treated patients (36.5% vs. 14.3%). Among 35 patients greater than or equal to 65 years of age, the proportion who did not require platelet transfusions was similar between treatment groups (32% vs. 30%, Oprelvekin and placebo, respectively).
### Gender
There is no FDA guidance on the use of Oprelvekin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oprelvekin with respect to specific racial populations.
### Renal Impairment
- Oprelvekin is eliminated primarily by the kidneys. The pharmacokinetics of Oprelvekin were studied in subjects with varying degrees of renal dysfunction. AUC0-∞, Cmax, and absolute bioavailability were significantly increased in subjects with severe renal impairment (creatinine clearance < 30 mL/min). There were no significant changes in the pharmacokinetic parameters in subjects with mild or moderate impairment. A significant decrease in the hemoglobin concentration was noted on Day 2 after a single dose of Oprelvekin in subjects with all degrees of renal impairment. By Day 14, the hemoglobin was decreased only in patients with severe renal impairment. Fluid retention associated with Oprelvekin treatment has not been studied in patients with renal impairment, but fluid balance should be carefully monitored in these patients
### Hepatic Impairment
There is no FDA guidance on the use of Oprelvekin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oprelvekin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oprelvekin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Oprelvekin Administration in the drug label.
### Monitoring
There is limited information regarding Oprelvekin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oprelvekin and IV administrations.
# Overdosage
- Doses of Oprelvekin above 125 mcg/kg have not been administered to humans. While clinical experience is limited, doses of Oprelvekin greater than 50 mcg/kg may be associated with an increased incidence of cardiovascular events in adult patients. If an overdose of Oprelvekin is administered, Oprelvekin should be discontinued, and the patient should be closely observed for signs of toxicity. Reinstitution of Oprelvekin therapy should be based upon individual patient factors (eg, evidence of toxicity, continued need for therapy).
# Pharmacology
## Mechanism of Action
- The primary hematopoietic activity of Oprelvekin is stimulation of megakaryocytopoiesis and thrombopoiesis. Oprelvekin has shown potent thrombopoietic activity in animal models of compromised hematopoiesis, including moderately to severely myelosuppressed mice and nonhuman primates. In these models, Oprelvekin improved platelet nadirs and accelerated platelet recoveries compared to controls.
- IL-11 has also been shown to have non-hematopoietic activities in animals including the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis, inhibition of pro-inflammatory cytokine production by macrophages, and the stimulation of osteoclastogenesis and neurogenesis. Non-hematopoietic pathologic changes observed in animals include fibrosis of tendons and joint capsules, periosteal thickening, papilledema, and embryotoxicity.
- IL-11 is produced by bone marrow stromal cells and is part of the cytokine family that shares the gp130 signal transducer. Primary osteoblasts and mature osteoclasts express mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Both bone-forming and bone-resorbing cells are potential targets of IL-11. (1)
## Structure
There is limited information regarding Oprelvekin Structure in the drug label.
## Pharmacodynamics
- In a study in which Oprelvekin was administered to non-myelosuppressed cancer patients, daily subcutaneous dosing for 14 days with Oprelvekin increased the platelet count in a dose-dependent manner. Platelet counts began to increase relative to baseline between five and nine days after the start of dosing with Oprelvekin After cessation of treatment, platelet counts continued to increase for up to seven days then returned toward baseline within 14 days. No change in platelet reactivity as measured by platelet activation in response to ADP, and platelet aggregation in response to ADP, epinephrine, collagen, ristocetin and arachidonic acid has been observed in association with Oprelvekin treatment.
- In a randomized, double-blind, placebo-controlled study in normal volunteers, subjects receiving Oprelvekin had a mean increase in plasma volume of >20%, and all subjects receiving Oprelvekin had at least a 10% increase in plasma volume. Red blood cell volume decreased similarly (due to repeated phlebotomy) in the Oprelvekin and placebo groups. As a result, whole blood volume increased approximately 10% and hemoglobin concentration decreased approximately 10% in subjects receiving Oprelvekin compared with subjects receiving placebo. Mean 24 hour sodium excretion decreased, and potassium excretion did not increase, in subjects receiving Oprelvekin compared with subjects receiving placebo.
## Pharmacokinetics
- The pharmacokinetics of Oprelvekin have been evaluated in studies of healthy, adult subjects and cancer patients receiving chemotherapy. In a study in which a single 50 mcg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 ± 5.4 ng/mL (mean ± S.D.) was reached at 3.2 ± 2.4 hrs (Tmax) following dosing. The terminal half-life was 6.9 ± 1.7 hrs. In a second study in which single 75 mcg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Oprelvekin was >80%. In a study in which multiple, subcutaneous doses of both 25 and 50 mcg/kg were administered to cancer patients receiving chemotherapy, Oprelvekin did not accumulate and clearance of Oprelvekin was not impaired following multiple doses.
- Oprelvekin was administered at doses ranging from 25 to 125 mcg/kg/day to 43 pediatric patients (ages 8 months to 18 years) and 1 adult patient receiving ICE (ifosfamide, carboplatin, etoposide) chemotherapy. Analysis of data from 40 pediatric patients showed that Cmax, Tmax, and terminal half-life were comparable to that in adults. The mean area under the concentration-time curve (AUC) for pediatric patients (8 months to 18 years), receiving 50 mcg/kg was approximately half that achieved in healthy adults receiving 50 mcg/kg. Available data suggest that clearance of Oprelvekin decreases with increasing age in children.
- Oprelvekin was administered as a single 50 mcg/kg dose subcutaneously to 48 healthy male and female adults aged 20 to 79 years; 18 subjects were aged 65 or older. The pharmacokinetic profile of Oprelvekin was similar between those 65 years of age or older and those younger than 65 years.
- In preclinical trials in rats, radiolabeled Oprelvekin was rapidly cleared from the serum and distributed to highly perfused organs. The kidney was the primary route of elimination. The amount of intact Oprelvekin in urine was low, indicating that the molecule was metabolized before excretion. In a clinical study, a single dose of Oprelvekin was administered to subjects with severely impaired renal function (creatinine clearance <30 mL/min). The mean ± S.D. values for Cmax and AUC were 30.8 ± 8.6 ng/mL and 373 ± 106 ng*hr/mL, respectively. When compared with control subjects in this study with normal renal function, the mean Cmax was 2.2 fold higher and the mean AUC was 2.6 fold (95% confidence interval, 1.7%-3.8%) higher in the subjects with severe renal impairment. In the subjects with severe renal impairment, clearance was approximately 40% of the value seen in subjects with normal renal function. The average terminal half-life was similar in subjects with severe renal impairment and those with normal renal function.
- A second clinical study of 24 subjects with varying degrees of renal function was also performed and confirmed the results observed in the first study. Single 50 mcg/kg subcutaneous and intravenous doses were administered in a randomized fashion. As the degree of renal impairment increased, the Oprelvekin AUC increased, although half-life remained unchanged. In the six patients with severe impairment, the mean ± S.D. Cmax and AUC were 23.6 ± 6.7 ng/mL and 373 ± 55.2 ng*hr/mL, respectively, compared with 13.1 ± 3.8 ng/mL and 195 ± 49.3 ng*hr/mL, respectively, in the six subjects with normal renal function. A comparable increase in exposure was observed after intravenous administration of Oprelvekin.
- The pharmacokinetic studies suggest that overall exposure to oprelvekin increases as renal function decreases, indicating that a 50% dose reduction of Oprelvekin is warranted for patients with severe renal impairment. No dosage reduction is required for smaller changes in renal function.
## Nonclinical Toxicology
There is limited information regarding Oprelvekin Nonclinical Toxicology in the drug label.
# Clinical Studies
Two randomized, double-blind, placebo-controlled trials in adults studied Oprelvekin for the prevention of severe thrombocytopenia following single or repeated sequential cycles of various myelosuppressive chemotherapy regimens.
### Study in Patients with Prior Chemotherapy-Induced Thrombocytopenia
- One study evaluated the effectiveness of Oprelvekin in eliminating the need for platelet transfusions in patients who had recovered from an episode of severe chemotherapy-induced thrombocytopenia (defined as a platelet count ≤20,000/μL), and were to receive one additional cycle of the same chemotherapy without dose reduction. Patients had various underlying non-myeloid malignancies, and were undergoing dose-intensive chemotherapy with a variety of regimens. Patients were randomized to receive Oprelvekin at a dose of 25 mcg/kg or 50 mcg/kg, or placebo. The primary endpoint was whether the patient required one or more platelet transfusions in the subsequent chemotherapy cycle. Ninety-three patients were randomized. Five patients withdrew from the study prior to receiving the study drug. As a result, eighty-eight patients were included in a modified intent-to-treat analysis. The results for the Oprelvekin 50 mcg/kg and placebo groups are summarized in TABLE 1. The placebo group includes one patient who underwent chemotherapy dose reduction and who avoided platelet transfusions.
- In the primary efficacy analysis, more patients avoided platelet transfusion in the Oprelvekin 50 mcg/kg arm than in the placebo arm (p = 0.04, Fisher's Exact test, 2-tailed). The difference in the proportion of patients avoiding platelet transfusions in the Oprelvekin 50 mcg/kg and placebo groups was 21% (95% confidence interval, 2%-40%). The results observed in patients receiving 25 mcg/kg of Oprelvekin were intermediate between those of the placebo and the 50 mcg/kg groups.
### Study in Patients Receiving Dose-Intensive Chemotherapy
- A second study evaluated the effectiveness of Oprelvekin in eliminating platelet transfusions over two dose-intensive chemotherapy cycles in breast cancer patients who had not previously experienced severe chemotherapy-induced thrombocytopenia. All patients received the same chemotherapy regimen (cyclophosphamide 3,200 mg/m2 and doxorubicin 75 mg/m2). All patients received concomitant filgrastim (G-CSF) in all cycles. The patients were stratified by whether or not they had received prior chemotherapy, and randomized to receive Oprelvekin 50 mcg/kg or placebo. The primary endpoint was whether or not a patient required one or more platelet transfusions in the two study cycles. Seventy-seven patients were randomized. Thirteen patients failed to complete both study cycles—eight of these had insufficient data to be evaluated for the primary endpoint. The results of this trial are summarized in TABLE 2.
- This study showed a trend in favor of Oprelvekin, particularly in the subgroup of patients with prior chemotherapy. Open-label treatment with Oprelvekin has been continued for up to four consecutive chemotherapy cycles without evidence of any adverse effect on the rate of neutrophil recovery or red blood cell transfusion requirements. Some patients continued to maintain platelet nadirs >20,000/μL for at least four sequential cycles of chemotherapy without the need for transfusions, chemotherapy dose reduction, or changes in treatment schedules.
- Platelet activation studies done on a limited number of patients showed no evidence of abnormal spontaneous platelet activation, or an abnormal response to ADP. In an unblinded, retrospective analysis of the two placebo-controlled studies, 19 of 69 patients (28%) receiving Oprelvekin 50 mcg/kg and 34 of 67 patients (51%) receiving placebo reported at least one hemorrhagic adverse event which involved bleeding.
# How Supplied
There is limited information regarding Oprelvekin How Supplied in the drug label.
## Storage
There is limited information regarding Oprelvekin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oprelvekin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Oprelvekin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Neumega
# Look-Alike Drug Names
There is limited information regarding Oprelvekin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oprelvekin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Black Box Warning
# Overview
Oprelvekin is a thrombopoietic growth factor that is FDA approved for the prophylaxis of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, candidiasis, nausea, oral candidiasis, vomiting, dizziness, fatigue, headache, blurred vision, conjunctival hyperemia and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Neumega in adults without severe renal impairment is 50 mcg/kg given once daily. Neumega should be administered subcutaneously as a single injection in either the abdomen, thigh, or hip (or upper arm if not self-injecting). A safe and effective dose has not been established in children.
- The recommended dose of Neumega in adults with severe renal impairment (creatinine clearance <30 mL/min) is 25 mcg/kg. An estimate of the patient's creatinine clearance (CLcr) in mL/min is required. CLcr in mL/min may be estimated from a spot serum creatinine (mg/dL) determination using the following formula:
- Dosing should be initiated six to 24 hours after the completion of chemotherapy. Platelet counts should be monitored periodically to assess the optimal duration of therapy. Dosing should be continued until the post-nadir platelet count is ≥50,000/μL. In controlled clinical trials, doses were administered in courses of 10 to 21 days. Dosing beyond 21 days per treatment course is not recommended.
- Treatment with Neumega should be discontinued at least two days before starting the next planned cycle of chemotherapy.
### Preparation of Neumega
- Neumega is a sterile, white, preservative-free, lyophilized powder for subcutaneous injection upon reconstitution. Reconstitute the Neumega 5 mg vial using the 1.0 mL of Sterile Water for Injection, USP (without preservative) contained in the pre-filled syringe included in the kit. The reconstituted Neumega solution is clear, colorless, isotonic, with a pH of 7.0, and contains 5 mg/mL of Neumega. Any unused portion of the reconstituted Neumega solution should be discarded.
- During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled. Excessive or vigorous agitation should be avoided.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is present or the solution is discolored, the vial should not be used.
- Administer Neumega within 3 hours following reconstitution. Reconstituted Neumega may be refrigerated [2°C to 8°C (36°F to 46°F)] or maintained at room temperature [up to 25°C (77°F)]. Do not freeze or shake the reconstituted solution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oprelvekin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oprelvekin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Oprelvekin 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 Oprelvekin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oprelvekin in pediatric patients.
# Contraindications
- Oprelvekin is contraindicated in patients with a history of hypersensitivity to Oprelvekin or any component of the product.
# Warnings
### Allergic Reactions Including Anaphylaxis
- In the post-marketing setting, Oprelvekin has caused allergic or hypersensitivity reactions, including anaphylaxis. The administration of Oprelvekin should be attended by appropriate precautions in case allergic reactions occur. In addition, patients should be counseled about the symptoms for which they should seek medical attention. Signs and symptoms reported included edema of the face, tongue, or larynx; shortness of breath; wheezing; chest pain; hypotension (including shock); dysarthria; loss of consciousness; mental status changes; rash; urticaria; flushing and fever. Reactions occurred after the first dose or subsequent doses of Oprelvekin. Administration of Oprelvekin should be permanently discontinued in any patient who develops an allergic or hypersensitivity reaction.
### Increased Toxicity Following Myeloablative Therapy
- Oprelvekin is not indicated following myeloablative chemotherapy. In a randomized, placebo-controlled Phase 2 study, the effectiveness of Oprelvekin was not demonstrated. In this study, a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia was observed in patients receiving Oprelvekin as compared to placebo.
- The following severe or fatal adverse reactions have been reported in post-marketing use in patients who received Oprelvekin following bone marrow transplantation: fluid retention or overload (eg, facial edema, pulmonary edema), capillary leak syndrome, pleural and pericardial effusion, papilledema and renal failure.
### Fluid Retention
- Oprelvekin is known to cause serious fluid retention that can result in peripheral edema, dyspnea on exertion, pulmonary edema, capillary leak syndrome, atrial arrhythmias, and exacerbation of pre-existing pleural effusions. Severe fluid retention, some cases resulting in death, was reported following recent bone marrow transplantation in patients who have received Oprelvekin. Oprelvekin is not indicated following myeloablative chemotherapy. It should be used with caution in patients with clinically evident congestive heart failure, patients who may be susceptible to developing congestive heart failure, patients receiving aggressive hydration, patients with a history of heart failure who are well-compensated and receiving appropriate medical therapy, and patients who may develop fluid retention as a result of associated medical conditions or whose medical condition may be exacerbated by fluid retention.
- Fluid retention is reversible within several days following discontinuation of Oprelvekin During dosing with Oprelvekin fluid balance should be monitored and appropriate medical management is advised.
- Close monitoring of fluid and electrolyte status should be performed in patients receiving chronic diuretic therapy. Sudden deaths have occurred in oprelvekin-treated patients receiving chronic diuretic therapy and ifosfamide who developed severe hypokalemia.
- Pre-existing fluid collections, including pericardial effusions or ascites, should be monitored. Drainage should be considered if medically indicated.
### Dilutional Anemia
- Moderate decreases in hemoglobin concentration, hematocrit, and red blood cell count (~10% to 15%) without a decrease in red blood cell mass have been observed. These changes are predominantly due to an increase in plasma volume (dilutional anemia) that is primarily related to renal sodium and water retention. The decrease in hemoglobin concentration typically begins within three to five days of the initiation of Oprelvekin, and is reversible over approximately a week following discontinuation of Oprelvekin.
### Cardiovascular Events
- Oprelvekin use is associated with cardiovascular events including arrhythmias and pulmonary edema. Cardiac arrest has been reported, but the causal relationship to Oprelvekin is uncertain. Use with caution in patients with a history of atrial arrhythmias, and only after consideration of the potential risks in relation to anticipated benefit. In clinical trials, cardiac events including atrial arrhythmias (atrial fibrillation or atrial flutter) occurred in 15% (23/157) of patients treated with Oprelvekin at doses of 50 mcg/kg. Arrhythmias were usually brief in duration; conversion to sinus rhythm typically occurred spontaneously or after rate-control drug therapy. Approximately one-half (11/24) of the patients who were rechallenged had recurrent atrial arrhythmias. Clinical sequelae, including stroke, have been reported in patients who experienced atrial arrhythmias while receiving Oprelvekin.
- The mechanism for induction of arrhythmias is not known. Oprelvekin was not directly arrhythmogenic in animal models. In some patients, development of atrial arrhythmias may be due to increased plasma volume associated with fluid retention.
- In the post-marketing setting, ventricular arrhythmias have been reported, generally occurring within two to seven days of initiation of treatment.
### Nervous System Events
- Stroke has been reported in the setting of patients who develop atrial fibrillation/flutter while receiving Oprelvekin. Patients with a history of stroke or transient ischemic attack may also be at increased risk for these events.
### Papilledema
- Papilledema has been reported in 2% (10/405) of patients receiving Oprelvekin in clinical trials following repeated cycles of exposure. The incidence was higher, 16% (7/43) in children than in adults, 1% (3/362). Nonhuman primates treated with Oprelvekin at a dose of 1,000 mcg/kg SC once daily for four to 13 weeks developed papilledema that was not associated with inflammation or any other histologic abnormality and was reversible after dosing was discontinued. Oprelvekin should be used with caution in patients with pre-existing papilledema, or with tumors involving the central nervous system since it is possible that papilledema could worsen or develop during treatment. Changes in visual acuity and/or visual field defects ranging from blurred vision to blindness can occur in patients with papilledema taking Oprelvekin.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- Three hundred twenty-four subjects, with ages ranging from eight months to 75 years, have been exposed to Oprelvekin treatment in clinical studies. Subjects have received up to six (eight in pediatric patients) sequential courses of Oprelvekin treatment, with each course lasting from one to 28 days. Apart from the sequelae of the underlying malignancy or cytotoxic chemotherapy, most adverse events were mild or moderate in severity and reversible after discontinuation of Oprelvekin dosing.
- In general, the incidence and type of adverse events were similar between Oprelvekin 50 mcg/kg and placebo groups. The most frequently reported serious adverse events were neutropenic fever, syncope, atrial fibrillation, fever and pneumonia. The most commonly reported adverse events were edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, and pleural effusions. The most frequently reported adverse reactions resulting in clinical intervention (eg, discontinuation of Oprelvekin, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were atrial arrhythmias, syncope, dyspnea, congestive heart failure, and pulmonary edema. Selected adverse events that occurred in ≥10% of Oprelvekin-treated patients are listed in TABLE 3.
- The following adverse events also occurred more frequently in cancer patients receiving Oprelvekin than in those receiving placebo: blurred vision, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, and eye hemorrhage. Other than a higher incidence of severe asthenia in Oprelvekin treated patients (10 [14%] in Oprelvekin patients versus two [3%] in placebo patients), the incidence of severe or life-threatening adverse events was comparable in the Oprelvekin and placebo treatment groups.
- Two patients with cancer treated with Oprelvekin experienced sudden death that the investigator considered possibly or probably related to Oprelvekin Both deaths occurred in patients with severe hypokalemia (<3.0 mEq/L) who had received high doses of ifosfamide and were receiving daily doses of a diuretic.
- Other serious events associated with Oprelvekin were papilledema and cardiovascular events including atrial arrhythmias and stroke. In addition, cardiomegaly was reported in children.
- The following adverse events, occurring in ≥10% of patients, were observed at equal or greater frequency in placebo-treated patients: asthenia, pain, chills, abdominal pain, infection, anorexia, constipation, dyspepsia, ecchymosis, myalgia, bone pain, nervousness, and alopecia. The incidence of fever, neutropenic fever, flu-like symptoms, thrombocytosis, thrombotic events, the average number of units of red blood cells transfused per patient, and the duration of neutropenia <500 cells/μL were similar in the Oprelvekin 50 mcg/kg and placebo groups.
### Immunogenicity
- In clinical studies that evaluated the immunogenicity of Oprelvekin, two of 181 patients (1%) developed antibodies to Oprelvekin. In one of these two patients, neutralizing antibodies to Oprelvekin were detected in an unvalidated assay. The clinical relevance of the presence of these antibodies is unknown. In the post-marketing setting, cases of allergic reactions, including anaphylaxis have been reported. The presence of antibodies to Oprelvekin was not assessed in these patients.
- The data reflect the percentage of patients whose test results were considered positive for antibodies to Oprelvekin and are highly dependent on the sensitivity and specificity of the assay. Additionally the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to Oprelvekin with incidence of antibodies to other products may be misleading.
### Abnormal Laboratory Values
- The most common laboratory abnormality reported in patients in clinical trials was a decrease in hemoglobin concentration predominantly as a result of expansion of the plasma volume. The increase in plasma volume is also associated with a decrease in the serum concentration of albumin and several other proteins (eg, transferrin and gamma globulins). A parallel decrease in calcium without clinical effects has been documented.
- After daily SC injections, treatment with Oprelvekin resulted in a two-fold increase in plasma fibrinogen. Other acute-phase proteins also increased. These protein levels returned to normal after dosing with Oprelvekin was discontinued. Von Willebrand factor (vWF) concentrations increased with a normal multimer pattern in healthy subjects receiving Oprelvekin.
## Postmarketing Experience
- 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reactions, (2) frequency of reporting, or (3) strength of causal connection to Oprelvekin.
- The following adverse reactions have been reported during the post-marketing use of Oprelvekin:
allergic reactions and anaphylaxis/anaphylactoid reactions
papilledema
visual disturbances ranging from blurred vision to blindness
optic neuropathy
ventricular arrhythmias
capillary leak syndrome
renal failure
injection site reactions (dermatitis, pain, and discoloration)
- allergic reactions and anaphylaxis/anaphylactoid reactions
- papilledema
- visual disturbances ranging from blurred vision to blindness
- optic neuropathy
- ventricular arrhythmias
- capillary leak syndrome
- renal failure
- injection site reactions (dermatitis, pain, and discoloration)
# Drug Interactions
- Most patients in trials evaluating Oprelvekin were treated concomitantly with filgrastim (G-CSF) with no adverse effect of Oprelvekin on the activity of G-CSF. No information is available on the clinical use of sargramostim (GM-CSF) with Oprelvekin in human subjects. However, in a study in nonhuman primates in which Oprelvekin and GM-CSF were coadministered, there were no adverse interactions between Oprelvekin and GM-CSF and no apparent difference in the pharmacokinetic profile of Oprelvekin.
- Drug interactions between Oprelvekin and other drugs have not been fully evaluated. Based on in vitro and nonclinical in vivo evaluations of Oprelvekin, drug-drug interactions with known substrates of P450 enzymes would not be predicted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Oprelvekin has been shown to have embryocidal effects in pregnant rats and rabbits when given in doses of 0.2 to 20 times the human dose. There are no adequate and well-controlled studies of Oprelvekin in pregnant women. Oprelvekin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Oprelvekin has been tested in studies of fertility, early embryonic development, and pre- and postnatal development in rats and in studies of organogenesis (teratogenicity) in rats and rabbits. Parental toxicity has been observed when Oprelvekin is given at doses of two to 20 times the human dose (≥100 mcg/kg/day) in the rat and at 0.02 to 2.0 times the human dose (≥1 mcg/kg/day) in the rabbit. Findings in pregnant rats consisted of transient hypoactivity and dyspnea after administration (maternal toxicity), as well as prolonged estrus cycle, increased early embryonic deaths and decreased numbers of live fetuses. In addition, low fetal body weights and a reduced number of ossified sacral and caudal vertebrae (ie, retarded fetal development) occurred in rats at 20 times the human dose. Findings in pregnant rabbits consisted of decreased fecal/urine eliminations (the only toxicity noted at 1 mcg/kg/day in dams) as well as decreased food consumption, body weight loss, abortion, increased embryonic and fetal deaths, and decreased numbers of live fetuses. No teratogenic effects of Oprelvekin were observed in rabbits at doses up to 0.6 times the human dose (30 mcg/kg/day).
- Adverse effects in the first generation offspring of rats given Oprelvekin at maternally toxic doses ≥2 times the human dose (≥100 mcg/kg/day) during both gestation and lactation included increased newborn mortality, decreased viability index on day 4 of lactation, and decreased body weights during lactation. In rats given 20 times the human dose (1000 mcg/kg/day) during both gestation and lactation, maternal toxicity and growth retardation of the first generation offspring resulted in an increased rate of fetal death of the second generation offspring.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oprelvekin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oprelvekin during labor and delivery.
### Nursing Mothers
It is not known if Oprelvekin 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 Oprelvekin, a decision should be made whether to discontinue nursing or to discontinue Oprelvekin, taking into account the importance of the drug to the mother.
### Pediatric Use
A safe and effective dose of Oprelvekin has not been established in children. In a Phase 1, single arm, dose-escalation study, 43 pediatric patients were treated with Oprelvekin at doses ranging from 25 to 125 mcg/kg/day following ICE chemotherapy. All patients required platelet transfusions and the lack of a comparator arm made the study design inadequate to assess efficacy. The projected effective dose (based on comparable AUC observed for the effective dose in healthy adults) in children appears to exceed the maximum tolerated pediatric dose of 50 mcg/kg/day. Papilledema was dose-limiting and occurred in 16% of children.
- The most common adverse events seen in pediatric studies included tachycardia (84%), conjunctival injection (57%), radiographic and echocardiographic evidence of cardiomegaly (21%) and periosteal changes (11%). These events occurred at a higher frequency in children than adults. The incidence of other adverse events was generally similar to those observed using Oprelvekin at a dose of 50 mcg/kg in the randomized studies in adults receiving chemotherapy.
- Studies in animals were predictive of the effect of Oprelvekin on developing bone in children. In growing rodents treated with 100, 300, or 1000 mcg/kg/day for a minimum of 28 days, thickening of femoral and tibial growth plates was noted, which did not completely resolve after a 28-day non-treatment period. In a nonhuman primate toxicology study of Oprelvekin animals treated for two to 13 weeks at doses of 10 to 1000 mcg/kg showed partially reversible joint capsule and tendon fibrosis and periosteal hyperostosis. An asymptomatic, laminated periosteal reaction in the diaphyses of the femur, tibia, and fibula has been observed in one patient during pediatric studies involving multiple courses of Oprelvekin treatment. The relationship of these findings to treatment with Oprelvekin is unclear. No studies have been performed to assess the long-term effects of Oprelvekin on growth and development.
### Geriatic Use
- Clinical studies of Oprelvekin did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger subjects. In a controlled study, 141 adult patients with various nonmyeloid malignancies were randomized (2:1) to Oprelvekin 50 mcg/kg/day or placebo administered subcutaneously for 14 days after chemotherapy was completed. Among 106 patients less than 65 years of age, the proportion who did not require platelet transfusions was higher among Oprelvekin-treated patients (36.5% vs. 14.3%). Among 35 patients greater than or equal to 65 years of age, the proportion who did not require platelet transfusions was similar between treatment groups (32% vs. 30%, Oprelvekin and placebo, respectively).
### Gender
There is no FDA guidance on the use of Oprelvekin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Oprelvekin with respect to specific racial populations.
### Renal Impairment
- Oprelvekin is eliminated primarily by the kidneys. The pharmacokinetics of Oprelvekin were studied in subjects with varying degrees of renal dysfunction. AUC0-∞, Cmax, and absolute bioavailability were significantly increased in subjects with severe renal impairment (creatinine clearance < 30 mL/min). There were no significant changes in the pharmacokinetic parameters in subjects with mild or moderate impairment. A significant decrease in the hemoglobin concentration was noted on Day 2 after a single dose of Oprelvekin in subjects with all degrees of renal impairment. By Day 14, the hemoglobin was decreased only in patients with severe renal impairment. Fluid retention associated with Oprelvekin treatment has not been studied in patients with renal impairment, but fluid balance should be carefully monitored in these patients
### Hepatic Impairment
There is no FDA guidance on the use of Oprelvekin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oprelvekin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oprelvekin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Oprelvekin Administration in the drug label.
### Monitoring
There is limited information regarding Oprelvekin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oprelvekin and IV administrations.
# Overdosage
- Doses of Oprelvekin above 125 mcg/kg have not been administered to humans. While clinical experience is limited, doses of Oprelvekin greater than 50 mcg/kg may be associated with an increased incidence of cardiovascular events in adult patients. If an overdose of Oprelvekin is administered, Oprelvekin should be discontinued, and the patient should be closely observed for signs of toxicity. Reinstitution of Oprelvekin therapy should be based upon individual patient factors (eg, evidence of toxicity, continued need for therapy).
# Pharmacology
## Mechanism of Action
- The primary hematopoietic activity of Oprelvekin is stimulation of megakaryocytopoiesis and thrombopoiesis. Oprelvekin has shown potent thrombopoietic activity in animal models of compromised hematopoiesis, including moderately to severely myelosuppressed mice and nonhuman primates. In these models, Oprelvekin improved platelet nadirs and accelerated platelet recoveries compared to controls.
- IL-11 has also been shown to have non-hematopoietic activities in animals including the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis, inhibition of pro-inflammatory cytokine production by macrophages, and the stimulation of osteoclastogenesis and neurogenesis. Non-hematopoietic pathologic changes observed in animals include fibrosis of tendons and joint capsules, periosteal thickening, papilledema, and embryotoxicity.
- IL-11 is produced by bone marrow stromal cells and is part of the cytokine family that shares the gp130 signal transducer. Primary osteoblasts and mature osteoclasts express mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Both bone-forming and bone-resorbing cells are potential targets of IL-11. (1)
## Structure
There is limited information regarding Oprelvekin Structure in the drug label.
## Pharmacodynamics
- In a study in which Oprelvekin was administered to non-myelosuppressed cancer patients, daily subcutaneous dosing for 14 days with Oprelvekin increased the platelet count in a dose-dependent manner. Platelet counts began to increase relative to baseline between five and nine days after the start of dosing with Oprelvekin After cessation of treatment, platelet counts continued to increase for up to seven days then returned toward baseline within 14 days. No change in platelet reactivity as measured by platelet activation in response to ADP, and platelet aggregation in response to ADP, epinephrine, collagen, ristocetin and arachidonic acid has been observed in association with Oprelvekin treatment.
- In a randomized, double-blind, placebo-controlled study in normal volunteers, subjects receiving Oprelvekin had a mean increase in plasma volume of >20%, and all subjects receiving Oprelvekin had at least a 10% increase in plasma volume. Red blood cell volume decreased similarly (due to repeated phlebotomy) in the Oprelvekin and placebo groups. As a result, whole blood volume increased approximately 10% and hemoglobin concentration decreased approximately 10% in subjects receiving Oprelvekin compared with subjects receiving placebo. Mean 24 hour sodium excretion decreased, and potassium excretion did not increase, in subjects receiving Oprelvekin compared with subjects receiving placebo.
## Pharmacokinetics
- The pharmacokinetics of Oprelvekin have been evaluated in studies of healthy, adult subjects and cancer patients receiving chemotherapy. In a study in which a single 50 mcg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 ± 5.4 ng/mL (mean ± S.D.) was reached at 3.2 ± 2.4 hrs (Tmax) following dosing. The terminal half-life was 6.9 ± 1.7 hrs. In a second study in which single 75 mcg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Oprelvekin was >80%. In a study in which multiple, subcutaneous doses of both 25 and 50 mcg/kg were administered to cancer patients receiving chemotherapy, Oprelvekin did not accumulate and clearance of Oprelvekin was not impaired following multiple doses.
- Oprelvekin was administered at doses ranging from 25 to 125 mcg/kg/day to 43 pediatric patients (ages 8 months to 18 years) and 1 adult patient receiving ICE (ifosfamide, carboplatin, etoposide) chemotherapy. Analysis of data from 40 pediatric patients showed that Cmax, Tmax, and terminal half-life were comparable to that in adults. The mean area under the concentration-time curve (AUC) for pediatric patients (8 months to 18 years), receiving 50 mcg/kg was approximately half that achieved in healthy adults receiving 50 mcg/kg. Available data suggest that clearance of Oprelvekin decreases with increasing age in children.
- Oprelvekin was administered as a single 50 mcg/kg dose subcutaneously to 48 healthy male and female adults aged 20 to 79 years; 18 subjects were aged 65 or older. The pharmacokinetic profile of Oprelvekin was similar between those 65 years of age or older and those younger than 65 years.
- In preclinical trials in rats, radiolabeled Oprelvekin was rapidly cleared from the serum and distributed to highly perfused organs. The kidney was the primary route of elimination. The amount of intact Oprelvekin in urine was low, indicating that the molecule was metabolized before excretion. In a clinical study, a single dose of Oprelvekin was administered to subjects with severely impaired renal function (creatinine clearance <30 mL/min). The mean ± S.D. values for Cmax and AUC were 30.8 ± 8.6 ng/mL and 373 ± 106 ng*hr/mL, respectively. When compared with control subjects in this study with normal renal function, the mean Cmax was 2.2 fold higher and the mean AUC was 2.6 fold (95% confidence interval, 1.7%-3.8%) higher in the subjects with severe renal impairment. In the subjects with severe renal impairment, clearance was approximately 40% of the value seen in subjects with normal renal function. The average terminal half-life was similar in subjects with severe renal impairment and those with normal renal function.
- A second clinical study of 24 subjects with varying degrees of renal function was also performed and confirmed the results observed in the first study. Single 50 mcg/kg subcutaneous and intravenous doses were administered in a randomized fashion. As the degree of renal impairment increased, the Oprelvekin AUC increased, although half-life remained unchanged. In the six patients with severe impairment, the mean ± S.D. Cmax and AUC were 23.6 ± 6.7 ng/mL and 373 ± 55.2 ng*hr/mL, respectively, compared with 13.1 ± 3.8 ng/mL and 195 ± 49.3 ng*hr/mL, respectively, in the six subjects with normal renal function. A comparable increase in exposure was observed after intravenous administration of Oprelvekin.
- The pharmacokinetic studies suggest that overall exposure to oprelvekin increases as renal function decreases, indicating that a 50% dose reduction of Oprelvekin is warranted for patients with severe renal impairment. No dosage reduction is required for smaller changes in renal function.
## Nonclinical Toxicology
There is limited information regarding Oprelvekin Nonclinical Toxicology in the drug label.
# Clinical Studies
Two randomized, double-blind, placebo-controlled trials in adults studied Oprelvekin for the prevention of severe thrombocytopenia following single or repeated sequential cycles of various myelosuppressive chemotherapy regimens.
### Study in Patients with Prior Chemotherapy-Induced Thrombocytopenia
- One study evaluated the effectiveness of Oprelvekin in eliminating the need for platelet transfusions in patients who had recovered from an episode of severe chemotherapy-induced thrombocytopenia (defined as a platelet count ≤20,000/μL), and were to receive one additional cycle of the same chemotherapy without dose reduction. Patients had various underlying non-myeloid malignancies, and were undergoing dose-intensive chemotherapy with a variety of regimens. Patients were randomized to receive Oprelvekin at a dose of 25 mcg/kg or 50 mcg/kg, or placebo. The primary endpoint was whether the patient required one or more platelet transfusions in the subsequent chemotherapy cycle. Ninety-three patients were randomized. Five patients withdrew from the study prior to receiving the study drug. As a result, eighty-eight patients were included in a modified intent-to-treat analysis. The results for the Oprelvekin 50 mcg/kg and placebo groups are summarized in TABLE 1. The placebo group includes one patient who underwent chemotherapy dose reduction and who avoided platelet transfusions.
- In the primary efficacy analysis, more patients avoided platelet transfusion in the Oprelvekin 50 mcg/kg arm than in the placebo arm (p = 0.04, Fisher's Exact test, 2-tailed). The difference in the proportion of patients avoiding platelet transfusions in the Oprelvekin 50 mcg/kg and placebo groups was 21% (95% confidence interval, 2%-40%). The results observed in patients receiving 25 mcg/kg of Oprelvekin were intermediate between those of the placebo and the 50 mcg/kg groups.
### Study in Patients Receiving Dose-Intensive Chemotherapy
- A second study evaluated the effectiveness of Oprelvekin in eliminating platelet transfusions over two dose-intensive chemotherapy cycles in breast cancer patients who had not previously experienced severe chemotherapy-induced thrombocytopenia. All patients received the same chemotherapy regimen (cyclophosphamide 3,200 mg/m2 and doxorubicin 75 mg/m2). All patients received concomitant filgrastim (G-CSF) in all cycles. The patients were stratified by whether or not they had received prior chemotherapy, and randomized to receive Oprelvekin 50 mcg/kg or placebo. The primary endpoint was whether or not a patient required one or more platelet transfusions in the two study cycles. Seventy-seven patients were randomized. Thirteen patients failed to complete both study cycles—eight of these had insufficient data to be evaluated for the primary endpoint. The results of this trial are summarized in TABLE 2.
- This study showed a trend in favor of Oprelvekin, particularly in the subgroup of patients with prior chemotherapy. Open-label treatment with Oprelvekin has been continued for up to four consecutive chemotherapy cycles without evidence of any adverse effect on the rate of neutrophil recovery or red blood cell transfusion requirements. Some patients continued to maintain platelet nadirs >20,000/μL for at least four sequential cycles of chemotherapy without the need for transfusions, chemotherapy dose reduction, or changes in treatment schedules.
- Platelet activation studies done on a limited number of patients showed no evidence of abnormal spontaneous platelet activation, or an abnormal response to ADP. In an unblinded, retrospective analysis of the two placebo-controlled studies, 19 of 69 patients (28%) receiving Oprelvekin 50 mcg/kg and 34 of 67 patients (51%) receiving placebo reported at least one hemorrhagic adverse event which involved bleeding.
# How Supplied
There is limited information regarding Oprelvekin How Supplied in the drug label.
## Storage
There is limited information regarding Oprelvekin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oprelvekin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Oprelvekin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Neumega
# Look-Alike Drug Names
There is limited information regarding Oprelvekin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Neumega | |
752dea94c015f89914390e0457dc7a5674b4f0f5 | wikidoc | Rotigotine | Rotigotine
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# Black Box Warning
# Overview
Rotigotine is a dopamine agonist that is FDA approved for the treatment of Parkinson's disease ,restless legs syndrome. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, insomnia and dyskinesia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Parkinson's Disease
- Treatment of the signs and symptoms of idiopathic Parkinson's disease.
- Rotigotine should be started at 2 mg/24 hours for patients with early-stage Parkinson's disease.
- Based upon individual patient clinical response and tolerability, rotigotine dosage may be increased weekly by 2 mg/24 hours if tolerated and if additional therapeutic effect is needed.
- The lowest effective dose was 4 mg/24 hours.
- The highest recommended dose for early-stage Parkinson's disease is 6 mg/24 hours.
Patients with advanced-stage Parkinson's disease may be initiated at 4 mg/24 hours. Based upon individual patient clinical response and tolerability, rotigotine dosage may be increased weekly by 2 mg/24 hours. The recommended dose for advanced-stage Parkinson's disease is 8 mg/24 hours.
### Restless Legs Syndrome
- Treatment of moderate-to-severe primary Restless Legs Syndrome.
- Rotigotine should be started at 1 mg/24 hours. Based upon individual patient clinical response and tolerability, rotigotine dosage may be increased weekly by 1 mg/24 hours if tolerated and if additional therapeutic effect is needed.
- The lowest effective dose was 1 mg/24 hours.
- The highest recommended dose is 3 mg/24 hours.
### Discontinuation of Treatment
For patients with Parkinson's disease, the daily dose should be reduced by a maximum of 2 mg/24 hours with a dose reduction preferably every other day, until complete withdrawal of rotigotine is achieved.
For patients with RLS, the daily dose should be reduced by 1 mg/24 hours preferably every other day, until complete withdrawal of rotigotine is achieved.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rotigotine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rotigotine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Rotigotine 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 Rotigotine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rotigotine in pediatric patients.
# Contraindications
- Rotigotine is contraindicated in patients who have demonstrated hypersensitivity to rotigotine or the components of the transdermal system.
# Warnings
Patients should be monitored for developing adverse reactions described in this section. If any of these adverse reactions develop, lowering or discontinuing the dose of rotigotine may be beneficial.
### Sulfite Sensitivity
- Rotigotine contains sodium metabisulfite, asulfite that may cause allergic-type reactions including anaphylactic symptoms and life t
- The overall prevalence of sulfite sensitivity in the general population is unknown.
- Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
### Falling Asleep During Activities of Daily Living and Somnolence
- Patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome treated with rotigotine have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on rotigotine, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.
- Some of these events have been reported as late as one year after initiation of treatment.
- In trials of Restless Legs Syndrome, 2% of patients treated with the highest recommended rotigotine dose (3 mg/24 hours) reported sleep attacks vs. 0% of placebo patients.
- Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.
- Somnolence is a common occurrence in patients receiving rotigotine.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for somnolence was 16% for early-stage Parkinson's disease, 4% for advanced-stage Parkinson's disease, and 6% for Restless Legs Syndrome.
- Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with rotigotine.
- Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with rotigotine.
- Before initiating treatment with rotigotine, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase this risk with rotigotine such as concomitant sedating medications and the presence of sleep disorders.
- If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), rotigotine should ordinarily be discontinued.
- If a decision is made to continue rotigotine, patients should be advised not to drive and to avoid other potentially dangerous activities.
- There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
### Hallucinations / Psychotic-Like Behavior
- There was an increased risk for hallucinations in patients with advanced-stage Parkinson's disease treated with rotigotine.
- For the highest recommended rotigotine dose, the incidence of the treatment difference (rotigotine % - placebo %) for hallucinations was 4% for patients with advanced-stage Parkinson's disease, and this difference increased with increasing dose.
- Hallucinations were of sufficient severity to cause discontinuation of treatment (mainly during the dose escalation/titration period) in 3% of advanced-stage Parkinson's disease patients treated with the highest recommended dose of rotigotine compared with 1% of placebo treated patients.
- Hallucinations have also been reported in post-marketing reports.
- Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during rotigotine treatment or after starting or increasing the dose of rotigotine.
- Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. These various manifestations of psychotic-like behavior were also observed during the clinical development of rotigotine for early- and advanced-stage Parkinson's disease and Restless Legs Syndrome.
- Patients with a major psychotic disorder should ordinarily not be treated with rotigotine because of the risk of exacerbating psychosis.
- In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of rotigotine.
### Symptomatic Hypotension
- Dopaminergic agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, especially during dose escalation. *Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, both Parkinson's and RLS patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk.
- Mild-moderate decreases in systolic blood pressure (≥ 20 mm Hg) and in diastolic blood pressure (≥ 10 mm Hg) occurred more frequently (rotigotine % ≥ 5% greater than placebo %) in all patients (i.e., early- and advanced-stage Parkinson's disease and Restless Legs Syndrome) with the highest recommended rotigotine dose. These decreases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position. More severe decreases in systolic blood pressure (> 40 mm Hg) and in diastolic blood pressure (≥ 20 mm Hg) also occurred more frequently (rotigotine % ≥ 2% greater than placebo %) in patients with early- and advanced-stage Parkinson's disease during measurements when supine, standing and/or changing from supine to standing position.
- Some threshold decreases in blood pressure described earlier appeared to be dependent on the dose of rotigotine and were also observed at the final study visit.
- An analysis using a variety of adverse reaction terms suggestive of orthostatic hypotension, including dizziness/postural dizziness and others, showed an increased risk for all patients treated with rotigotine.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for adverse reactions suggestive of hypotension/orthostatic hypotension was 18% for early-stage Parkinson's disease, 4% for advanced-stage Parkinson's disease, and 1% for Restless Legs Syndrome.
- This increased risk for symptomatic hypotension and decreases in blood pressure was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this study. The increased risk for significant decreases in blood pressure or orthostatic hypotension occurred especially in the dose escalation/titration period.
### Syncope
- Syncope has been reported in patients using dopamine agonists, and for this reason patients should be alerted to the possibility of syncope. *Because the studies of rotigotine excluded patients with clinically relevant cardiovascular disease, patients with severe cardiovascular disease should be treated with caution.
### Impulse Control / Compulsive Behaviors
- Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including rotigotine, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease.
- In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with rotigotine.
- Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking rotigotine.
### Elevation of Blood Pressure and Heart Rate
- Some patients treated with rotigotine exhibited moderately severe increases in systolic blood pressure (> 180 mm Hg) and/or in diastolic blood pressure (> 105 mm Hg) while supine and/or standing.
- In patients with advanced-stage Parkinson's disease, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 2% for systolic blood pressure > 180 mm Hg and of 4% for diastolic blood pressure > 105 mm Hg. In patients with Restless Legs Syndrome, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 4% for diastolic blood pressure > 105 mm Hg.
Mild-moderate increases in systolic blood pressure (≥ 20 mm Hg) and in diastolic blood pressure (≥ 10 mm Hg) occurred more frequently (rotigotine % ≥ 5% greater than placebo %) in all patients (i.e., early- and advanced-stage Parkinson's disease and Restless Legs Syndrome) with the highest recommended rotigotine dose.
- These increases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position.
- More severe increases in systolic blood pressure (> 40 mm Hg) and in diastolic blood pressure (≥ 20 mm Hg) also occurred more frequently (rotigotine % ≥ 2% greater than placebo %) in patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome during measurements when supine, standing and/or changing from supine to standing position.
- Some threshold increases in blood pressure described earlier appeared to be dependent on the dose of rotigotine and were also observed at the final study visit.
- In the placebo-controlled trials, there was an increased risk for hypertension as an adverse reaction with the highest recommended dose for advanced-stage Parkinson's disease (rotigotine 3% vs. placebo 0%) and for Restless Legs Syndrome (rotigotine 4% vs. placebo 0%).
- Some patients treated with rotigotine exhibited moderately increased pulse (> 100 beats per minute) while supine and/or standing. In patients with advanced-stage Parkinson's disease, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 2% for increased pulse. In patients with Restless Legs Syndrome, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 5% for increased pulse.
- These findings of blood pressure and heart rate elevations should be considered when treating patients with cardiovascular disease.
### Weight Gain and Fluid Retention
- Patients taking the highest recommended rotigotine dose for early-stage Parkinson's disease had a higher incidence (2%) of substantial weight gain (more than 10% of baseline weight) than subjects taking placebo (0%).
- In advanced-stage Parkinson's disease, the incidence of weight gain more than 10% of baseline weight was 9% rotigotine (for highest recommended dose) and 1% placebo. This weight gain was frequently associated with the development of peripheral edema in patients with Parkinson's disease, suggesting that rotigotine may cause substantial fluid retention in some Parkinson's patients. Although the weight gain was usually well-tolerated in subjects observed in the Parkinson's clinical studies, it could cause greater difficulty in patients who may be especially vulnerable to negative clinical consequences from fluid retention such as those with significant congestive heart failure or renal insufficiency.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for peripheral edema was 1% for early-stage Parkinson's disease, and 8% for advanced-stage Parkinson's disease. *These treatment differences increased further with treatment at rotigotine dosing above the highest recommended doses.
### Dyskinesia
- Rotigotine may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate pre-existing dyskinesia.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for dyskinesia was 7% for patients with advanced-stage Parkinson's disease, and this incidence increased with increasing dose.
- There was also an increased risk (rotigotine 3% vs. placebo 0%) for discontinuation from the study because of dyskinesia for the highest recommended rotigotine dose in these same patients.
### Application Site Reactions
- Application site reactions (ASRs) were reported at a greater frequency in the rotigotine-treated patients than in placebo patients in the double-blind, placebo-controlled dose-response studies with rotigotine.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for various ASRs was 15% for early-stage Parkinson's disease, 23% for advanced-stage Parkinson's disease, and 39% for Restless Legs Syndrome.
- ASRs exhibited a dose-dependent relationship for all doses for patients with early- and advanced-stage Parkinson's disease and Restless Legs Syndrome.
- ASRs were also of sufficient severity to cause study discontinuation for patients with early-stage Parkinson's disease (rotigotine 3% vs. placebo 0%), advanced-stage Parkinsons's disease (rotigotine 2% vs. placebo 0%, and Restless Legs Syndrome (rotigotine 12% vs. placebo 0%) who were treated with the highest recommended rotigotine dose.
- Of ASRs in rotigotine-treated patients, most were mild or moderate in intensity.
- The signs and symptoms of these reactions generally were localized erythema, edema, or pruritus limited to the patch area and usually did not lead to dose reduction.
- Generalized skin reactions (e.g., allergic rash, including erythematous, macular-papular rash, or pruritus), have been reported at lower rates than ASRs during the development of rotigotine.
- In a clinical study designed to investigate the cumulative skin irritation of rotigotine, daily rotation of rotigotine application sites has been shown to reduce the incidence of ASRs in comparison to repetitive application to the same site.
- In a clinical study investigating the skin sensitizing potential of rotigotine in 221 healthy subjects, no case of contact sensitization was observed. *Localized sensitization reactions were observed in a study with healthy subjects by continuously rotating a 0.5 mg/24 hours transdermal system, after induction of maximal irritational stress was achieved by repetitive transdermal system application to the same site.
- If a patient reports a persistent application site reaction (of more than a few days), reports an increase in severity, or reports a skin reaction spreading outside the application site, an assessment of the risk and benefits for the individual patient should be conducted.
- If a generalized skin reaction associated with the use of rotigotine is observed, rotigotine should be discontinued.
### Melanoma
- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using rotigotine for any indication.
- Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
### Augmentation and Rebound in RLS
- Augmentation is a worsening of RLS symptoms during treatment, leading to an increase in overall symptom severity or earlier time of symptom onset each day compared to before initiation of treatment.
- Use of dopaminergic medicinal products, including rotigotine, may result in augmentation.
Rebound, an exacerbation of RLS symptoms, is considered to be an end of dose effect, related to the half-life of the therapeutic agent. Reports in the published literature indicate discontinuation or wearing off of dopaminergic medications can result in rebound.
### Magnetic Resonance Imaging and Cardioversion
- The backing layer of rotigotine contains aluminum.
- To avoid skin burns, rotigotine should be removed prior to magnetic resonance imaging or cardioversion.
### Heat Application
- The effect of application of heat to the transdermal system has not been studied. However, heat application has been shown to increase absorption several fold with other transdermal products.
- Patients should be advised to avoid exposing the rotigotine application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.
### Withdrawal-Emergent-Hyperpyrexia and Confusion
- A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, and/or autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy. Therefore it is recommended that the dose be tapered at the end of rotigotine treatment as a prophylactic measure.
### Fibrotic Complications
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
### Binding to Melanin
- As has been reported with other dopamine agonists, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat and monkey was evident after a single dose of rotigotine, but was slowly cleared over the 14-day observation period.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment / total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice.
Adverse Reactions Incidence in Controlled Clinical Studies in Early-Stage Parkinson's Disease
The safety of rotigotine was evaluated in a total of 649 early-stage Parkinson's disease patients who participated in three double-blind, placebo-controlled studies with durations of 3 to 9 months. Additional safety information was collected in short-term studies, and two open-label extension studies in patients with early-stage Parkinson's disease.
The incidence of adverse reactions in a randomized, double-blinded, placebo-controlled, fixed-dose trial is shown in Table 1. Incidences for the non-recommended 8 mg/24 hour dose are also shown.
In the double-blind, placebo-controlled, dose-response study in patients with early-stage Parkinson's disease, the most commonly observed adverse reactions (≥ 5% greater than placebo) for the highest recommended dose of rotigotine (6 mg/24 hours) were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, and insomnia.
In this trial, 12% of patients treated with the highest, recommended rotigotine dose (6 mg/24 hours) discontinued treatment because of adverse reactions, compared with 6% of patients who received placebo.
The incidence of certain adverse reactions with rotigotine treatment was notably increased compared to placebo treatment (i.e., rotigotine % - placebo % = ≥ 5%) in either the titration or maintenance phases of the dose-response trial. During the titration phase, an increased incidence (in descending order of % treatment difference) was observed for nausea, somnolence, vomiting, application site reactions (ASRs), dizziness, sweating increased, anorexia and vision abnormal. During the maintenance phase, an increased incidence was observed for nausea, and ASRs. Some adverse reactions developing in the titration phase persisted (≥ 7 days) into the maintenance phase. These "persistent" adverse reactions included ASRs, anorexia, somnolence, nausea, and vision abnormal.
Adverse Reactions Incidence in Controlled Clinical Studies in Advanced-Stage Parkinson's Disease
The safety evaluation of rotigotine was based on a total of 672 rotigotine-treated subjects with advanced-stage Parkinson's disease who participated in 3 double-blind, placebo-controlled studies (2 fixed-dose trials and one flexible dose trial) with durations of 3 to 7 months. Patients received concomitant levodopa in these studies. Additional safety information was collected in earlier short-term studies, and 2 open-label extension studies in subjects with advanced-stage Parkinson's disease.
The incidence of adverse reactions in a randomized, double-blinded, placebo-controlled, fixed-dose trial is shown in Table 2. Incidences for the non-recommended 12 mg/24 hour dose are also shown.
In the dose-response, placebo-controlled trial for advanced-stage Parkinson's disease, the most common adverse reactions (≥ 5% greater than placebo) for the highest recommended dose of rotigotine (8 mg/24 hours) were application site reactions, nausea, somnolence, and headache.
In this trial, approximately 15% of patients treated with the highest, recommended rotigotine dose (8 mg/24 hours) discontinued treatment because of adverse reactions, compared with 9% of patients who received placebo.
The incidence of certain adverse reactions with rotigotine treatment was notably increased compared to placebo treatment (i.e., rotigotine % - placebo % = ≥ 5%) in either the titration or maintenance phases of the dose-response trial. During the titration phase, an increased incidence (in descending order of % treatment difference) was observed for nausea, hallucinations, constipation, dyskinesia, and dizziness. During the maintenance phase, an increased incidence was observed for ASRs, peripheral edema, and dyskinesia. Some adverse reactions developing in the titration phase persisted (≥ 7 days) into the maintenance phase. A notably "persistent" adverse reaction was ASRs.
Adverse Reactions Incidence in Controlled Clinical Studies in Restless Legs Syndrome
The safety evaluation of rotigotine was based on a total of 745 rotigotine-treated subjects with RLS who participated in 2 double-blind, placebo-controlled studies with maintenance durations of 6 months. Additional safety information was collected in earlier short-term studies, and 3 open-label extension studies in subjects with RLS.
The incidence of adverse reactions in two randomized, double-blinded, placebo-controlled, fixed-dose trials are shown in Table 3.
In the two randomized, double-blinded, placebo-controlled, fixed-dose trials for RLS, the most common adverse reactions (≥ 5% greater than placebo) for the highest recommended dose of rotigotine (3 mg/24 hours) were application site reactions, nausea, somnolence, and headache.
In the two dose-response, placebo-controlled trials, 24% of rotigotine-treated patients treated with the highest recommended dose (3 mg/24 hours) discontinued treatment because of adverse reactions, compared with 3% of patients who received placebo.
The incidence of certain adverse reactions with rotigotine treatment was notably increased compared to placebo treatment (i.e., rotigotine % - placebo % = ≥ 5%) in either the titration or maintenance phases of the dose-response trials. During the titration phase, an increased incidence (in descending order of % treatment difference) was observed for ASRs, and disturbances in initiating and/or maintaining sleep. During the maintenance phase, an increased incidence was observed for ASRs. Some adverse reactions developing in the titration phase persisted (≥ 7 days) into the maintenance phase. These "persistent" adverse reactions were ASRs, nausea, and disturbances in initiating and/or maintaining sleep.
### Laboratory Changes
Some clinical laboratory analytes were abnormal for patients treated with the highest recommended rotigotine dose in the dose-response trials for patients with early- and advanced-stage Parkinson's disease and with RLS.
There was a treatment difference (rotigotine % - placebo %) of 6% for decreased hemoglobin (below the normal reference range) and of 3% for decreased hematocrit (below the normal reference range) in patients with early-stage Parkinson's disease. There was a treatment difference of 4% for a decreased hemoglobin (below the normal reference range) and of 3% for decreased hematocrit (below the normal reference range) in patients with advanced-stage Parkinson's disease. There was a treatment difference of 3% for a decreased hemoglobin (below the normal reference range) in patients with RLS. There was also a treatment difference of 2% for markedly decreased hemoglobin and hematocrit in patients with advanced-stage Parkinson's disease and of 1% for markedly decreased hematocrit in patients with RLS.
There was a treatment difference of 9% for increased serum BUN (above the normal reference range) in patients with early-stage Parkinson's disease. There was a treatment difference of 1% for markedly increased serum BUN in patients with advanced-stage Parkinson's disease.
There was a treatment difference of 9% for decreased serum glucose (below the normal reference range) in patients with early-stage Parkinson's disease and of 3% in patients with advanced-stage Parkinson's disease. There was a treatment difference of 1% for markedly decreased serum glucose in patients with advanced-stage Parkinson's disease.
## Postmarketing Experience
There is limited information regarding Rotigotine Postmarketing Experience in the drug label.
# Drug Interactions
### Dopamine Antagonists
It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rotigotine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women. In studies conducted in mice, rats, and rabbits, rotigotine was shown to have adverse effects on embryo-fetal development when administered during pregnancy at doses similar to or lower than those used clinically. Rotigotine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Rotigotine administered subcutaneously (10, 30, or 90 mg/kg/day) to pregnant mice during organogenesis (gestation days 6 through 15) resulted in increased incidences of delayed skeletal ossification and decreased fetal body weights at the two highest doses and an increase in embryo-fetal death at the high dose. The no-effect dose for embryo-fetal developmental toxicity in mice is approximately 6 times the maximum recommended human dose (MRHD) for Parkinson's disease (8 mg/24 hours) on a body surface area (mg/m2) basis. Rotigotine administered subcutaneously (0.5, 1.5, or 5 mg/kg/day) to pregnant rats during organogenesis (gestation days 6 through 17) resulted in increased embryo-fetal death at all doses. The lowest effect dose is less than the MRHD on a mg/m2 basis. This effect in rats is thought to be due to the prolactin-lowering effect of rotigotine. When rotigotine was administered subcutaneously (5, 10, or 30 mg/kg/day) to pregnant rabbits during organogenesis (gestation days 7 through 19), an increase in embryo-fetal death occurred at the two highest doses tested. The no-effect dose is 12 times the MRHD on a mg/m2 basis.
In a study in which rotigotine was administered subcutaneously (0.1, 0.3, or 1 mg/kg/day) to rats throughout pregnancy and lactation (gestation day 6 through postnatal day 21), impaired growth and development during lactation and long-term neurobehavioral abnormalities were observed in the offspring at the highest dose tested; when those offspring were mated, growth and survival of the next generation were adversely affected. The no-effect dose for pre- and postnatal developmental toxicity (0.3 mg/kg/day) is less than the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rotigotine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rotigotine during labor and delivery.
### Nursing Mothers
Rotigotine decreases prolactin secretion in humans and could potentially inhibit lactation.
Studies have shown that rotigotine and/or its metabolite(s) are excreted in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when rotigotine is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients for any indication have not been established.
### Geriatic Use
Of subjects treated with rotigotine in clinical studies for the treatment of Parkinson's disease, approximately 50% were 65 years old and over, and approximately 11% were 75 and over. Among subjects treated with rotigotine in clinical studies for the treatment of RLS, 26% were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
No overall differences in plasma levels of rotigotine were observed between patients who were 65 to 80 years old compared with younger patients receiving the same rotigotine doses.
### Gender
There is no FDA guidance on the use of Rotigotine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rotigotine with respect to specific racial populations.
### Renal Impairment
The effect of renal function on rotigotine pharmacokinetics has been studied in subjects with mild to severe impairment of renal function including subjects requiring dialysis compared to healthy subjects. There were no relevant changes in rotigotine plasma concentrations. In subjects with severe renal impairment not on dialysis, (i.e., creatinine clearance 15 to <30 ml/min), exposure to rotigotine conjugates was doubled. No dosage adjustment is recommended.
### Hepatic Impairment
The effect of impaired hepatic function on the pharmacokinetics of rotigotine has been studied in subjects with moderate impairment of hepatic function (Child-Pugh classification – Grade B). There were no relevant changes in rotigotine plasma concentrations. No dose adjustment is necessary in subjects with moderate impairment of hepatic function. No information is available on subjects with severe impairment of hepatic function.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rotigotine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rotigotine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Transdermal
### Monitoring
- Careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation.
- Monitor for melanomas frequently and on a regular basis when using Neupro for any indication.
- Monitored for developing adverse reactions
# IV Compatibility
There is limited information regarding the compatibility of Rotigotine and IV administrations.
# Overdosage
Since rotigotine is a transdermal system, overdosing is not likely to occur in clinical practice unless patients forget to remove the previous day's transdermal system; patients should be advised regarding this possibility.
### Overdose Symptoms
The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation.
### Overdose Management
There is no known antidote for overdosage of dopamine agonists. In case of suspected overdose, the excess transdermal system(s) should immediately be removed from the patient. Concentrations of rotigotine decrease after patch removal. The terminal half-life of rotigotine is 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. If it is necessary to discontinue use of rotigotine after overdose, it should be discontinued gradually to prevent neuroleptic malignant syndrome. The daily dose should be reduced by 2 mg/24 hours for Parkinson's disease patients and 1 mg/24 hours for RLS patients with a dose reduction preferably every other day, until complete withdrawal of rotigotine is achieved. Before completely stopping use of rotigotine in the event of an overdose.
The patient should be monitored closely, including heart rate, heart rhythm, and blood pressure. As shown in a study of renally impaired patients, dialysis is not expected to be beneficial. Treatment of overdose may require general supportive measures to maintain vital signs.
# Pharmacology
## Mechanism of Action
Rotigotine is a non-ergoline dopamine agonist. The precise mechanism of action of rotigotine as a treatment for Parkinson's disease is unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudate-putamen in the brain. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine receptors.
## Structure
The chemical name of rotigotine is (6S)-6-{propylamino}-5,6,7,8-tetrahydro-1-naphthalenol. The empirical formula is C19H25NOS. The molecular weight is 315.48. The structural formula for rotigotine is:
## Pharmacodynamics
### Cardiac Electrophysiology
There is no indication of a QT/QTc prolonging effect of rotigotine in doses up to 24 mg/24 hours. The effects of rotigotine at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose) parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
## Pharmacokinetics
On average, approximately 45% of the rotigotine from the patch is released within 24 hours (0.2 mg/cm2). Rotigotine is primarily eliminated in the urine as inactive conjugates. After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.
### Absorption and Bioavailability
When single doses of 8 mg/24 hours are applied to the trunk, there is an average lag time of approximately 3 hours until drug is detected in plasma (range 1 to 8 hours). Tmax typically occurs between 15 to 18 hours post dose but can occur from 4 to 27 hours post dose. However, there is no characteristic peak concentration observed. Rotigotine displays dose-proportionality over a daily dose range of 1 mg/24 hours to 24 mg/24 hours. In the clinical studies of rotigotine effectiveness, the transdermal system application site was rotated from day to day (abdomen, thigh, hip, flank, shoulder, or upper arm) and the mean measured plasma concentrations of rotigotine were stable over the six months of maintenance treatment. Relative bioavailability for the different application sites at steady-state was evaluated in subjects with Parkinson's disease. In a single trial conducted in patients with early-stage Parkinson's disease differences in bioavailability ranged from less than 1% (abdomen vs. hip) to 46% (shoulder vs. thigh) with shoulder application showing higher bioavailability.
Because rotigotine is administered transdermally, food should not affect absorption, and the product may be administered without regard to the timing of meals.
In a 14-day clinical study with rotigotine administered to healthy subjects, steady-state plasma concentrations were achieved within 2 to 3 days of daily dosing.
File:Rotigotine ADVERSE REACTIONS 3.png
### Distribution
The weight normalized apparent volume of distribution (Vd/F) in humans is approximately 84 L/kg after repeated dose administration.
The binding of rotigotine to human plasma proteins is approximately 92 % in vitro and 89.5 % in vivo.
### Metabolism and Elimination
Rotigotine is extensively metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine.
After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.
Rotigotine is primarily excreted in urine (~71%) as inactive conjugates of the parent compound and N-desalkyl metabolites. A smaller proportion is excreted in feces (~23%). The major metabolites found in urine were rotigotine sulfate (16% to 22% of the absorbed dose), rotigotine glucuronide (11% to 15%), and N-despropyl-rotigotine sulfate metabolite (14% to 20%) and N-desthienylethyl-rotigotine sulfate metabolite (10% to 21%). Approximately 11% is renally eliminated as other metabolites. A small amount of unconjugated rotigotine is renally eliminated (<1% of the absorbed dose).
### Drug Interaction Studies
In vitro studies indicate that multiple CYP-isoforms are capable of catalyzing the metabolism of rotigotine. In human liver microsomes, no extensive inhibition of the metabolism of rotigotine was observed when co-incubated with CYP isoform specific inhibitors. If an individual CYP isoform is inhibited, other isoforms can catalyze rotigotine metabolism.
Rotigotine, the 5-O-glucuronide and its desalkyl and monohydroxy metabolites were analyzed for interactions with the human CYP isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 in vitro. Based on these results, no risk for inhibition of CYP1A2, CYP2C9 and CYP3A4 catalyzed metabolism of other drugs is predicted at therapeutic rotigotine concentrations. There is a low risk of inhibition of CYP2C19 and CYP2D6 catalyzed metabolism of other drugs at therapeutic concentrations.
In human hepatocytes in vitro, there was no indication for induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4.
Rotigotine is metabolized by multiple sulfotransferases and two UDP-glucuronosyltransferases (UGT1A9 and UGT2B15). These multiple pathways make it unlikely that inhibition of any one pathway would alter rotigotine concentrations significantly.
In vitro, no potential for displacement of warfarin by rotigotine (and vice versa) from their respective human serum albumin binding sites was detected.
The effect of rotigotine on the pharmacokinetics of digoxin has been investigated in vitro in Caco-2 cells. Rotigotine did not influence the P-glycoprotein-mediated transport of digoxin. Therefore, rotigotine would not be expected to affect the pharmacokinetics of digoxin.
Co-administration of rotigotine (up to 4 mg/24 hours) with cimetidine (400 mg b.i.d.), an inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4, did not alter the steady-state pharmacokinetics of rotigotine in healthy subjects.
Co-administration of levodopa/carbidopa (100/25 mg b.i.d.) with rotigotine (4 mg/24 hours) had no effect on the steady-state pharmacokinetics of rotigotine; rotigotine had no effect on the pharmacokinetics of L-levodopa/carbidopa.
Co-administration of rotigotine (3 mg/24 hours) did not affect the pharmacodynamics and pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).
Co-administration of the CYP2C19 selective inhibitor omeprazole (40 mg/day) had no effect on the steady-state pharmacokinetics of rotigotine (4 mg/24 hours).
### Pharmacokinetics in Special Populations
There were no relevant changes in rotigotine plasma concentrations in subjects with moderate hepatic impairment (Child Pugh classification – Grade B). No information is available on subjects with severe impairment of hepatic function.
There were no relevant changes in rotigotine plasma concentrations (up to end stage renal disease requiring hemodialysis). In subjects with severe renal impairment not on dialysis, (i.e., creatinine clearance 15 to <30 ml/min), exposure to conjugated rotigotine metabolites was doubled.
Female and male subjects and patients had similar plasma concentrations (body weight normalized).
Plasma concentrations of rotigotine in patients 65 to 80 years of age were similar to those in younger patients, approximately 40 to 64 years of age. Although not studied, exposures in older subjects (>80 years) may be higher due to skin changes with aging.
The pharmacokinetics of rotigotine in subjects below the age of 18 years has not been established.
The pharmacokinetic profile was similar in Caucasians, Blacks, and Japanese. No dose adjustment is necessary based on ethnicity.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies of rotigotine were conducted in mice at doses of 0, 3, 10, and 30 mg/kg and in rats at doses of 0, 0.3, 1, and 3 mg/kg; in both studies rotigotine was administered subcutaneously once every 48 hours. No significant increases in tumors occurred in mice at doses up to 9 times the maximum recommended human dose (MRHD) in Parkinson's disease (8 mg/24 hours).
In rats, there were increases in Leydig cell tumors and in uterine tumors (adenocarcinomas, squamous cell carcinomas) at all doses. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. Therefore, there were no tumor findings considered relevant to humans at plasma exposures (AUC) up to 4-6 times that in humans at the MRHD.
Rotigotine was negative in the in vitro bacterial reverse mutation (Ames) and in the in vivo micronucleus assays. Rotigotine was mutagenic and clastogenic in the in vivo mouse lymphoma tk assay.
When rotigotine was administered subcutaneously (1.5, 5, or 15 mg/kg/day) to female rats prior to and during mating and continuing through gestation day 7, an absence of implantation was observed at all doses. The lowest dose tested is 2 times the MRHD on a mg/m2 basis. In male rats treated from 70 days prior to and during mating, there was no effect on fertility; however, a decrease in epididymal sperm motility was observed at the highest dose tested. The no-effect dose (5 mg/kg/day) is 6 times the MRHD on a mg/m2 basis. When rotigotine was administered subcutaneously to female mice at doses of 10, 30, and 90 mg/kg/day from 2 weeks until 4 days before mating and then at a dose of 6 mg/kg/day (all groups) (approximately 4 times the MRHD on a mg/m2 basis) from 3 days before mating until gestation day 7, a markedly reduced (low dose) or complete absence of implantation (mid and high doses) was observed. The effects on implantation in rodents are thought to be due to the prolactin-lowering effect of rotigotine. In humans, chorionic gonadotropin, not prolactin, is essential for implantation.
### Animal Toxicology and/or Pharmacology
Albino rats:
Retinal degeneration was observed in albino rats in a 6-month toxicity study at the highest dose of rotigotine (plasma exposure at least 15 times that in humans at the MRHD. Retinal degeneration was not observed in the 2-year carcinogenicity studies in albino rat (plasma AUCs up to 4-6 times that in humans at the MRHD) or albino mouse, or in monkeys treated for 1 year. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
# Clinical Studies
### Parkinson's Disease
The effectiveness of rotigotine in the treatment of the signs and symptoms of idiopathic Parkinson's disease was established in five parallel group, randomized, double-blind placebo-controlled trials conducted in the U.S. and abroad. Three of these five trials enrolled patients with early-stage Parkinson's disease (not receiving levodopa), and two enrolled patients with advanced-stage Parkinson's disease who were receiving levodopa. Depending on trial design, patients underwent a weekly titration of rotigotine in 2 mg/24 hours increments to either the randomized dose or optimal dose. Back titrations by 2 mg/24 hours decrement of rotigotine were permitted for intolerable adverse events. Patch application sites were changed on a daily basis.
Change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS), parts II + III, served as the primary outcome assessment measure in the early-stage studies. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV). Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. Part III is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.
Change from baseline in time spent "off" (hours) based on daily diaries was the primary outcome assessment in the two trials of advanced-stage Parkinson's disease (with levodopa).
Patients (N=649) in the three trials of early-stage Parkinson's disease had limited or no prior exposure to levodopa (off levodopa for at least 28 days prior to baseline or levodopa use for no more than 6 months). Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study.
PD-1
This trial was a multicenter, multinational dose-response study in which 316 early-stage Parkinson's disease patients were titrated over 4 weeks to their randomized treatment with either placebo or one of four fixed doses of rotigotine (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours). The patches were applied to the upper abdomen and the sites of application were rotated on a daily basis.
Patients underwent a weekly titration (increasing the number of 2 mg/24 hours patches or placebo patches at weekly intervals) over 4 weeks such that the target doses of rotigotine were achieved for all groups by the end of 3 weeks and were administered over the fourth week of the titration phase. Patients then continued on treatment for a 7 week maintenance phase followed by a down titration during the last week. Two back titrations by a single patch (i.e., 2 mg/24 hours decrement of rotigotine or placebo) at a time were permitted for intolerable adverse events. The mean age of patients was approximately 60 years (range 33-83 years; approximately 36 % were ≥ 65 years) and the study enrolled more men (62%) than women (39%). Most patients (85%) were Caucasian and most randomized patients (≥ 88%) completed the full treatment period.
Mean baseline combined UPDRS (Parts II + III) scores were similar among all treatment groups, between 27.1 and 28.5 for all groups. The mean change from baseline and difference from placebo for each treatment group is shown in Table 5. Statistically significant mean changes reflecting dose-related improvement were observed at the three highest doses, and the 6 mg/24 hours and 8 mg/24 hours doses had a similar effect.
PD-2
This trial was a randomized, double-blind, multinational, flexible rotigotine dose (2 mg/24 hours, 4 mg/24 hours, or 6 mg/24 hours), parallel group study in which 277 early-stage Parkinson's disease patients were assigned (2: 1 ratio) to treatment with rotigotine or placebo for a period up to about 28 weeks. This trial was conducted in 47 sites in North America (U.S. and Canada). Patches were applied to different body parts including upper or lower abdomen, thigh, hip, flank, shoulder, and/ or upper arm and patch application sites were to be rotated on a daily basis. Patients underwent a weekly titration (consisting of 2 mg/24 hours increments at weekly intervals) over 3 weeks to a maximal dose of 6 mg/24 hours depending on efficacy and tolerability, and then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 4 days. Back/down titration by a single patch (i.e., 2 mg/24 hours decrement of rotigotine or placebo) was permitted during the titration phase for intolerable adverse events but was not permitted during the maintenance phase (i.e., patients with intolerable adverse events had to leave the study). Primary efficacy data were collected after a treatment period of up to approximately 27 weeks.
The mean age of patients was approximately 63 years (range 32-86 years; approximately 45% were ≥65 years), approximately two-thirds of all patients were men, and nearly all patients were Caucasian. Approximately 90% of patients randomized to rotigotine achieved a maximal daily dose of 6 mg/24 hours; 70% maintained this dose for most (>20 weeks) of the maintenance phase. Most enrolled patients (≥81%) completed the full treatment period.
Mean baseline combined UPDRS (Parts II + III) was similar in both groups (29.9 rotigotine group, 30.0 placebo). Rotigotine-treated patients experienced a mean change in the combined UPDRS (Parts II + III) from baseline to end of treatment (end of treatment week 27 or last visit for patients discontinuing early) of -4.0 (Table 6), and the difference from placebo was statistically significant.
PD-3
This study was a randomized, double-blind multinational, flexible rotigotine dose (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours), three-arm, parallel-group study using a double-dummy treatment in which 561 early-stage Parkinson's disease patients were assigned to treatment with either placebo or rotigotine or active oral comparator in a ratio of 1: 2: 2 for a period up to about 39 weeks. This study was conducted in up to 81 sites in many countries outside of North America. Patches were applied to different body parts including upper or lower abdomen, thigh, hip, flank, shoulder, and/ or upper arm and patch application sites were to be rotated on a daily basis. Treatment with a patch and placebo was given to all patients in a double-blinded manner such that no one would know the actual treatment (i.e., rotigotine, comparator, or placebo). Patients underwent a weekly dose escalation/titration of patch (consisting of 2 mg/24 hours increments of rotigotine or placebo) and a dose escalation of capsules of comparator or placebo over 13 weeks (13 week titration was planned for the comparator treatment) up to a maximal dose of 8 mg/24 hours of rotigotine depending on achieving optimal efficacy or intolerability at a lower dose. Patients randomized to rotigotine achieved the maximal dose of 8 mg/24 hours after a 4 week titration if maximal efficacy and intolerability had not occurred over a 4 week titration period. Patients then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 12 days. A single back titration by a single patch (i.e., 2 mg/24 hours decrement of rotigotine or placebo) or capsule was permitted during the titration phase for intolerable adverse events but was not permitted during the maintenance phase (i.e., patients with intolerable adverse events had to discontinue from this study). Primary efficacy data were collected after a treatment period of up to approximately 37 weeks of randomized treatment.
The mean age of patients was approximately 61 years (range 30-86 years; approximately 41% were ≥65 years), nearly 60% of all patients were men, and nearly all patients were Caucasian. About 73% of patients completed the full treatment period. The mean daily dose of rotigotine was just less than 8 mg/24 hours and approximately 90 % of patients achieved the maximal daily dose of 8 mg/24 hours.
Mean baseline combined UPDRS (Parts II + III) was similar across all groups (33.2 rotigotine, 31.3 placebo, 32.2 comparator). rotigotine-treated patients experienced a mean change in the combined UPDRS (Parts II + III) from baseline to end of treatment (end of treatment week 37 or last visit for patients discontinuing early) of -6.8, and the difference from placebo treated patients showed a mean change from baseline of –2.3 (see TABLE 7), a difference that was statistically significant.
Patients (N=658) in the three trials of rotigotine in advanced-stage Parkinson's disease had to be experiencing "on-off" periods at baseline, despite treatment with optimal doses of levodopa. Patients continued concomitant levodopa during the trial; however, reductions in the dosage of levodopa were allowed if patients experienced adverse events that the investigator considered related to dopaminergic therapy. Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study. In the North American trial, COMT-inhibitors were not permitted.
PD-4
This trial was a multinational, three-arm, parallel group study in which 351 advanced-stage Parkinson's disease patients were titrated over 5 weeks to treatment with either placebo or rotigotine (8 mg/24 hours or 12 mg/24 hours) and maintained treatment for 24 weeks followed by a down titration over the last week. This study was conducted in 55 sites in North America (U.S. and Canada).
Mean baseline "off" times were similar among all treatment groups (6.4, 6.8, and 6.3 hours for the placebo, rotigotine 8 mg/24 hours and 12 mg/24 hours treatment groups, respectively). Rotigotine-treated patients experienced a mean change in "off" time from baseline to end of treatment of -2.7 hours for the 8 mg/24 hours treatment arm and -2.1 hours for the 12 mg/24 hours treatment arm (Table 8), and the difference from placebo was statistically significant for both rotigotine doses (8 mg/24 hours, 12 mg/24 hours). Onset of treatment benefit began as early as the first week of treatment.
PD-5
This trial was a multinational, flexible dose, three-arm, parallel-group study using a double-dummy treatment in which 506 advanced-stage Parkinson's disease patients were titrated over 7 weeks to treatment with either rotigotine from a minimum dose of 4 mg/24 hours up to an optimal dose not exceeding 16 mg/24 hours, active oral comparator, or placebo and maintained treatment for 16 weeks followed by a down titration over 6 days. This study was conducted in 77 sites in many countries outside of North America.
Mean baseline "off" times were similar among all treatment groups (6.6, 6.2, and 6.0 hours for the placebo, rotigotine, and comparator treatment groups, respectively). rotigotine-treated patients experienced a mean 2.5 hour decrease change in "off" time from baseline to end of treatment (Table 9), and the difference from placebo was statistically significant. Onset of treatment benefit began as early as the first week of treatment. The optimal rotigotine dose was established as 4 mg/24 hours for 2% of patients, 6 mg/24 hours for 6%, 8 mg/24 hours for 8%, 10 mg/24 hours for 9%, 12 mg/24 hours for 16%, 14 mg/24 hours for 11% and 16 mg/24 hours for 44%.
### Restless Legs Syndrome
The clinical program included 1309 patients with moderate to severe RLS. The efficacy of rotigotine in the treatment of Restless Legs Syndrome (RLS) was primarily evaluated in 2 fixed-dose, randomized, double-blind, placebo-controlled trials with maintenance periods of 6 months duration. Patients received rotigotine doses ranging from 0.5 mg/24 hours to 3 mg/24 hours or placebo once daily. In these 2 trials, the mean duration of RLS was 2.1 to 3.1 years, mean age was approximately 55 years (range 19-78 years), approximately 68% were women, and 97% were Caucasian. In both trials, patches were applied to different application sites including the abdomen, thigh, hip, flank, shoulder, and/or upper arm and patch application sites were rotated on a daily basis.
The two outcome measures used to assess the effect of treatment as co-primary efficacy endpoints were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.
RLS-1
This trial was a multicenter, 5-arm, parallel-group, fixed-dose trial of rotigotine in subjects with moderate-to-severe RLS. A total of 505 subjects were randomized in this trial, participating at approximately 50 sites in the US. Subjects received placebo or rotigotine (0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Subjects began treatment at a daily dosage of 0.5 mg/24 hours rotigotine and were titrated over a 4 week period to their assigned daily dose followed by a 6 month maintenance period and 7 day down titration period.
Mean baseline IRLS sum score were similar among all treatment groups (23.5, 23.1, 23.2, 23.3, and 23.6 for the placebo, rotigotine 0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 4 rotigotine dose groups. The mean changes from baseline and differences from placebo in IRLS sum score and CGI Item 1 are shown for each treatment group in Table 10. The difference between the 2 highest treatment groups (2 mg/24 hours and 3 mg/24 hours) and placebo were statistically significant. Of the rotigotine-treated patients, 23% had an IRLS score of 0 compared to 9.1% of placebo patients at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.
RLS-2
This trial was a multicenter, 4-arm, parallel-group trial of rotigotine in subjects with moderate-to-severe RLS. A total of 458 subjects were randomized in this trial, participating at approximately 50 sites in 8 European countries. Patients received placebo or rotigotine (1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Patients began treatment at a daily dosage of 1 mg/24 hours rotigotine and were titrated over a 3 week period to their assigned daily dose followed by a 6 month maintenance period and 7 day down-titration period.
Mean baseline IRLS sum score were similar among all treatment groups (28.1, 28.1, 28.2, and 28.0 for the placebo, rotigotine 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 3 rotigotine dose groups. The mean changes from baseline and differences from placebo in IRLS sum score and CGI Item 1 are shown for each treatment group in Table 11. The difference between all 3 treatment groups (1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours) and placebo were statistically significant. Of the rotigotine-treated patients, 24% had an IRLS score of 0 compared to 12% of placebo patients at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.
# How Supplied
- Each transdermal system is packaged in a separate pouch.
- Each strength is available in cartons of 30 transdermal systems.
## Storage
- Store at 20º - 25ºC (68º - 77ºF); excursions permitted between 15º - 30ºC (59º - 86ºF).
- Rotigotine should be stored in the original pouch.
- Do not store outside of pouch.
- Apply the transdermal system immediately upon removal from the pouch.
- Discard used systems in household trash in a manner that prevents accidental application or ingestion by children, pets or others.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Sulfite Sensitivity
Advise patients about potential for sulfite sensitivity. Rotigotine contains sodium metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people. An allergy to sulfites is not the same as an allergy to sulfa.
### Falling Asleep During Activities of Daily Living and Somnolence
Advise and alert patients about the potential for sedating effects associated with rotigotine, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with rotigotine to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of rotigotine.
Because of the possible additive effects, caution should also be used when patients are taking alcohol, sedating medications, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with rotigotine.
### Hallucinations / Psychotic-Like Behavior
Inform patients that hallucinations and other psychotic-like behavior can occur while taking rotigotine and that the elderly are at a higher risk than younger patients with Parkinson's disease.
### Symptomatic Hypotension
Advise patients that they may develop symptomatic (or asymptomatic) hypotension while taking rotigotine. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with rotigotine.
### Syncope
Advise patients about the potential for syncope in patients using dopamine agonists. For this reason, patients should be alerted to the possibility of syncope while taking rotigotine.
### Impulse Control / Compulsive Behaviors
Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications generally used for the treatment of Parkinson's disease, including rotigotine. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with rotigotine. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking rotigotine. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking rotigotine.
### Elevation of Blood Pressure and Heart Rate
Advise patients that rotigotine can increase blood pressure and heart rate.
### Weight Gain and Fluid Retention
Advise patients that rotigotine can cause increased weight and fluid retention manifesting itself as peripheral edema.
### Dyskinesias
Inform patients that rotigotine may cause and/or exacerbate pre-existing dyskinesias.
### Application Site Reactions
Inform patients that application site reactions can occur and that the rotigotine transdermal system application site should be rotated on a daily basis. Rotigotine should not be applied to the same application site more than once every 14 days. Patients should report persistent application site reaction (of more than a few days), increases in severity, or skin reactions that spread outside the application site.
If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be avoided until the skin heals. Exposure could lead to changes in the skin color.
### Melanoma
Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to monitor for melanomas frequently and on a regular basis when using rotigotine for any indication.
### Augmentation and Rebound in RLS
Inform patients that rotigotine may cause RLS symptoms to have an earlier onset during the day or become worse.
### Magnetic Resonance Imaging and Cardioversion
Inform patients to remove rotigotine before undergoing magnetic resonance imaging (MRI) or cardioversion. These procedures could cause a burn to the site where rotigotine is applied.
### Heat Application
Advise patients about the potential for heat application to increase drug absorption. Because applying external heat (e.g., a heating pad, sauna, or hot bath) to the transdermal system may increase the amount of drug absorbed, patients should be instructed not to apply heating pads or other sources of heat to the area of the transdermal system. Direct sun exposure of the transdermal system should be avoided.
### Nausea, Vomiting, and Dyspepsia
Inform patients that rotigotine causes nausea, vomiting, and general gastrointestinal distress (i.e., dyspepsia/abdominal discomfort). Nausea and vomiting may occur more frequently during initial therapy and may require dose adjustment.
### Instructions for Use
Instruct patients to wear rotigotine continuously for 24 hours. After 24 hours, the patch should be removed and a new one applied immediately. Patients can choose the most convenient time of day or night to apply rotigotine but should be advised to apply the patch at approximately the same time each day. If a patient forgets to change a patch, a new patch should be applied as soon as possible and replaced at the usual time the following day. Advise patients that they should only discontinue use of rotigotine under the supervision of a healthcare professional to prevent withdrawal issues.
The application site for rotigotine should be moved on a daily basis (for example, from the right side to the left side and from the upper body to the lower body). rotigotine should not be applied to the same application site more than once every 14 days.
Rotigotine should be applied immediately after opening the pouch and removing the protective liner. The system should be pressed firmly in place for 30 seconds, making sure there is good contact, especially around the edges.
Rotigotine should be applied once daily to clean, dry, and intact skin on the abdomen, thigh, hip, flank, shoulder, or upper arm. Shave hairy areas at least 3 days prior to applying the patch. Do not apply to areas that could be rubbed by tight clothing, or under a waistband, to skin folds, or to skin that is red or irritated. Creams, lotions, ointments, oils, and powders should not be applied to the skin area where rotigotine will be placed. Patients should wash their hands to remove any drug and should be careful not to touch their eyes or any objects.
Instruct patients not to cut or damage rotigotine.
Care should be used to avoid dislodging the patch while showering, bathing or during physical activity. If the edges of the patch lift, rotigotine may be taped down with bandage tape. If the patch detaches, a new one may be applied immediately to a different site. The patient should then change the patch according to their regular schedule.
Removal of the patch: Rotigotine should always be removed slowly and carefully to avoid irritation. After removal the patch should be folded over so that it sticks to itself and should be discarded so that children and pets cannot reach it. Wash the site with soap and water to remove any drug or adhesive. Baby or mineral oil may be used to remove any excess residue. Alcohol and other solvents (such as nail polish remover) may cause skin irritation and should not be used.
# Precautions with Alcohol
Alcohol-Rotigotine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Neupro
# Look-Alike Drug Names
There is limited information regarding Rotigotine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rotigotine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
# Disclaimer
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# Black Box Warning
# Overview
Rotigotine is a dopamine agonist that is FDA approved for the treatment of Parkinson's disease ,restless legs syndrome. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, insomnia and dyskinesia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Parkinson's Disease
- Treatment of the signs and symptoms of idiopathic Parkinson's disease.
- Rotigotine should be started at 2 mg/24 hours for patients with early-stage Parkinson's disease.
- Based upon individual patient clinical response and tolerability, rotigotine dosage may be increased weekly by 2 mg/24 hours if tolerated and if additional therapeutic effect is needed.
- The lowest effective dose was 4 mg/24 hours.
- The highest recommended dose for early-stage Parkinson's disease is 6 mg/24 hours.
Patients with advanced-stage Parkinson's disease may be initiated at 4 mg/24 hours. Based upon individual patient clinical response and tolerability, rotigotine dosage may be increased weekly by 2 mg/24 hours. The recommended dose for advanced-stage Parkinson's disease is 8 mg/24 hours.
### Restless Legs Syndrome
- Treatment of moderate-to-severe primary Restless Legs Syndrome.
- Rotigotine should be started at 1 mg/24 hours. Based upon individual patient clinical response and tolerability, rotigotine dosage may be increased weekly by 1 mg/24 hours if tolerated and if additional therapeutic effect is needed.
- The lowest effective dose was 1 mg/24 hours.
- The highest recommended dose is 3 mg/24 hours.
### Discontinuation of Treatment
For patients with Parkinson's disease, the daily dose should be reduced by a maximum of 2 mg/24 hours with a dose reduction preferably every other day, until complete withdrawal of rotigotine is achieved.
For patients with RLS, the daily dose should be reduced by 1 mg/24 hours preferably every other day, until complete withdrawal of rotigotine is achieved.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rotigotine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rotigotine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Rotigotine 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 Rotigotine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rotigotine in pediatric patients.
# Contraindications
- Rotigotine is contraindicated in patients who have demonstrated hypersensitivity to rotigotine or the components of the transdermal system.
# Warnings
Patients should be monitored for developing adverse reactions described in this section. If any of these adverse reactions develop, lowering or discontinuing the dose of rotigotine may be beneficial.
### Sulfite Sensitivity
- Rotigotine contains sodium metabisulfite, asulfite that may cause allergic-type reactions including anaphylactic symptoms and life t
- The overall prevalence of sulfite sensitivity in the general population is unknown.
- Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
### Falling Asleep During Activities of Daily Living and Somnolence
- Patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome treated with rotigotine have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on rotigotine, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.
- Some of these events have been reported as late as one year after initiation of treatment.
- In trials of Restless Legs Syndrome, 2% of patients treated with the highest recommended rotigotine dose (3 mg/24 hours) reported sleep attacks vs. 0% of placebo patients.
- Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.
- Somnolence is a common occurrence in patients receiving rotigotine.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for somnolence was 16% for early-stage Parkinson's disease, 4% for advanced-stage Parkinson's disease, and 6% for Restless Legs Syndrome.
- Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with rotigotine.
- Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities during treatment with rotigotine.
- Before initiating treatment with rotigotine, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase this risk with rotigotine such as concomitant sedating medications and the presence of sleep disorders.
- If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), rotigotine should ordinarily be discontinued.
- If a decision is made to continue rotigotine, patients should be advised not to drive and to avoid other potentially dangerous activities.
- There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
### Hallucinations / Psychotic-Like Behavior
- There was an increased risk for hallucinations in patients with advanced-stage Parkinson's disease treated with rotigotine.
- For the highest recommended rotigotine dose, the incidence of the treatment difference (rotigotine % - placebo %) for hallucinations was 4% for patients with advanced-stage Parkinson's disease, and this difference increased with increasing dose.
- Hallucinations were of sufficient severity to cause discontinuation of treatment (mainly during the dose escalation/titration period) in 3% of advanced-stage Parkinson's disease patients treated with the highest recommended dose of rotigotine compared with 1% of placebo treated patients.
- Hallucinations have also been reported in post-marketing reports.
- Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during rotigotine treatment or after starting or increasing the dose of rotigotine.
- Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. These various manifestations of psychotic-like behavior were also observed during the clinical development of rotigotine for early- and advanced-stage Parkinson's disease and Restless Legs Syndrome.
- Patients with a major psychotic disorder should ordinarily not be treated with rotigotine because of the risk of exacerbating psychosis.
- In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of rotigotine.
### Symptomatic Hypotension
- Dopaminergic agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, especially during dose escalation. *Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, both Parkinson's and RLS patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk.
- Mild-moderate decreases in systolic blood pressure (≥ 20 mm Hg) and in diastolic blood pressure (≥ 10 mm Hg) occurred more frequently (rotigotine % ≥ 5% greater than placebo %) in all patients (i.e., early- and advanced-stage Parkinson's disease and Restless Legs Syndrome) with the highest recommended rotigotine dose. These decreases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position. More severe decreases in systolic blood pressure (> 40 mm Hg) and in diastolic blood pressure (≥ 20 mm Hg) also occurred more frequently (rotigotine % ≥ 2% greater than placebo %) in patients with early- and advanced-stage Parkinson's disease during measurements when supine, standing and/or changing from supine to standing position.
- Some threshold decreases in blood pressure described earlier appeared to be dependent on the dose of rotigotine and were also observed at the final study visit.
- An analysis using a variety of adverse reaction terms suggestive of orthostatic hypotension, including dizziness/postural dizziness and others, showed an increased risk for all patients treated with rotigotine.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for adverse reactions suggestive of hypotension/orthostatic hypotension was 18% for early-stage Parkinson's disease, 4% for advanced-stage Parkinson's disease, and 1% for Restless Legs Syndrome.
- This increased risk for symptomatic hypotension and decreases in blood pressure was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this study. The increased risk for significant decreases in blood pressure or orthostatic hypotension occurred especially in the dose escalation/titration period.
### Syncope
- Syncope has been reported in patients using dopamine agonists, and for this reason patients should be alerted to the possibility of syncope. *Because the studies of rotigotine excluded patients with clinically relevant cardiovascular disease, patients with severe cardiovascular disease should be treated with caution.
### Impulse Control / Compulsive Behaviors
- Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including rotigotine, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease.
- In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with rotigotine.
- Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking rotigotine.
### Elevation of Blood Pressure and Heart Rate
- Some patients treated with rotigotine exhibited moderately severe increases in systolic blood pressure (> 180 mm Hg) and/or in diastolic blood pressure (> 105 mm Hg) while supine and/or standing.
- In patients with advanced-stage Parkinson's disease, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 2% for systolic blood pressure > 180 mm Hg and of 4% for diastolic blood pressure > 105 mm Hg. In patients with Restless Legs Syndrome, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 4% for diastolic blood pressure > 105 mm Hg.
Mild-moderate increases in systolic blood pressure (≥ 20 mm Hg) and in diastolic blood pressure (≥ 10 mm Hg) occurred more frequently (rotigotine % ≥ 5% greater than placebo %) in all patients (i.e., early- and advanced-stage Parkinson's disease and Restless Legs Syndrome) with the highest recommended rotigotine dose.
- These increases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position.
- More severe increases in systolic blood pressure (> 40 mm Hg) and in diastolic blood pressure (≥ 20 mm Hg) also occurred more frequently (rotigotine % ≥ 2% greater than placebo %) in patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome during measurements when supine, standing and/or changing from supine to standing position.
- Some threshold increases in blood pressure described earlier appeared to be dependent on the dose of rotigotine and were also observed at the final study visit.
- In the placebo-controlled trials, there was an increased risk for hypertension as an adverse reaction with the highest recommended dose for advanced-stage Parkinson's disease (rotigotine 3% vs. placebo 0%) and for Restless Legs Syndrome (rotigotine 4% vs. placebo 0%).
- Some patients treated with rotigotine exhibited moderately increased pulse (> 100 beats per minute) while supine and/or standing. In patients with advanced-stage Parkinson's disease, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 2% for increased pulse. In patients with Restless Legs Syndrome, there was an increased risk (treatment difference = highest recommended rotigotine dose % - placebo %) of 5% for increased pulse.
- These findings of blood pressure and heart rate elevations should be considered when treating patients with cardiovascular disease.
### Weight Gain and Fluid Retention
- Patients taking the highest recommended rotigotine dose for early-stage Parkinson's disease had a higher incidence (2%) of substantial weight gain (more than 10% of baseline weight) than subjects taking placebo (0%).
- In advanced-stage Parkinson's disease, the incidence of weight gain more than 10% of baseline weight was 9% rotigotine (for highest recommended dose) and 1% placebo. This weight gain was frequently associated with the development of peripheral edema in patients with Parkinson's disease, suggesting that rotigotine may cause substantial fluid retention in some Parkinson's patients. Although the weight gain was usually well-tolerated in subjects observed in the Parkinson's clinical studies, it could cause greater difficulty in patients who may be especially vulnerable to negative clinical consequences from fluid retention such as those with significant congestive heart failure or renal insufficiency.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for peripheral edema was 1% for early-stage Parkinson's disease, and 8% for advanced-stage Parkinson's disease. *These treatment differences increased further with treatment at rotigotine dosing above the highest recommended doses.
### Dyskinesia
- Rotigotine may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate pre-existing dyskinesia.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for dyskinesia was 7% for patients with advanced-stage Parkinson's disease, and this incidence increased with increasing dose.
- There was also an increased risk (rotigotine 3% vs. placebo 0%) for discontinuation from the study because of dyskinesia for the highest recommended rotigotine dose in these same patients.
### Application Site Reactions
- Application site reactions (ASRs) were reported at a greater frequency in the rotigotine-treated patients than in placebo patients in the double-blind, placebo-controlled dose-response studies with rotigotine.
- For the highest recommended rotigotine dose, the treatment different incidence (rotigotine % - placebo %) for various ASRs was 15% for early-stage Parkinson's disease, 23% for advanced-stage Parkinson's disease, and 39% for Restless Legs Syndrome.
- ASRs exhibited a dose-dependent relationship for all doses for patients with early- and advanced-stage Parkinson's disease and Restless Legs Syndrome.
- ASRs were also of sufficient severity to cause study discontinuation for patients with early-stage Parkinson's disease (rotigotine 3% vs. placebo 0%), advanced-stage Parkinsons's disease (rotigotine 2% vs. placebo 0%, and Restless Legs Syndrome (rotigotine 12% vs. placebo 0%) who were treated with the highest recommended rotigotine dose.
- Of ASRs in rotigotine-treated patients, most were mild or moderate in intensity.
- The signs and symptoms of these reactions generally were localized erythema, edema, or pruritus limited to the patch area and usually did not lead to dose reduction.
- Generalized skin reactions (e.g., allergic rash, including erythematous, macular-papular rash, or pruritus), have been reported at lower rates than ASRs during the development of rotigotine.
- In a clinical study designed to investigate the cumulative skin irritation of rotigotine, daily rotation of rotigotine application sites has been shown to reduce the incidence of ASRs in comparison to repetitive application to the same site.
- In a clinical study investigating the skin sensitizing potential of rotigotine in 221 healthy subjects, no case of contact sensitization was observed. *Localized sensitization reactions were observed in a study with healthy subjects by continuously rotating a 0.5 mg/24 hours transdermal system, after induction of maximal irritational stress was achieved by repetitive transdermal system application to the same site.
- If a patient reports a persistent application site reaction (of more than a few days), reports an increase in severity, or reports a skin reaction spreading outside the application site, an assessment of the risk and benefits for the individual patient should be conducted.
- If a generalized skin reaction associated with the use of rotigotine is observed, rotigotine should be discontinued.
### Melanoma
- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using rotigotine for any indication.
- Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
### Augmentation and Rebound in RLS
- Augmentation is a worsening of RLS symptoms during treatment, leading to an increase in overall symptom severity or earlier time of symptom onset each day compared to before initiation of treatment.
- Use of dopaminergic medicinal products, including rotigotine, may result in augmentation.
Rebound, an exacerbation of RLS symptoms, is considered to be an end of dose effect, related to the half-life of the therapeutic agent. Reports in the published literature indicate discontinuation or wearing off of dopaminergic medications can result in rebound.
### Magnetic Resonance Imaging and Cardioversion
- The backing layer of rotigotine contains aluminum.
- To avoid skin burns, rotigotine should be removed prior to magnetic resonance imaging or cardioversion.
### Heat Application
- The effect of application of heat to the transdermal system has not been studied. However, heat application has been shown to increase absorption several fold with other transdermal products.
- Patients should be advised to avoid exposing the rotigotine application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.
### Withdrawal-Emergent-Hyperpyrexia and Confusion
- A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, and/or autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy. Therefore it is recommended that the dose be tapered at the end of rotigotine treatment as a prophylactic measure.
### Fibrotic Complications
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
### Binding to Melanin
- As has been reported with other dopamine agonists, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat and monkey was evident after a single dose of rotigotine, but was slowly cleared over the 14-day observation period.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment / total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice.
Adverse Reactions Incidence in Controlled Clinical Studies in Early-Stage Parkinson's Disease
The safety of rotigotine was evaluated in a total of 649 early-stage Parkinson's disease patients who participated in three double-blind, placebo-controlled studies with durations of 3 to 9 months. Additional safety information was collected in short-term studies, and two open-label extension studies in patients with early-stage Parkinson's disease.
The incidence of adverse reactions in a randomized, double-blinded, placebo-controlled, fixed-dose trial is shown in Table 1. Incidences for the non-recommended 8 mg/24 hour dose are also shown.
In the double-blind, placebo-controlled, dose-response study in patients with early-stage Parkinson's disease, the most commonly observed adverse reactions (≥ 5% greater than placebo) for the highest recommended dose of rotigotine (6 mg/24 hours) were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, hyperhidrosis, and insomnia.
In this trial, 12% of patients treated with the highest, recommended rotigotine dose (6 mg/24 hours) discontinued treatment because of adverse reactions, compared with 6% of patients who received placebo.
The incidence of certain adverse reactions with rotigotine treatment was notably increased compared to placebo treatment (i.e., rotigotine % - placebo % = ≥ 5%) in either the titration or maintenance phases of the dose-response trial. During the titration phase, an increased incidence (in descending order of % treatment difference) was observed for nausea, somnolence, vomiting, application site reactions (ASRs), dizziness, sweating increased, anorexia and vision abnormal. During the maintenance phase, an increased incidence was observed for nausea, and ASRs. Some adverse reactions developing in the titration phase persisted (≥ 7 days) into the maintenance phase. These "persistent" adverse reactions included ASRs, anorexia, somnolence, nausea, and vision abnormal.
Adverse Reactions Incidence in Controlled Clinical Studies in Advanced-Stage Parkinson's Disease
The safety evaluation of rotigotine was based on a total of 672 rotigotine-treated subjects with advanced-stage Parkinson's disease who participated in 3 double-blind, placebo-controlled studies (2 fixed-dose trials and one flexible dose trial) with durations of 3 to 7 months. Patients received concomitant levodopa in these studies. Additional safety information was collected in earlier short-term studies, and 2 open-label extension studies in subjects with advanced-stage Parkinson's disease.
The incidence of adverse reactions in a randomized, double-blinded, placebo-controlled, fixed-dose trial is shown in Table 2. Incidences for the non-recommended 12 mg/24 hour dose are also shown.
In the dose-response, placebo-controlled trial for advanced-stage Parkinson's disease, the most common adverse reactions (≥ 5% greater than placebo) for the highest recommended dose of rotigotine (8 mg/24 hours) were application site reactions, nausea, somnolence, and headache.
In this trial, approximately 15% of patients treated with the highest, recommended rotigotine dose (8 mg/24 hours) discontinued treatment because of adverse reactions, compared with 9% of patients who received placebo.
The incidence of certain adverse reactions with rotigotine treatment was notably increased compared to placebo treatment (i.e., rotigotine % - placebo % = ≥ 5%) in either the titration or maintenance phases of the dose-response trial. During the titration phase, an increased incidence (in descending order of % treatment difference) was observed for nausea, hallucinations, constipation, dyskinesia, and dizziness. During the maintenance phase, an increased incidence was observed for ASRs, peripheral edema, and dyskinesia. Some adverse reactions developing in the titration phase persisted (≥ 7 days) into the maintenance phase. A notably "persistent" adverse reaction was ASRs.
Adverse Reactions Incidence in Controlled Clinical Studies in Restless Legs Syndrome
The safety evaluation of rotigotine was based on a total of 745 rotigotine-treated subjects with RLS who participated in 2 double-blind, placebo-controlled studies with maintenance durations of 6 months. Additional safety information was collected in earlier short-term studies, and 3 open-label extension studies in subjects with RLS.
The incidence of adverse reactions in two randomized, double-blinded, placebo-controlled, fixed-dose trials are shown in Table 3.
In the two randomized, double-blinded, placebo-controlled, fixed-dose trials for RLS, the most common adverse reactions (≥ 5% greater than placebo) for the highest recommended dose of rotigotine (3 mg/24 hours) were application site reactions, nausea, somnolence, and headache.
In the two dose-response, placebo-controlled trials, 24% of rotigotine-treated patients treated with the highest recommended dose (3 mg/24 hours) discontinued treatment because of adverse reactions, compared with 3% of patients who received placebo.
The incidence of certain adverse reactions with rotigotine treatment was notably increased compared to placebo treatment (i.e., rotigotine % - placebo % = ≥ 5%) in either the titration or maintenance phases of the dose-response trials. During the titration phase, an increased incidence (in descending order of % treatment difference) was observed for ASRs, and disturbances in initiating and/or maintaining sleep. During the maintenance phase, an increased incidence was observed for ASRs. Some adverse reactions developing in the titration phase persisted (≥ 7 days) into the maintenance phase. These "persistent" adverse reactions were ASRs, nausea, and disturbances in initiating and/or maintaining sleep.
### Laboratory Changes
Some clinical laboratory analytes were abnormal for patients treated with the highest recommended rotigotine dose in the dose-response trials for patients with early- and advanced-stage Parkinson's disease and with RLS.
There was a treatment difference (rotigotine % - placebo %) of 6% for decreased hemoglobin (below the normal reference range) and of 3% for decreased hematocrit (below the normal reference range) in patients with early-stage Parkinson's disease. There was a treatment difference of 4% for a decreased hemoglobin (below the normal reference range) and of 3% for decreased hematocrit (below the normal reference range) in patients with advanced-stage Parkinson's disease. There was a treatment difference of 3% for a decreased hemoglobin (below the normal reference range) in patients with RLS. There was also a treatment difference of 2% for markedly decreased hemoglobin and hematocrit in patients with advanced-stage Parkinson's disease and of 1% for markedly decreased hematocrit in patients with RLS.
There was a treatment difference of 9% for increased serum BUN (above the normal reference range) in patients with early-stage Parkinson's disease. There was a treatment difference of 1% for markedly increased serum BUN in patients with advanced-stage Parkinson's disease.
There was a treatment difference of 9% for decreased serum glucose (below the normal reference range) in patients with early-stage Parkinson's disease and of 3% in patients with advanced-stage Parkinson's disease. There was a treatment difference of 1% for markedly decreased serum glucose in patients with advanced-stage Parkinson's disease.
## Postmarketing Experience
There is limited information regarding Rotigotine Postmarketing Experience in the drug label.
# Drug Interactions
### Dopamine Antagonists
It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rotigotine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women. In studies conducted in mice, rats, and rabbits, rotigotine was shown to have adverse effects on embryo-fetal development when administered during pregnancy at doses similar to or lower than those used clinically. Rotigotine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Rotigotine administered subcutaneously (10, 30, or 90 mg/kg/day) to pregnant mice during organogenesis (gestation days 6 through 15) resulted in increased incidences of delayed skeletal ossification and decreased fetal body weights at the two highest doses and an increase in embryo-fetal death at the high dose. The no-effect dose for embryo-fetal developmental toxicity in mice is approximately 6 times the maximum recommended human dose (MRHD) for Parkinson's disease (8 mg/24 hours) on a body surface area (mg/m2) basis. Rotigotine administered subcutaneously (0.5, 1.5, or 5 mg/kg/day) to pregnant rats during organogenesis (gestation days 6 through 17) resulted in increased embryo-fetal death at all doses. The lowest effect dose is less than the MRHD on a mg/m2 basis. This effect in rats is thought to be due to the prolactin-lowering effect of rotigotine. When rotigotine was administered subcutaneously (5, 10, or 30 mg/kg/day) to pregnant rabbits during organogenesis (gestation days 7 through 19), an increase in embryo-fetal death occurred at the two highest doses tested. The no-effect dose is 12 times the MRHD on a mg/m2 basis.
In a study in which rotigotine was administered subcutaneously (0.1, 0.3, or 1 mg/kg/day) to rats throughout pregnancy and lactation (gestation day 6 through postnatal day 21), impaired growth and development during lactation and long-term neurobehavioral abnormalities were observed in the offspring at the highest dose tested; when those offspring were mated, growth and survival of the next generation were adversely affected. The no-effect dose for pre- and postnatal developmental toxicity (0.3 mg/kg/day) is less than the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rotigotine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rotigotine during labor and delivery.
### Nursing Mothers
Rotigotine decreases prolactin secretion in humans and could potentially inhibit lactation.
Studies have shown that rotigotine and/or its metabolite(s) are excreted in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when rotigotine is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients for any indication have not been established.
### Geriatic Use
Of subjects treated with rotigotine in clinical studies for the treatment of Parkinson's disease, approximately 50% were 65 years old and over, and approximately 11% were 75 and over. Among subjects treated with rotigotine in clinical studies for the treatment of RLS, 26% were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
No overall differences in plasma levels of rotigotine were observed between patients who were 65 to 80 years old compared with younger patients receiving the same rotigotine doses.
### Gender
There is no FDA guidance on the use of Rotigotine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rotigotine with respect to specific racial populations.
### Renal Impairment
The effect of renal function on rotigotine pharmacokinetics has been studied in subjects with mild to severe impairment of renal function including subjects requiring dialysis compared to healthy subjects. There were no relevant changes in rotigotine plasma concentrations. In subjects with severe renal impairment not on dialysis, (i.e., creatinine clearance 15 to <30 ml/min), exposure to rotigotine conjugates was doubled. No dosage adjustment is recommended.
### Hepatic Impairment
The effect of impaired hepatic function on the pharmacokinetics of rotigotine has been studied in subjects with moderate impairment of hepatic function (Child-Pugh classification – Grade B). There were no relevant changes in rotigotine plasma concentrations. No dose adjustment is necessary in subjects with moderate impairment of hepatic function. No information is available on subjects with severe impairment of hepatic function.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rotigotine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rotigotine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Transdermal
### Monitoring
- Careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation.
- Monitor for melanomas frequently and on a regular basis when using Neupro for any indication.
- Monitored for developing adverse reactions
# IV Compatibility
There is limited information regarding the compatibility of Rotigotine and IV administrations.
# Overdosage
Since rotigotine is a transdermal system, overdosing is not likely to occur in clinical practice unless patients forget to remove the previous day's transdermal system; patients should be advised regarding this possibility.
### Overdose Symptoms
The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation.
### Overdose Management
There is no known antidote for overdosage of dopamine agonists. In case of suspected overdose, the excess transdermal system(s) should immediately be removed from the patient. Concentrations of rotigotine decrease after patch removal. The terminal half-life of rotigotine is 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. If it is necessary to discontinue use of rotigotine after overdose, it should be discontinued gradually to prevent neuroleptic malignant syndrome. The daily dose should be reduced by 2 mg/24 hours for Parkinson's disease patients and 1 mg/24 hours for RLS patients with a dose reduction preferably every other day, until complete withdrawal of rotigotine is achieved. Before completely stopping use of rotigotine in the event of an overdose.
The patient should be monitored closely, including heart rate, heart rhythm, and blood pressure. As shown in a study of renally impaired patients, dialysis is not expected to be beneficial. Treatment of overdose may require general supportive measures to maintain vital signs.
# Pharmacology
## Mechanism of Action
Rotigotine is a non-ergoline dopamine agonist. The precise mechanism of action of rotigotine as a treatment for Parkinson's disease is unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudate-putamen in the brain. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine receptors.
## Structure
The chemical name of rotigotine is (6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol. The empirical formula is C19H25NOS. The molecular weight is 315.48. The structural formula for rotigotine is:
## Pharmacodynamics
### Cardiac Electrophysiology
There is no indication of a QT/QTc prolonging effect of rotigotine in doses up to 24 mg/24 hours. The effects of rotigotine at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose) parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
## Pharmacokinetics
On average, approximately 45% of the rotigotine from the patch is released within 24 hours (0.2 mg/cm2). Rotigotine is primarily eliminated in the urine as inactive conjugates. After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.
### Absorption and Bioavailability
When single doses of 8 mg/24 hours are applied to the trunk, there is an average lag time of approximately 3 hours until drug is detected in plasma (range 1 to 8 hours). Tmax typically occurs between 15 to 18 hours post dose but can occur from 4 to 27 hours post dose. However, there is no characteristic peak concentration observed. Rotigotine displays dose-proportionality over a daily dose range of 1 mg/24 hours to 24 mg/24 hours. In the clinical studies of rotigotine effectiveness, the transdermal system application site was rotated from day to day (abdomen, thigh, hip, flank, shoulder, or upper arm) and the mean measured plasma concentrations of rotigotine were stable over the six months of maintenance treatment. Relative bioavailability for the different application sites at steady-state was evaluated in subjects with Parkinson's disease. In a single trial conducted in patients with early-stage Parkinson's disease differences in bioavailability ranged from less than 1% (abdomen vs. hip) to 46% (shoulder vs. thigh) with shoulder application showing higher bioavailability.
Because rotigotine is administered transdermally, food should not affect absorption, and the product may be administered without regard to the timing of meals.
In a 14-day clinical study with rotigotine administered to healthy subjects, steady-state plasma concentrations were achieved within 2 to 3 days of daily dosing.
File:Rotigotine ADVERSE REACTIONS 3.png
### Distribution
The weight normalized apparent volume of distribution (Vd/F) in humans is approximately 84 L/kg after repeated dose administration.
The binding of rotigotine to human plasma proteins is approximately 92 % in vitro and 89.5 % in vivo.
### Metabolism and Elimination
Rotigotine is extensively metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine.
After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.
Rotigotine is primarily excreted in urine (~71%) as inactive conjugates of the parent compound and N-desalkyl metabolites. A smaller proportion is excreted in feces (~23%). The major metabolites found in urine were rotigotine sulfate (16% to 22% of the absorbed dose), rotigotine glucuronide (11% to 15%), and N-despropyl-rotigotine sulfate metabolite (14% to 20%) and N-desthienylethyl-rotigotine sulfate metabolite (10% to 21%). Approximately 11% is renally eliminated as other metabolites. A small amount of unconjugated rotigotine is renally eliminated (<1% of the absorbed dose).
### Drug Interaction Studies
In vitro studies indicate that multiple CYP-isoforms are capable of catalyzing the metabolism of rotigotine. In human liver microsomes, no extensive inhibition of the metabolism of rotigotine was observed when co-incubated with CYP isoform specific inhibitors. If an individual CYP isoform is inhibited, other isoforms can catalyze rotigotine metabolism.
Rotigotine, the 5-O-glucuronide and its desalkyl and monohydroxy metabolites were analyzed for interactions with the human CYP isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 in vitro. Based on these results, no risk for inhibition of CYP1A2, CYP2C9 and CYP3A4 catalyzed metabolism of other drugs is predicted at therapeutic rotigotine concentrations. There is a low risk of inhibition of CYP2C19 and CYP2D6 catalyzed metabolism of other drugs at therapeutic concentrations.
In human hepatocytes in vitro, there was no indication for induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4.
Rotigotine is metabolized by multiple sulfotransferases and two UDP-glucuronosyltransferases (UGT1A9 and UGT2B15). These multiple pathways make it unlikely that inhibition of any one pathway would alter rotigotine concentrations significantly.
In vitro, no potential for displacement of warfarin by rotigotine (and vice versa) from their respective human serum albumin binding sites was detected.
The effect of rotigotine on the pharmacokinetics of digoxin has been investigated in vitro in Caco-2 cells. Rotigotine did not influence the P-glycoprotein-mediated transport of digoxin. Therefore, rotigotine would not be expected to affect the pharmacokinetics of digoxin.
Co-administration of rotigotine (up to 4 mg/24 hours) with cimetidine (400 mg b.i.d.), an inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4, did not alter the steady-state pharmacokinetics of rotigotine in healthy subjects.
Co-administration of levodopa/carbidopa (100/25 mg b.i.d.) with rotigotine (4 mg/24 hours) had no effect on the steady-state pharmacokinetics of rotigotine; rotigotine had no effect on the pharmacokinetics of L-levodopa/carbidopa.
Co-administration of rotigotine (3 mg/24 hours) did not affect the pharmacodynamics and pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).
Co-administration of the CYP2C19 selective inhibitor omeprazole (40 mg/day) had no effect on the steady-state pharmacokinetics of rotigotine (4 mg/24 hours).
### Pharmacokinetics in Special Populations
There were no relevant changes in rotigotine plasma concentrations in subjects with moderate hepatic impairment (Child Pugh classification – Grade B). No information is available on subjects with severe impairment of hepatic function.
There were no relevant changes in rotigotine plasma concentrations (up to end stage renal disease requiring hemodialysis). In subjects with severe renal impairment not on dialysis, (i.e., creatinine clearance 15 to <30 ml/min), exposure to conjugated rotigotine metabolites was doubled.
Female and male subjects and patients had similar plasma concentrations (body weight normalized).
Plasma concentrations of rotigotine in patients 65 to 80 years of age were similar to those in younger patients, approximately 40 to 64 years of age. Although not studied, exposures in older subjects (>80 years) may be higher due to skin changes with aging.
The pharmacokinetics of rotigotine in subjects below the age of 18 years has not been established.
The pharmacokinetic profile was similar in Caucasians, Blacks, and Japanese. No dose adjustment is necessary based on ethnicity.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies of rotigotine were conducted in mice at doses of 0, 3, 10, and 30 mg/kg and in rats at doses of 0, 0.3, 1, and 3 mg/kg; in both studies rotigotine was administered subcutaneously once every 48 hours. No significant increases in tumors occurred in mice at doses up to 9 times the maximum recommended human dose (MRHD) in Parkinson's disease (8 mg/24 hours).
In rats, there were increases in Leydig cell tumors and in uterine tumors (adenocarcinomas, squamous cell carcinomas) at all doses. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. Therefore, there were no tumor findings considered relevant to humans at plasma exposures (AUC) up to 4-6 times that in humans at the MRHD.
Rotigotine was negative in the in vitro bacterial reverse mutation (Ames) and in the in vivo micronucleus assays. Rotigotine was mutagenic and clastogenic in the in vivo mouse lymphoma tk assay.
When rotigotine was administered subcutaneously (1.5, 5, or 15 mg/kg/day) to female rats prior to and during mating and continuing through gestation day 7, an absence of implantation was observed at all doses. The lowest dose tested is 2 times the MRHD on a mg/m2 basis. In male rats treated from 70 days prior to and during mating, there was no effect on fertility; however, a decrease in epididymal sperm motility was observed at the highest dose tested. The no-effect dose (5 mg/kg/day) is 6 times the MRHD on a mg/m2 basis. When rotigotine was administered subcutaneously to female mice at doses of 10, 30, and 90 mg/kg/day from 2 weeks until 4 days before mating and then at a dose of 6 mg/kg/day (all groups) (approximately 4 times the MRHD on a mg/m2 basis) from 3 days before mating until gestation day 7, a markedly reduced (low dose) or complete absence of implantation (mid and high doses) was observed. The effects on implantation in rodents are thought to be due to the prolactin-lowering effect of rotigotine. In humans, chorionic gonadotropin, not prolactin, is essential for implantation.
### Animal Toxicology and/or Pharmacology
Albino rats:
Retinal degeneration was observed in albino rats in a 6-month toxicity study at the highest dose of rotigotine (plasma exposure [AUC] at least 15 times that in humans at the MRHD. Retinal degeneration was not observed in the 2-year carcinogenicity studies in albino rat (plasma AUCs up to 4-6 times that in humans at the MRHD) or albino mouse, or in monkeys treated for 1 year. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
# Clinical Studies
### Parkinson's Disease
The effectiveness of rotigotine in the treatment of the signs and symptoms of idiopathic Parkinson's disease was established in five parallel group, randomized, double-blind placebo-controlled trials conducted in the U.S. and abroad. Three of these five trials enrolled patients with early-stage Parkinson's disease (not receiving levodopa), and two enrolled patients with advanced-stage Parkinson's disease who were receiving levodopa. Depending on trial design, patients underwent a weekly titration of rotigotine in 2 mg/24 hours increments to either the randomized dose or optimal dose. Back titrations by 2 mg/24 hours decrement of rotigotine were permitted for intolerable adverse events. Patch application sites were changed on a daily basis.
Change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS), parts II + III, served as the primary outcome assessment measure in the early-stage studies. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV). Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. Part III is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.
Change from baseline in time spent "off" (hours) based on daily diaries was the primary outcome assessment in the two trials of advanced-stage Parkinson's disease (with levodopa).
Patients (N=649) in the three trials of early-stage Parkinson's disease had limited or no prior exposure to levodopa (off levodopa for at least 28 days prior to baseline or levodopa use for no more than 6 months). Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study.
PD-1
This trial was a multicenter, multinational dose-response study in which 316 early-stage Parkinson's disease patients were titrated over 4 weeks to their randomized treatment with either placebo or one of four fixed doses of rotigotine (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours). The patches were applied to the upper abdomen and the sites of application were rotated on a daily basis.
Patients underwent a weekly titration (increasing the number of 2 mg/24 hours patches or placebo patches at weekly intervals) over 4 weeks such that the target doses of rotigotine were achieved for all groups by the end of 3 weeks and were administered over the fourth week of the titration phase. Patients then continued on treatment for a 7 week maintenance phase followed by a down titration during the last week. Two back titrations by a single patch (i.e., 2 mg/24 hours decrement of rotigotine or placebo) at a time were permitted for intolerable adverse events. The mean age of patients was approximately 60 years (range 33-83 years; approximately 36 % were ≥ 65 years) and the study enrolled more men (62%) than women (39%). Most patients (85%) were Caucasian and most randomized patients (≥ 88%) completed the full treatment period.
Mean baseline combined UPDRS (Parts II + III) scores were similar among all treatment groups, between 27.1 and 28.5 for all groups. The mean change from baseline and difference from placebo for each treatment group is shown in Table 5. Statistically significant mean changes reflecting dose-related improvement were observed at the three highest doses, and the 6 mg/24 hours and 8 mg/24 hours doses had a similar effect.
PD-2
This trial was a randomized, double-blind, multinational, flexible rotigotine dose (2 mg/24 hours, 4 mg/24 hours, or 6 mg/24 hours), parallel group study in which 277 early-stage Parkinson's disease patients were assigned (2: 1 ratio) to treatment with rotigotine or placebo for a period up to about 28 weeks. This trial was conducted in 47 sites in North America (U.S. and Canada). Patches were applied to different body parts including upper or lower abdomen, thigh, hip, flank, shoulder, and/ or upper arm and patch application sites were to be rotated on a daily basis. Patients underwent a weekly titration (consisting of 2 mg/24 hours increments at weekly intervals) over 3 weeks to a maximal dose of 6 mg/24 hours depending on efficacy and tolerability, and then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 4 days. Back/down titration by a single patch (i.e., 2 mg/24 hours decrement of rotigotine or placebo) was permitted during the titration phase for intolerable adverse events but was not permitted during the maintenance phase (i.e., patients with intolerable adverse events had to leave the study). Primary efficacy data were collected after a treatment period of up to approximately 27 weeks.
The mean age of patients was approximately 63 years (range 32-86 years; approximately 45% were ≥65 years), approximately two-thirds of all patients were men, and nearly all patients were Caucasian. Approximately 90% of patients randomized to rotigotine achieved a maximal daily dose of 6 mg/24 hours; 70% maintained this dose for most (>20 weeks) of the maintenance phase. Most enrolled patients (≥81%) completed the full treatment period.
Mean baseline combined UPDRS (Parts II + III) was similar in both groups (29.9 rotigotine group, 30.0 placebo). Rotigotine-treated patients experienced a mean change in the combined UPDRS (Parts II + III) from baseline to end of treatment (end of treatment week 27 or last visit for patients discontinuing early) of -4.0 (Table 6), and the difference from placebo was statistically significant.
PD-3
This study was a randomized, double-blind multinational, flexible rotigotine dose (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours), three-arm, parallel-group study using a double-dummy treatment in which 561 early-stage Parkinson's disease patients were assigned to treatment with either placebo or rotigotine or active oral comparator in a ratio of 1: 2: 2 for a period up to about 39 weeks. This study was conducted in up to 81 sites in many countries outside of North America. Patches were applied to different body parts including upper or lower abdomen, thigh, hip, flank, shoulder, and/ or upper arm and patch application sites were to be rotated on a daily basis. Treatment with a patch and placebo was given to all patients in a double-blinded manner such that no one would know the actual treatment (i.e., rotigotine, comparator, or placebo). Patients underwent a weekly dose escalation/titration of patch (consisting of 2 mg/24 hours increments of rotigotine or placebo) and a dose escalation of capsules of comparator or placebo over 13 weeks (13 week titration was planned for the comparator treatment) up to a maximal dose of 8 mg/24 hours of rotigotine depending on achieving optimal efficacy or intolerability at a lower dose. Patients randomized to rotigotine achieved the maximal dose of 8 mg/24 hours after a 4 week titration if maximal efficacy and intolerability had not occurred over a 4 week titration period. Patients then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 12 days. A single back titration by a single patch (i.e., 2 mg/24 hours decrement of rotigotine or placebo) or capsule was permitted during the titration phase for intolerable adverse events but was not permitted during the maintenance phase (i.e., patients with intolerable adverse events had to discontinue from this study). Primary efficacy data were collected after a treatment period of up to approximately 37 weeks of randomized treatment.
The mean age of patients was approximately 61 years (range 30-86 years; approximately 41% were ≥65 years), nearly 60% of all patients were men, and nearly all patients were Caucasian. About 73% of patients completed the full treatment period. The mean daily dose of rotigotine was just less than 8 mg/24 hours and approximately 90 % of patients achieved the maximal daily dose of 8 mg/24 hours.
Mean baseline combined UPDRS (Parts II + III) was similar across all groups (33.2 rotigotine, 31.3 placebo, 32.2 comparator). rotigotine-treated patients experienced a mean change in the combined UPDRS (Parts II + III) from baseline to end of treatment (end of treatment week 37 or last visit for patients discontinuing early) of -6.8, and the difference from placebo treated patients showed a mean change from baseline of –2.3 (see TABLE 7), a difference that was statistically significant.
Patients (N=658) in the three trials of rotigotine in advanced-stage Parkinson's disease had to be experiencing "on-off" periods at baseline, despite treatment with optimal doses of levodopa. Patients continued concomitant levodopa during the trial; however, reductions in the dosage of levodopa were allowed if patients experienced adverse events that the investigator considered related to dopaminergic therapy. Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study. In the North American trial, COMT-inhibitors were not permitted.
PD-4
This trial was a multinational, three-arm, parallel group study in which 351 advanced-stage Parkinson's disease patients were titrated over 5 weeks to treatment with either placebo or rotigotine (8 mg/24 hours or 12 mg/24 hours) and maintained treatment for 24 weeks followed by a down titration over the last week. This study was conducted in 55 sites in North America (U.S. and Canada).
Mean baseline "off" times were similar among all treatment groups (6.4, 6.8, and 6.3 hours for the placebo, rotigotine 8 mg/24 hours and 12 mg/24 hours treatment groups, respectively). Rotigotine-treated patients experienced a mean change in "off" time from baseline to end of treatment of -2.7 hours for the 8 mg/24 hours treatment arm and -2.1 hours for the 12 mg/24 hours treatment arm (Table 8), and the difference from placebo was statistically significant for both rotigotine doses (8 mg/24 hours, 12 mg/24 hours). Onset of treatment benefit began as early as the first week of treatment.
PD-5
This trial was a multinational, flexible dose, three-arm, parallel-group study using a double-dummy treatment in which 506 advanced-stage Parkinson's disease patients were titrated over 7 weeks to treatment with either rotigotine from a minimum dose of 4 mg/24 hours up to an optimal dose not exceeding 16 mg/24 hours, active oral comparator, or placebo and maintained treatment for 16 weeks followed by a down titration over 6 days. This study was conducted in 77 sites in many countries outside of North America.
Mean baseline "off" times were similar among all treatment groups (6.6, 6.2, and 6.0 hours for the placebo, rotigotine, and comparator treatment groups, respectively). rotigotine-treated patients experienced a mean 2.5 hour decrease change in "off" time from baseline to end of treatment (Table 9), and the difference from placebo was statistically significant. Onset of treatment benefit began as early as the first week of treatment. The optimal rotigotine dose was established as 4 mg/24 hours for 2% of patients, 6 mg/24 hours for 6%, 8 mg/24 hours for 8%, 10 mg/24 hours for 9%, 12 mg/24 hours for 16%, 14 mg/24 hours for 11% and 16 mg/24 hours for 44%.
### Restless Legs Syndrome
The clinical program included 1309 patients with moderate to severe RLS. The efficacy of rotigotine in the treatment of Restless Legs Syndrome (RLS) was primarily evaluated in 2 fixed-dose, randomized, double-blind, placebo-controlled trials with maintenance periods of 6 months duration. Patients received rotigotine doses ranging from 0.5 mg/24 hours to 3 mg/24 hours or placebo once daily. In these 2 trials, the mean duration of RLS was 2.1 to 3.1 years, mean age was approximately 55 years (range 19-78 years), approximately 68% were women, and 97% were Caucasian. In both trials, patches were applied to different application sites including the abdomen, thigh, hip, flank, shoulder, and/or upper arm and patch application sites were rotated on a daily basis.
The two outcome measures used to assess the effect of treatment as co-primary efficacy endpoints were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.
RLS-1
This trial was a multicenter, 5-arm, parallel-group, fixed-dose trial of rotigotine in subjects with moderate-to-severe RLS. A total of 505 subjects were randomized in this trial, participating at approximately 50 sites in the US. Subjects received placebo or rotigotine (0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Subjects began treatment at a daily dosage of 0.5 mg/24 hours rotigotine and were titrated over a 4 week period to their assigned daily dose followed by a 6 month maintenance period and 7 day down titration period.
Mean baseline IRLS sum score were similar among all treatment groups (23.5, 23.1, 23.2, 23.3, and 23.6 for the placebo, rotigotine 0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 4 rotigotine dose groups. The mean changes from baseline and differences from placebo in IRLS sum score and CGI Item 1 are shown for each treatment group in Table 10. The difference between the 2 highest treatment groups (2 mg/24 hours and 3 mg/24 hours) and placebo were statistically significant. Of the rotigotine-treated patients, 23% had an IRLS score of 0 compared to 9.1% of placebo patients at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.
RLS-2
This trial was a multicenter, 4-arm, parallel-group trial of rotigotine in subjects with moderate-to-severe RLS. A total of 458 subjects were randomized in this trial, participating at approximately 50 sites in 8 European countries. Patients received placebo or rotigotine (1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Patients began treatment at a daily dosage of 1 mg/24 hours rotigotine and were titrated over a 3 week period to their assigned daily dose followed by a 6 month maintenance period and 7 day down-titration period.
Mean baseline IRLS sum score were similar among all treatment groups (28.1, 28.1, 28.2, and 28.0 for the placebo, rotigotine 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 3 rotigotine dose groups. The mean changes from baseline and differences from placebo in IRLS sum score and CGI Item 1 are shown for each treatment group in Table 11. The difference between all 3 treatment groups (1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours) and placebo were statistically significant. Of the rotigotine-treated patients, 24% had an IRLS score of 0 compared to 12% of placebo patients at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.
# How Supplied
- Each transdermal system is packaged in a separate pouch.
- Each strength is available in cartons of 30 transdermal systems.
## Storage
- Store at 20º - 25ºC (68º - 77ºF); excursions permitted between 15º - 30ºC (59º - 86ºF).
- Rotigotine should be stored in the original pouch.
- Do not store outside of pouch.
- Apply the transdermal system immediately upon removal from the pouch.
- Discard used systems in household trash in a manner that prevents accidental application or ingestion by children, pets or others.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Sulfite Sensitivity
Advise patients about potential for sulfite sensitivity. Rotigotine contains sodium metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people. An allergy to sulfites is not the same as an allergy to sulfa.
### Falling Asleep During Activities of Daily Living and Somnolence
Advise and alert patients about the potential for sedating effects associated with rotigotine, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with rotigotine to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of rotigotine.
Because of the possible additive effects, caution should also be used when patients are taking alcohol, sedating medications, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with rotigotine.
### Hallucinations / Psychotic-Like Behavior
Inform patients that hallucinations and other psychotic-like behavior can occur while taking rotigotine and that the elderly are at a higher risk than younger patients with Parkinson's disease.
### Symptomatic Hypotension
Advise patients that they may develop symptomatic (or asymptomatic) hypotension while taking rotigotine. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with rotigotine.
### Syncope
Advise patients about the potential for syncope in patients using dopamine agonists. For this reason, patients should be alerted to the possibility of syncope while taking rotigotine.
### Impulse Control / Compulsive Behaviors
Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications generally used for the treatment of Parkinson's disease, including rotigotine. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with rotigotine. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking rotigotine. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking rotigotine.
### Elevation of Blood Pressure and Heart Rate
Advise patients that rotigotine can increase blood pressure and heart rate.
### Weight Gain and Fluid Retention
Advise patients that rotigotine can cause increased weight and fluid retention manifesting itself as peripheral edema.
### Dyskinesias
Inform patients that rotigotine may cause and/or exacerbate pre-existing dyskinesias.
### Application Site Reactions
Inform patients that application site reactions can occur and that the rotigotine transdermal system application site should be rotated on a daily basis. Rotigotine should not be applied to the same application site more than once every 14 days. Patients should report persistent application site reaction (of more than a few days), increases in severity, or skin reactions that spread outside the application site.
If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be avoided until the skin heals. Exposure could lead to changes in the skin color.
### Melanoma
Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to monitor for melanomas frequently and on a regular basis when using rotigotine for any indication.
### Augmentation and Rebound in RLS
Inform patients that rotigotine may cause RLS symptoms to have an earlier onset during the day or become worse.
### Magnetic Resonance Imaging and Cardioversion
Inform patients to remove rotigotine before undergoing magnetic resonance imaging (MRI) or cardioversion. These procedures could cause a burn to the site where rotigotine is applied.
### Heat Application
Advise patients about the potential for heat application to increase drug absorption. Because applying external heat (e.g., a heating pad, sauna, or hot bath) to the transdermal system may increase the amount of drug absorbed, patients should be instructed not to apply heating pads or other sources of heat to the area of the transdermal system. Direct sun exposure of the transdermal system should be avoided.
### Nausea, Vomiting, and Dyspepsia
Inform patients that rotigotine causes nausea, vomiting, and general gastrointestinal distress (i.e., dyspepsia/abdominal discomfort). Nausea and vomiting may occur more frequently during initial therapy and may require dose adjustment.
### Instructions for Use
Instruct patients to wear rotigotine continuously for 24 hours. After 24 hours, the patch should be removed and a new one applied immediately. Patients can choose the most convenient time of day or night to apply rotigotine but should be advised to apply the patch at approximately the same time each day. If a patient forgets to change a patch, a new patch should be applied as soon as possible and replaced at the usual time the following day. Advise patients that they should only discontinue use of rotigotine under the supervision of a healthcare professional to prevent withdrawal issues.
The application site for rotigotine should be moved on a daily basis (for example, from the right side to the left side and from the upper body to the lower body). rotigotine should not be applied to the same application site more than once every 14 days.
Rotigotine should be applied immediately after opening the pouch and removing the protective liner. The system should be pressed firmly in place for 30 seconds, making sure there is good contact, especially around the edges.
Rotigotine should be applied once daily to clean, dry, and intact skin on the abdomen, thigh, hip, flank, shoulder, or upper arm. Shave hairy areas at least 3 days prior to applying the patch. Do not apply to areas that could be rubbed by tight clothing, or under a waistband, to skin folds, or to skin that is red or irritated. Creams, lotions, ointments, oils, and powders should not be applied to the skin area where rotigotine will be placed. Patients should wash their hands to remove any drug and should be careful not to touch their eyes or any objects.
Instruct patients not to cut or damage rotigotine.
Care should be used to avoid dislodging the patch while showering, bathing or during physical activity. If the edges of the patch lift, rotigotine may be taped down with bandage tape. If the patch detaches, a new one may be applied immediately to a different site. The patient should then change the patch according to their regular schedule.
Removal of the patch: Rotigotine should always be removed slowly and carefully to avoid irritation. After removal the patch should be folded over so that it sticks to itself and should be discarded so that children and pets cannot reach it. Wash the site with soap and water to remove any drug or adhesive. Baby or mineral oil may be used to remove any excess residue. Alcohol and other solvents (such as nail polish remover) may cause skin irritation and should not be used.
# Precautions with Alcohol
Alcohol-Rotigotine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Neupro[1]
# Look-Alike Drug Names
There is limited information regarding Rotigotine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Neupro | |
de4fd99ed50852c68f2929f9606a45273e556aac | wikidoc | NeuroNames | NeuroNames
NeuroNames is a system of nomenclature for the human and/or macaque brain.
It is maintained by the University of Washington and is a part of a tool called "BrainInfo". BrainInfo helps one identify structures in the brain. One can either search by a structure name or locate a structure in the brain atlas and get information such as its location in the classical brain hierarchy, other names used for the structure, the name in several languages, images of the structure, what cells it has, connectivity information and genes expressed there.
Currently, NeuroNames contains more than 15,000 neuroanatomical terms(and the number keeps increasing). In addition, it defines more than 1,500 other neuroanatomical entities.
It is a component of the Metathesaurus of the Unified Medical Language System. | NeuroNames
NeuroNames is a system of nomenclature for the human and/or macaque brain.
It is maintained by the University of Washington and is a part of a tool called "BrainInfo". BrainInfo helps one identify structures in the brain. One can either search by a structure name or locate a structure in the brain atlas and get information such as its location in the classical brain hierarchy, other names used for the structure, the name in several languages, images of the structure, what cells it has, connectivity information and genes expressed there.
Currently, NeuroNames contains more than 15,000 neuroanatomical terms(and the number keeps increasing). In addition, it defines more than 1,500 other neuroanatomical entities.
It is a component of the Metathesaurus of the Unified Medical Language System. | https://www.wikidoc.org/index.php/NeuroNames | |
73917ee94fa68378d54a4e9f883376ae0860e3f5 | wikidoc | Neuroligin | Neuroligin
Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-Neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse. Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components. Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures. Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis. In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders.
# Structure
Neuroligins bind with the aid of Ca2+ to the α-neurexin LNS (laminin, neurexin and sex hormone-binding globulin-like folding units) domains and to the β-neurexin LNS domain which then establishes a heterophilic trans-synaptic recognition code. Through the observation of the crystal structure of neuroligin-1, it was determined that neuroligin-1 forms a protein dimer when two neurexin-1 beta monomers bind to the neuroligin-1's two opposite surfaces. This forms a heterotetramer, which contains an interface for binding Ca2+. The interaction of neuroligin and neurexin to form a heterotetramer is monitored by alternatively spliced sites located near the binding interface for Ca2+ in both the neuroligin-1 and the neurexin-1 beta. Subsequently, the presence of native neuroligin dimers was confirmed in neurons through biochemical detection, which included heterodimers composed of different neuroligin species, increasing the potential heterogeneity of endogenous neuroligin core dimer complexes.
The extracellular domain of NLGN consists mostly of a region that is homologous to acetylcholinesterases, but the amino acids important for catalysis in AChE are not conserved in NLGN, which lack esterase activity. Furthermore, this AChE homologous region is crucial for the proper function of NLGN.
# Genetics
Neuroligins have been identified in both vertebrates and invertebrates, including humans, rodents, chickens, Drosophila melanogaster, Caenorhabditis elegans, honeybees and Aplysia. Three genes for neuroligin expression have been found in mice and rats, while humans express five genes. Drosophila express four genes, honeybees express five genes, and both C. elegans and Aplysia express a single gene for neuroligin.
The known neuroligin genes in Homo sapiens include NLGN1, NLGN2, NLGN3, NLGN4X and NLGN5 (also known as NLGN4Y). Each gene has been found to have unique influences on synaptic transmission.
## Expression
Expression of neuroligins may differ between species. Neuroligin 1 is expressed specifically in the CNS at excitatory synapses. In humans, expression of neuroligin 1 is low before birth and increases between postnatal days 1-8 and remains high through adulthood. This postnatal increase during active synaptogenesis corresponds to increased expression of postsynaptic density protein-95 (PSD-95). Neuroligin 2 is mainly concentrated at inhibitory synapses in the CNS, but in mice and humans it may also be expressed in tissues such as the pancreas, lung, endothelia, uterus and colon. Neuroligin 3 is expressed in CNS neurons, as well as a variety of glial cells in mice and rats and the brain, heart, skeletal muscle, placenta and pancreas in humans. Neuroligin 4X, found only in humans, is expressed in the heart, liver, skeletal muscle, pancreas and low levels in the brain. Neuroligin 5 (or 4Y), located on the Y chromosome, is only 19 amino acids different from neuroligin 4X. Neuroligin mRNA are present in human endothelial cells from large blood vessels and in Dorsal Root Ganglions.
## Alternative splicing
Alternative splicing, a modification that occurs after transcription of mRNA, regulates neuroligins’ binding selectivity for α- or β-neurexins as well as the function of synapses. Alternative splicing in neuroligins occurs in the main functional domain, the acetylcholinesterase-homologous region. Because neuroligin has two conserved splice sites in this region, sites A and B, up to four different isoforms are possible for each neuroligin gene. Neurexins also undergo alternative splicing, and certain splice variants of neuroligins and neurexins are more selective for one another. Specific pairing of splice variants also affects synaptic function. For example, neuroligins lacking the B splice insert and β-neurexins with the S4 insert promote differentiation of inhibitory, GABAergic synapses. On the other hand, neuroligins with the B insert and β-neurexins lacking the S4 insert promote differentiation of excitatory, glutamatergic synapses. The A insert may promote neuroligin localization and function at inhibitory synapses, but the mechanisms are unknown.
# Activity with neurexin
Neurexin and neuroligin work together to gather and maintain the cytoskeleton components needed to localize synaptic vesicles. Neurexin is necessary for containing the voltage-gated Ca2+ channels that are required for the release of vesicles, while neuroligin binds neurexin in order to localize the necessary neurotransmitter receptors and proteins for postsynaptic specialization. At the postsynaptic site, neuroligins are networked to specialized proteins that stimulate specific neurotransmitter receptors and channels to densely occupy specialized regions of the postsynaptic terminal during the maturation of the synapse. Because all developing synapses contain neurexins and neuroligins, developing cells can make many different connections to other cells.
# Synapse formation
Neuroligin is sufficient to form new functional presynaptic terminals in vitro. However, evidence suggests that additional adhesion molecules, such as immunoglobulin-domain and cadherin family proteins, mediate the initial contact between the axons and dendrites for a synapse. Neurexins and neuroligins then reinforce the contact.
In addition to the selectivity of splice variants, the levels of neuroligins, neurexins, and other interacting proteins present on the pre- and postsynaptic membranes influence the differentiation and balance of synapses. As synapses form during synaptogenesis, they differentiate into one of two categories: excitatory or inhibitory. Excitatory synapses increase probability of firing an action potential in the postsynaptic neuron and are often glutamatergic, or synapses in which the neurotransmitter glutamate is released. Inhibitory synapses decrease probability of firing an action potential in the postsynaptic neuron and are often GABAergic, in which the neurotransmitter GABA is released. Especially during early development, neurons must receive an appropriate balance of excitatory vs. inhibitory synaptic input, referred to as the E/I ratio. In fact, an imbalance in the E/I ratio is thought to be involved in autistic spectrum disorders.
Neuroligin 1 localizes at excitatory synapses, neuroligin 2 at inhibitory synapses and neuroligin 3 at both. Reduction in the levels of neuroligins 1, 2 and 3 results in a strong reduction of inhibitory input but little reduction in excitatory input. In addition, Neuroligins interacts with PSD-95, an intracellular protein that anchors synaptic proteins in the post-synaptic density of excitatory synapses, and gephyrin, the respective scaffolding protein of inhibitory post-synapses. In addition, neuroligin 2 and 4 specifically interact with collybistin a protein that regulates the localization of gephyrin. The level of PSD-95 appears to influence the balance of excitatory and inhibitory inputs. An increase in the ratio of PSD-95 to neuroligin resulted in an increase in the E/I ratio, and a decrease in the PSD-95/neuroligin ratio had the opposite effect. Also, overexpression of PSD-95 redirects neuroligin-2 from excitatory to inhibitory synapses, strengthening excitatory input and reducing inhibitory input. These interactions of neuroligin, neurexin and interacting proteins such as PSD-95 point to a potential regulatory mechanism that controls development and balance of excitatory and inhibitory synapses, governed by homeostatic feedback mechanisms.
# Clinical significance to ASD
Neuroligin dysfunction has been implicated in autism spectrum disorders. Different genetic alterations have been detected in neuroligin genes in patients with ASD, including point mutations, missense mutations and internal deletions. In studies done on family members with X-linked autism, specific mutations of NLGN3 and NLGN4 have been identified. These mutations have been shown to affect how neuroligins function and have been shown to interfere with synaptic transmission. 19 of the 69 known proteins mutated in X-linked autism encode postsynaptic proteins, Neuroligins included.
## NLGN3 mutations
A mutated NLGN3 gene, R451C, has been cloned. The mutant has been shown to cause defective neuroligin trafficking and retention of the mutant protein in the endoplasmic reticulum. The small amount of mutant protein that reached the cell membrane demonstrated diminished binding activity for neurexin-1, consistent with a loss of function. The mutant gene has been cloned and was introduced into mice, resulting in impaired social interactions, enhanced spatial learning abilities and increased inhibitory synaptic transmission. Deleting NLGN3 did not produce these effects, thus indicating R451C to be a gain-of-function mutation. This supports the claim that increased inhibitory synaptic transmission may contribute to human autism spectrum disorders.
## NLGN4 mutations
Mutations in NLGN4 have also been found in persons with X-linked autism. A frame shift mutation 1186T has been found to cause an early stop codon and premature protein truncation. This mutation results in intracellular retention of mutant proteins, possibly causing impaired function of a synaptic cell adhesion molecule, and modifying the binding of the neuroligin protein to its presynaptic partners, neurexins, thus interrupting essential synaptic function. Other mutations of NLGN4 found in relation to autism spectrum disorders include a 2-bp deletion, 1253delAG, in the NLGN4 gene, which causes a frameshift and a premature stop codon. Another mutation is a hemizygous deletion in the NLGN4 gene encompassing exons 4, 5 and 6. The 757-kb deletion was predicted to result in a significantly truncated protein. | Neuroligin
Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-Neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse.[2] Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components. Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures.[3] Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis.[4] In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders.[5]
# Structure
Neuroligins bind with the aid of Ca2+ to the α-neurexin LNS (laminin, neurexin and sex hormone-binding globulin-like folding units) domains and to the β-neurexin LNS domain which then establishes a heterophilic trans-synaptic recognition code.[6] Through the observation of the crystal structure of neuroligin-1, it was determined that neuroligin-1 forms a protein dimer when two neurexin-1 beta monomers bind to the neuroligin-1's two opposite surfaces. This forms a heterotetramer, which contains an interface for binding Ca2+. The interaction of neuroligin and neurexin to form a heterotetramer is monitored by alternatively spliced sites located near the binding interface for Ca2+ in both the neuroligin-1 and the neurexin-1 beta.[7] Subsequently, the presence of native neuroligin dimers was confirmed in neurons through biochemical detection, which included heterodimers composed of different neuroligin species,[8] increasing the potential heterogeneity of endogenous neuroligin core dimer complexes.
The extracellular domain of NLGN consists mostly of a region that is homologous to acetylcholinesterases, but the amino acids important for catalysis in AChE are not conserved in NLGN, which lack esterase activity. Furthermore, this AChE homologous region is crucial for the proper function of NLGN.[2]
# Genetics
Neuroligins have been identified in both vertebrates and invertebrates, including humans, rodents, chickens, Drosophila melanogaster, Caenorhabditis elegans, honeybees and Aplysia. Three genes for neuroligin expression have been found in mice and rats, while humans express five genes.[9] Drosophila express four genes, honeybees express five genes, and both C. elegans and Aplysia express a single gene for neuroligin.[10]
The known neuroligin genes in Homo sapiens include NLGN1, NLGN2, NLGN3, NLGN4X and NLGN5 (also known as NLGN4Y). Each gene has been found to have unique influences on synaptic transmission.
## Expression
Expression of neuroligins may differ between species. Neuroligin 1 is expressed specifically in the CNS at excitatory synapses. In humans, expression of neuroligin 1 is low before birth and increases between postnatal days 1-8 and remains high through adulthood. This postnatal increase during active synaptogenesis corresponds to increased expression of postsynaptic density protein-95 (PSD-95). Neuroligin 2 is mainly concentrated at inhibitory synapses in the CNS, but in mice and humans it may also be expressed in tissues such as the pancreas, lung, endothelia, uterus and colon. Neuroligin 3 is expressed in CNS neurons, as well as a variety of glial cells in mice and rats and the brain, heart, skeletal muscle, placenta and pancreas in humans. Neuroligin 4X, found only in humans, is expressed in the heart, liver, skeletal muscle, pancreas and low levels in the brain. Neuroligin 5 (or 4Y), located on the Y chromosome, is only 19 amino acids different from neuroligin 4X.[9] Neuroligin mRNA are present in human endothelial cells from large blood vessels [11] and in Dorsal Root Ganglions.[12]
## Alternative splicing
Alternative splicing, a modification that occurs after transcription of mRNA, regulates neuroligins’ binding selectivity for α- or β-neurexins as well as the function of synapses. Alternative splicing in neuroligins occurs in the main functional domain, the acetylcholinesterase-homologous region.[13] Because neuroligin has two conserved splice sites in this region, sites A and B, up to four different isoforms are possible for each neuroligin gene.[9] Neurexins also undergo alternative splicing, and certain splice variants of neuroligins and neurexins are more selective for one another. Specific pairing of splice variants also affects synaptic function. For example, neuroligins lacking the B splice insert and β-neurexins with the S4 insert promote differentiation of inhibitory, GABAergic synapses. On the other hand, neuroligins with the B insert and β-neurexins lacking the S4 insert promote differentiation of excitatory, glutamatergic synapses. The A insert may promote neuroligin localization and function at inhibitory synapses, but the mechanisms are unknown.[13]
# Activity with neurexin
Neurexin and neuroligin work together to gather and maintain the cytoskeleton components needed to localize synaptic vesicles. Neurexin is necessary for containing the voltage-gated Ca2+ channels that are required for the release of vesicles, while neuroligin binds neurexin in order to localize the necessary neurotransmitter receptors and proteins for postsynaptic specialization. At the postsynaptic site, neuroligins are networked to specialized proteins that stimulate specific neurotransmitter receptors and channels to densely occupy specialized regions of the postsynaptic terminal during the maturation of the synapse. Because all developing synapses contain neurexins and neuroligins, developing cells can make many different connections to other cells.[3]
# Synapse formation
Neuroligin is sufficient to form new functional presynaptic terminals in vitro.[9] However, evidence suggests that additional adhesion molecules, such as immunoglobulin-domain and cadherin family proteins, mediate the initial contact between the axons and dendrites for a synapse. Neurexins and neuroligins then reinforce the contact.[13]
In addition to the selectivity of splice variants, the levels of neuroligins, neurexins, and other interacting proteins present on the pre- and postsynaptic membranes influence the differentiation and balance of synapses. As synapses form during synaptogenesis, they differentiate into one of two categories: excitatory or inhibitory. Excitatory synapses increase probability of firing an action potential in the postsynaptic neuron and are often glutamatergic, or synapses in which the neurotransmitter glutamate is released. Inhibitory synapses decrease probability of firing an action potential in the postsynaptic neuron and are often GABAergic, in which the neurotransmitter GABA is released. Especially during early development, neurons must receive an appropriate balance of excitatory vs. inhibitory synaptic input, referred to as the E/I ratio. In fact, an imbalance in the E/I ratio is thought to be involved in autistic spectrum disorders.[14]
Neuroligin 1 localizes at excitatory synapses, neuroligin 2 at inhibitory synapses and neuroligin 3 at both. Reduction in the levels of neuroligins 1, 2 and 3 results in a strong reduction of inhibitory input but little reduction in excitatory input.[13] In addition, Neuroligins interacts with PSD-95, an intracellular protein that anchors synaptic proteins in the post-synaptic density of excitatory synapses, and gephyrin, the respective scaffolding protein of inhibitory post-synapses.[15] In addition, neuroligin 2 and 4 specifically interact with collybistin a protein that regulates the localization of gephyrin. The level of PSD-95 appears to influence the balance of excitatory and inhibitory inputs. An increase in the ratio of PSD-95 to neuroligin resulted in an increase in the E/I ratio, and a decrease in the PSD-95/neuroligin ratio had the opposite effect.[14] Also, overexpression of PSD-95 redirects neuroligin-2 from excitatory to inhibitory synapses, strengthening excitatory input and reducing inhibitory input.[13] These interactions of neuroligin, neurexin and interacting proteins such as PSD-95 point to a potential regulatory mechanism that controls development and balance of excitatory and inhibitory synapses, governed by homeostatic feedback mechanisms.[14]
# Clinical significance to ASD
Neuroligin dysfunction has been implicated in autism spectrum disorders. Different genetic alterations have been detected in neuroligin genes in patients with ASD, including point mutations, missense mutations and internal deletions.[11] In studies done on family members with X-linked autism, specific mutations of NLGN3 and NLGN4 have been identified. These mutations have been shown to affect how neuroligins function and have been shown to interfere with synaptic transmission. 19 of the 69 known proteins mutated in X-linked autism encode postsynaptic proteins, Neuroligins included.
## NLGN3 mutations
A mutated NLGN3 gene, R451C, has been cloned. The mutant has been shown to cause defective neuroligin trafficking and retention of the mutant protein in the endoplasmic reticulum.[16] The small amount of mutant protein that reached the cell membrane demonstrated diminished binding activity for neurexin-1, consistent with a loss of function.[17] The mutant gene has been cloned and was introduced into mice, resulting in impaired social interactions, enhanced spatial learning abilities and increased inhibitory synaptic transmission. Deleting NLGN3 did not produce these effects, thus indicating R451C to be a gain-of-function mutation. This supports the claim that increased inhibitory synaptic transmission may contribute to human autism spectrum disorders.[18]
## NLGN4 mutations
Mutations in NLGN4 have also been found in persons with X-linked autism. A frame shift mutation 1186T has been found to cause an early stop codon and premature protein truncation. This mutation results in intracellular retention of mutant proteins, possibly causing impaired function of a synaptic cell adhesion molecule,[16] and modifying the binding of the neuroligin protein to its presynaptic partners, neurexins, thus interrupting essential synaptic function.[19] Other mutations of NLGN4 found in relation to autism spectrum disorders include a 2-bp deletion, 1253delAG, in the NLGN4 gene, which causes a frameshift and a premature stop codon.[20] Another mutation is a hemizygous deletion in the NLGN4 gene encompassing exons 4, 5 and 6. The 757-kb deletion was predicted to result in a significantly truncated protein.[21] | https://www.wikidoc.org/index.php/Neuroligin | |
afb298866e4b560b6e862a5c086de56c39bbddbe | wikidoc | Neurotoxin | Neurotoxin
# Overview
A neurotoxin is a toxin that acts specifically on nerve cells – neurons – usually by interacting with membrane proteins such as ion channels. Many of the venoms and other toxins that organisms use in defense against vertebrates are neurotoxins. A common effect is paralysis, which sets in very rapidly. The venom of bees, scorpions, pufferfish, spiders and snakes can contain many different toxins. Many neurotoxins act by affecting voltage-dependent ion channels. For example, tetrodotoxin and batrachotoxin affect sodium channels, maurotoxin, agitoxin, charybdotoxin, margatoxin, slotoxin, scyllatoxin and hefutoxin act on potassium channels, and calciseptine, taicatoxin and calcicludine act on calcium channels.
Toxins ingested from the environment are described as exogenous and include gases (such as carbon monoxide), metals (such as mercury), liquids (ethanol) and an endless list of solids.
When exogenous toxins are ingested, the effect on neurons is largely dependent on dosage. Thus, ethanol (alcohol) is inebriating in low doses, only producing mild neurotoxicity. Prolonged exposure to "safe" alcohol levels slowly weakens and kills neurons.
Neurotoxicity also occurs from substances produced within the body - endogenous neurotoxins. A prime example of a neurotoxin in the brain is glutamate, which is paradoxically also a primary neurotransmitter. When the glutamate concentration around a neuron reaches a critical point the neuron kills itself by a process called apoptosis. This whole process is called excitotoxicity, so named because glutamate normally acts as an excitatory neurotransmitter at lower levels.
A potent neurotoxin such as batrachotoxin affects the nervous system by causing depolarization of nerve and muscle fibres due to increased sodium ion permeability of the excitable cell membrane.
A number of artificial neurotoxins, known as nerve agents, have been developed for use as chemical weapons.
A very potent neurotoxin is tetrodotoxin. This chemical acts to block sodium channels in neurons, preventing action potentials. This leads to paralysis and eventually death (Wski) | Neurotoxin
# Overview
A neurotoxin is a toxin that acts specifically on nerve cells – neurons – usually by interacting with membrane proteins such as ion channels. Many of the venoms and other toxins that organisms use in defense against vertebrates are neurotoxins. A common effect is paralysis, which sets in very rapidly. The venom of bees, scorpions, pufferfish, spiders and snakes can contain many different toxins. Many neurotoxins act by affecting voltage-dependent ion channels. For example, tetrodotoxin and batrachotoxin affect sodium channels, maurotoxin, agitoxin, charybdotoxin, margatoxin, slotoxin, scyllatoxin and hefutoxin act on potassium channels, and calciseptine, taicatoxin and calcicludine act on calcium channels.
Toxins ingested from the environment are described as exogenous and include gases (such as carbon monoxide), metals (such as mercury), liquids (ethanol) and an endless list of solids.
When exogenous toxins are ingested, the effect on neurons is largely dependent on dosage. Thus, ethanol (alcohol) is inebriating in low doses, only producing mild neurotoxicity. Prolonged exposure to "safe" alcohol levels slowly weakens and kills neurons.
Neurotoxicity also occurs from substances produced within the body - endogenous neurotoxins. A prime example of a neurotoxin in the brain is glutamate, which is paradoxically also a primary neurotransmitter. When the glutamate concentration around a neuron reaches a critical point the neuron kills itself by a process called apoptosis. This whole process is called excitotoxicity, so named because glutamate normally acts as an excitatory neurotransmitter at lower levels.
A potent neurotoxin such as batrachotoxin affects the nervous system by causing depolarization of nerve and muscle fibres due to increased sodium ion permeability of the excitable cell membrane.
A number of artificial neurotoxins, known as nerve agents, have been developed for use as chemical weapons.
A very potent neurotoxin is tetrodotoxin. This chemical acts to block sodium channels in neurons, preventing action potentials. This leads to paralysis and eventually death (Wski) | https://www.wikidoc.org/index.php/Neurotoxicology | |
174492697e87789801e81015234f17a07bdfbeea | wikidoc | Neutrospec | Neutrospec
NeutroSpec (Technetium fanolesomab) is a monoclonal antibody manufactured by Palatin Technologies and used in radiological imaging.
# History and Use
NeutroSpec was approved by the FDA in June 2004 for imaging of patients with symptoms of appendicitis. It consisted of a monoclonal antibody against CD15. The antibody was labeled with technetium-99 so as to be visible on a gamma camera. Since anti-CD15 antibodies bind selectively to Neutrophils it could be used to localize the site of an infection.
# Deaths and Associated Recall
The FDA received reports from Palatin Technologies of 2 deaths and 15 additional life-threatening adverse events in patients receiving NeutroSpec. These events occurred within minutes of administration of NeutroSpec and included shortness of breath, low blood pressure, and cardiopulmonary arrest. Affected patients required resuscitation with intravenous fluids, blood pressure support, and oxygen. Most, but not all, of the patients who experienced these events had existing cardiac and/or pulmonary conditions that may have placed them at higher risk for these adverse events. A review of all post-marketing reports showed an additional 46 patients who experienced adverse events that were similar but less severe. All of the reactions occurred immediately after NeutroSpec was administered.
Marketing of the product was suspended in December of 2005. | Neutrospec
NeutroSpec (Technetium fanolesomab) is a monoclonal antibody manufactured by Palatin Technologies and used in radiological imaging.
## History and Use
NeutroSpec was approved by the FDA in June 2004 for imaging of patients with symptoms of appendicitis. It consisted of a monoclonal antibody against CD15. The antibody was labeled with technetium-99 so as to be visible on a gamma camera. Since anti-CD15 antibodies bind selectively to Neutrophils it could be used to localize the site of an infection.
## Deaths and Associated Recall
The FDA received reports from Palatin Technologies of 2 deaths and 15 additional life-threatening adverse events in patients receiving NeutroSpec. These events occurred within minutes of administration of NeutroSpec and included shortness of breath, low blood pressure, and cardiopulmonary arrest. Affected patients required resuscitation with intravenous fluids, blood pressure support, and oxygen. Most, but not all, of the patients who experienced these events had existing cardiac and/or pulmonary conditions that may have placed them at higher risk for these adverse events. A review of all post-marketing reports showed an additional 46 patients who experienced adverse events that were similar but less severe. All of the reactions occurred immediately after NeutroSpec was administered.
Marketing of the product was suspended in December of 2005.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Neutrospec | |
9296c833953871e52dc8783a156387f37b9d6256 | wikidoc | Nevirapine | Nevirapine
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# Black Box Warning
# Overview
Nevirapine is a non-nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash and myalgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Nevirapine tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
- Dosage:
- One 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nevirapine in adult patients.
### Non–Guideline-Supported Use
- Prophylaxis of perinatal VIH infection
- Prophylaxis of post natal VIH infection
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Nevirapine tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
- Dosage for pediatric patients 15 days and older:
- 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter.
- The total daily dose should not exceed 400 mg for any patient.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nevirapine in pediatric patients.
### Non–Guideline-Supported Use
- Prophylaxis of perinatal VIH infection
- Prophylaxis of post natal VIH infection
# Contraindications
- Nevirapine tablets are contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
- Nevirapine is contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens.
# Warnings
The most serious adverse reactions associated with nevirapine are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy or renal dysfunction.
The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at 2 weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash.
Severe, life threatening and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups.
The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the subjects with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.
Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible.
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%) and patients with higher CD4+ cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). However, all patients, regardless of gender, CD4+ cell count or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+ cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated.
Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
Severe and life threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterized by rash, constitutional findings and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of nevirapine recipients compared to less than 1% of placebo subjects.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms or hypersensitivity reaction.
If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations.
Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase nevirapine dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved. The total duration of the once daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with nevirapine.
In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.
Nevirapine must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.
Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and nevirapine is not recommended. Coadministration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. Coadministration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# 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 associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy or renal dysfunction.
In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups. Female gender and higher CD4+ cell counts (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) place patients at increased risk of these events.
Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received nevirapine and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving nevirapine than in controls.
The most common clinical toxicity of nevirapine is rash, which can be severe or life threatening. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046 and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving nevirapine compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of nevirapine recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of nevirapine-associated rash.
Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving nevirapine in placebo-controlled trials are shown in Table 2.
Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving nevirapine than in controls. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue nevirapine therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing nevirapine and control regimens.
Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of nevirapine (n = 305) in which pediatric subjects received combination treatment with nevirapine. In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of nevirapine (n = 37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine. Cases of allergic reaction, including one case of anaphylaxis, were also reported.
The safety of nevirapine was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with nevirapine oral suspension, lamuvidine and zidovudine for 48 weeks. Rash (all causality) was reported in 21% of the subjects, four (3%) of whom discontinued drug due to rash. All four subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%) and hepatotoxicity (2%).
Safety information on use of nevirapine in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.
## Postmarketing Experience
In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of nevirapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Body as a Whole: fever, somnolence, drug withdrawal, redistribution/accumulation of body fat.
- Gastrointestinal: vomiting
- Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
- Hematology: anemia, eosinophilia, neutropenia
- Investigations: decreased serum phosphorus
- Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions
- Neurologic: paraesthesia
- Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported.
In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.
# Drug Interactions
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when coadministered with nevirapine.
The specific pharmacokinetic changes that occur with coadministration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction trials conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction trials in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when coadministering these drugs.
The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is coadministered with nevirapine, anticoagulation levels should be monitored frequently
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
There are no adequate and well controlled trials of nevirapine in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.
Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women.
Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nevirapine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nevirapine during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving nevirapine.
### Pediatric Use
The safety, pharmacokinetic profile and virologic and immunologic responses of nevirapine have been evaluated in HIV-1 infected pediatric subjects age 3 months to 18 years. The safety and pharmacokinetic profile of nevirapine has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3 months.
The most frequently reported adverse events related to nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine.
### Geriatic Use
Clinical trials of nevirapine did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection 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
Women appear to be at higher risk than men of developing rash with nevirapine.
### Race
An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.
### Renal Impairment
In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCL greater than or equal to 20 mL/min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated.
### Hepatic Impairment
Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
### Females of Reproductive Potential and Males
In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of nevirapine.
### Immunocompromised Patients
There is no FDA guidance one the use of Nevirapine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine tablets. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In some cases, hepatic injury has progressed despite discontinuation of treatment.
# IV Compatibility
There is limited information regarding the compatibility of Nevirapine and IV administrations.
# Overdosage
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 mg to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of nevirapine.
# Pharmacology
## Mechanism of Action
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, ß, γ or δ) are not inhibited by nevirapine.
## Structure
Nevirapine has the following structural formula:
## Pharmacodynamics
There is limited information regarding Nevirapine Pharmacodynamics in the drug label.
## Pharmacokinetics
Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar), (n = 242) were attained at 400 mg/day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate trial in HIV-1 infected subjects (n = 6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or didanosine.
Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg/mL. Nevirapine concentrations in human cerebrospinal fluid (n = 6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.
In vivo trials in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady-state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.
Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20% to 25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2 to 4 weeks of dosing with 200 to 400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25 to 30 hours following multiple dosing with 200 to 400 mg/day.
## Nonclinical Toxicology
The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14 to 302 nM, n = 29) against clinical isolates of HIV-1 clades A, B, C, D, F, G and H and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n = 3) or HIV-2 isolates (n = 3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.
HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n = 24) or nevirapine and ZDV (n = 14) were monitored in Phase 1 and 2 trials over 1 to ≥ 12 weeks. After one week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week 8 of nevirapine monotherapy, 100% of the subjects tested (n = 24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline and had one or more of the nevirapine-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n = 71) receiving nevirapine once daily (n = 25) or twice daily (n = 46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.
Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine and efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.
Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for 2 years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for 2 years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.
Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.
# Clinical Studies
Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2,249 HIV-1 infected subjects with less than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with nevirapine + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were nevirapine, 200 mg daily for 2 weeks followed by 200 mg twice daily or placebo and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1,309 subjects (58%), two or more NRTIs in 771 (34%) and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV-1 RNA of 4.58 log10 copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.
The change from baseline in CD4+ cell count through one year of therapy was significantly greater for the nevirapine group compared to the placebo group for the overall trial population (64 cells/mm3 vs. 22 cells/mm3, respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm3 vs. 25 cells/mm3, respectively).
At 2 years into the trial, 16% of subjects on nevirapine had experienced class C CDC events as compared to 21% of subjects on the control arm.
Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4+ cell counts of 200 to 600 cells/mm3 at baseline. BI 1046 compared treatment with nevirapine + zidovudine + didanosine to nevirapine + zidovudine and zidovudine + didanosine. Treatment doses were nevirapine at 200 mg daily for 2 weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily and didanosine at 125 mg or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log10 copies/mL (25,704 copies/mL) and mean baseline CD4+ cell count of 376 cells/mm3. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with nevirapine + zidovudine + didanosine, 19% for subjects treated with zidovudine + didanosine and 0% for subjects treated with nevirapine + zidovudine.
CD4+ cell counts in the nevirapine + ZDV + ddI group increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increase of 87 cells/mm3 in the ZDV + ddI subjects. The nevirapine + ZDV group mean decreased by 6 cells/mm3 below baseline.
The pediatric safety and efficacy of nevirapine was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received nevirapine oral suspension for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years and 12 to less than or equal to 16 years) and randomized to receive one of two nevirapine doses, determined by 2 different dosing methods in combination with zidovudine and lamivudine. The total daily dose of nevirapine did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.
Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log10 copies/mL and a median baseline CD4+ cell count of 527 cells/mm3 (range 37 to 2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, nine (7%) discontinued due to adverse reactions and three (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies/mL at 48 weeks was 47% (58/123).
# How Supplied
Nevirapine 200 mg tablets:
- Bottles of 60 tablets (NDC 0378-4050-91)
- Bottles of 180 tablets (NDC 0378-4050-80)
- Bottles of 500 tablets (NDC 0378-4050-05)
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C and/or increased transaminases at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the 2-week lead-in period, do not escalate the nevirapine dose until the rash resolves. The total duration of the once daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult a physician. Nevirapine tablets should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash.
Inform patients to take nevirapine tablets every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Advise patients to report to their doctor the use of any other medications.
Inform patients that it is not known whether nevirapine therapy reduces the risk of transmission of HIV-1 to others through sexual contact. Effective treatment combined with safer sex practices may reduce the chance of passing HIV to others through sexual contact. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.
Nevirapine is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Advise patients to remain under the care of a physician when using nevirapine.
Advise patients taking nevirapine oral suspension to ask their pharmacist for a dosing cup if they do not have one.
Inform patients that they should not take nevirapine tablets or oral suspension and nevirapine extended-release tablets at the same time.
Nevirapine may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.
Nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Monitor methadone-maintained patients beginning nevirapine therapy for evidence of withdrawal and adjust methadone dose accordingly.
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
# Precautions with Alcohol
Alcohol-Nevirapine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Viramune
- Viramune O/S
- Viramune XR
# Look-Alike Drug Names
There is limited information regarding Nevirapine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nevirapine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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# Black Box Warning
# Overview
Nevirapine is a non-nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash and myalgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Nevirapine tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
- Dosage:
- One 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nevirapine in adult patients.
### Non–Guideline-Supported Use
- Prophylaxis of perinatal VIH infection
- Prophylaxis of post natal VIH infection
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Nevirapine tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
- Dosage for pediatric patients 15 days and older:
- 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter.
- The total daily dose should not exceed 400 mg for any patient.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nevirapine in pediatric patients.
### Non–Guideline-Supported Use
- Prophylaxis of perinatal VIH infection
- Prophylaxis of post natal VIH infection
# Contraindications
- Nevirapine tablets are contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
- Nevirapine is contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens.
# Warnings
The most serious adverse reactions associated with nevirapine are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy or renal dysfunction.
The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at 2 weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash.
Severe, life threatening and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups.
The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the subjects with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.
Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible.
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%) and patients with higher CD4+ cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). However, all patients, regardless of gender, CD4+ cell count or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+ cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated.
Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
Severe and life threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterized by rash, constitutional findings and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of nevirapine recipients compared to less than 1% of placebo subjects.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms or hypersensitivity reaction.
If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations.
Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase nevirapine dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved. The total duration of the once daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with nevirapine.
In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.
Nevirapine must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.
Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and nevirapine is not recommended. Coadministration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. Coadministration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# 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 associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy or renal dysfunction.
In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups. Female gender and higher CD4+ cell counts (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) place patients at increased risk of these events.
Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received nevirapine and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving nevirapine than in controls.
The most common clinical toxicity of nevirapine is rash, which can be severe or life threatening. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046 and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving nevirapine compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of nevirapine recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of nevirapine-associated rash.
Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving nevirapine in placebo-controlled trials are shown in Table 2.
Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving nevirapine than in controls. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue nevirapine therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing nevirapine and control regimens.
Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of nevirapine (n = 305) in which pediatric subjects received combination treatment with nevirapine. In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of nevirapine (n = 37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine. Cases of allergic reaction, including one case of anaphylaxis, were also reported.
The safety of nevirapine was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with nevirapine oral suspension, lamuvidine and zidovudine for 48 weeks. Rash (all causality) was reported in 21% of the subjects, four (3%) of whom discontinued drug due to rash. All four subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%) and hepatotoxicity (2%).
Safety information on use of nevirapine in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.
## Postmarketing Experience
In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of nevirapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Body as a Whole: fever, somnolence, drug withdrawal, redistribution/accumulation of body fat.
- Gastrointestinal: vomiting
- Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
- Hematology: anemia, eosinophilia, neutropenia
- Investigations: decreased serum phosphorus
- Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions
- Neurologic: paraesthesia
- Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported.
In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.
# Drug Interactions
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when coadministered with nevirapine.
The specific pharmacokinetic changes that occur with coadministration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction trials conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction trials in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when coadministering these drugs.
The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is coadministered with nevirapine, anticoagulation levels should be monitored frequently
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
There are no adequate and well controlled trials of nevirapine in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.
Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women.
Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nevirapine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nevirapine during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving nevirapine.
### Pediatric Use
The safety, pharmacokinetic profile and virologic and immunologic responses of nevirapine have been evaluated in HIV-1 infected pediatric subjects age 3 months to 18 years. The safety and pharmacokinetic profile of nevirapine has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3 months.
The most frequently reported adverse events related to nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine.
### Geriatic Use
Clinical trials of nevirapine did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection 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
Women appear to be at higher risk than men of developing rash with nevirapine.
### Race
An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.
### Renal Impairment
In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCL greater than or equal to 20 mL/min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated.
### Hepatic Impairment
Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.
### Females of Reproductive Potential and Males
In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of nevirapine.
### Immunocompromised Patients
There is no FDA guidance one the use of Nevirapine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine tablets. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In some cases, hepatic injury has progressed despite discontinuation of treatment.
# IV Compatibility
There is limited information regarding the compatibility of Nevirapine and IV administrations.
# Overdosage
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 mg to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of nevirapine.
# Pharmacology
## Mechanism of Action
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, ß, γ or δ) are not inhibited by nevirapine.
## Structure
Nevirapine has the following structural formula:
## Pharmacodynamics
There is limited information regarding Nevirapine Pharmacodynamics in the drug label.
## Pharmacokinetics
Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar), (n = 242) were attained at 400 mg/day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox®** 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate trial in HIV-1 infected subjects (n = 6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or didanosine.
Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg/mL. Nevirapine concentrations in human cerebrospinal fluid (n = 6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.
In vivo trials in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady-state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.
Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20% to 25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2 to 4 weeks of dosing with 200 to 400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25 to 30 hours following multiple dosing with 200 to 400 mg/day.
## Nonclinical Toxicology
The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14 to 302 nM, n = 29) against clinical isolates of HIV-1 clades A, B, C, D, F, G and H and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n = 3) or HIV-2 isolates (n = 3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.
HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n = 24) or nevirapine and ZDV (n = 14) were monitored in Phase 1 and 2 trials over 1 to ≥ 12 weeks. After one week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week 8 of nevirapine monotherapy, 100% of the subjects tested (n = 24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline and had one or more of the nevirapine-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n = 71) receiving nevirapine once daily (n = 25) or twice daily (n = 46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.
Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine and efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.
Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for 2 years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for 2 years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.
Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.
# Clinical Studies
Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2,249 HIV-1 infected subjects with less than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with nevirapine + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were nevirapine, 200 mg daily for 2 weeks followed by 200 mg twice daily or placebo and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1,309 subjects (58%), two or more NRTIs in 771 (34%) and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV-1 RNA of 4.58 log10 copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.
The change from baseline in CD4+ cell count through one year of therapy was significantly greater for the nevirapine group compared to the placebo group for the overall trial population (64 cells/mm3 vs. 22 cells/mm3, respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm3 vs. 25 cells/mm3, respectively).
At 2 years into the trial, 16% of subjects on nevirapine had experienced class C CDC events as compared to 21% of subjects on the control arm.
Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4+ cell counts of 200 to 600 cells/mm3 at baseline. BI 1046 compared treatment with nevirapine + zidovudine + didanosine to nevirapine + zidovudine and zidovudine + didanosine. Treatment doses were nevirapine at 200 mg daily for 2 weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily and didanosine at 125 mg or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log10 copies/mL (25,704 copies/mL) and mean baseline CD4+ cell count of 376 cells/mm3. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with nevirapine + zidovudine + didanosine, 19% for subjects treated with zidovudine + didanosine and 0% for subjects treated with nevirapine + zidovudine.
CD4+ cell counts in the nevirapine + ZDV + ddI group increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increase of 87 cells/mm3 in the ZDV + ddI subjects. The nevirapine + ZDV group mean decreased by 6 cells/mm3 below baseline.
The pediatric safety and efficacy of nevirapine was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received nevirapine oral suspension for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years and 12 to less than or equal to 16 years) and randomized to receive one of two nevirapine doses, determined by 2 different dosing methods [body surface area (150 mg/m2) and weight-based dosing (4 or 7 mg/kg)] in combination with zidovudine and lamivudine. The total daily dose of nevirapine did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.
Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log10 copies/mL and a median baseline CD4+ cell count of 527 cells/mm3 (range 37 to 2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, nine (7%) discontinued due to adverse reactions and three (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies/mL at 48 weeks was 47% (58/123).
# How Supplied
Nevirapine 200 mg tablets:
- Bottles of 60 tablets (NDC 0378-4050-91)
- Bottles of 180 tablets (NDC 0378-4050-80)
- Bottles of 500 tablets (NDC 0378-4050-05)
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C and/or increased transaminases at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the 2-week lead-in period, do not escalate the nevirapine dose until the rash resolves. The total duration of the once daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult a physician. Nevirapine tablets should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash.
Inform patients to take nevirapine tablets every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Advise patients to report to their doctor the use of any other medications.
Inform patients that it is not known whether nevirapine therapy reduces the risk of transmission of HIV-1 to others through sexual contact. Effective treatment combined with safer sex practices may reduce the chance of passing HIV to others through sexual contact. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.
Nevirapine is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Advise patients to remain under the care of a physician when using nevirapine.
Advise patients taking nevirapine oral suspension to ask their pharmacist for a dosing cup if they do not have one.
Inform patients that they should not take nevirapine tablets or oral suspension and nevirapine extended-release tablets at the same time.
Nevirapine may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.
Nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Monitor methadone-maintained patients beginning nevirapine therapy for evidence of withdrawal and adjust methadone dose accordingly.
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
# Precautions with Alcohol
Alcohol-Nevirapine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Viramune [1]
- Viramune O/S
- Viramune XR
# Look-Alike Drug Names
There is limited information regarding Nevirapine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nevirapine | |
c8735c498d2696b5383025ba40c51d3d1f079cd4 | wikidoc | Niaprazine | Niaprazine
# Overview
Niaprazine (Nopron) is a sedative-hypnotic drug of the phenylpiperazine class. It has been used in the treatment of sleep disturbances since the early 1970s in several European countries, including France, Italy, and Luxembourg. It is commonly used with children and adolescents on account of its favorable safety and tolerability profile and lack of abuse potential.
Originally believed to act as an antihistamine and anticholinergic, niaprazine was later discovered to have no significant binding affinity for either the H1 or the mACh receptors (Ki = > 1 μM), and was instead found to act as a potent and selective 5-HT2A and α1-adrenergic receptor antagonist (Ki = 75 nM and 86 nM, respectively). It is virtually inactive at 5-HT1A, 5-HT2B, D2, and β-adrenergic, as well as at SERT and VMAT (Ki = all > 1 μM), but it does have some weak affinity for the α2-adrenergic receptor (Ki = 730 nM), likely acting as an antagonist there as well.
Niaprazine has been shown to metabolize to the compound pFPP in a similar manner to how trazodone and nefazodone metabolize to mCPP. It is unclear what role, if any, pFPP plays in the clinical effects of niaprazine. However, from animal studies it is known that pFPP, unlike niaprazine, does not produce sedative effects, and instead exerts a behavioral profile indicative of serotonergic activation. | Niaprazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Niaprazine (Nopron) is a sedative-hypnotic drug of the phenylpiperazine class.[1] It has been used in the treatment of sleep disturbances since the early 1970s in several European countries, including France, Italy, and Luxembourg.[2][3] It is commonly used with children and adolescents on account of its favorable safety and tolerability profile and lack of abuse potential.[4][5][6][7][8][9]
Originally believed to act as an antihistamine and anticholinergic,[10] niaprazine was later discovered to have no significant binding affinity for either the H1 or the mACh receptors (Ki = > 1 μM), and was instead found to act as a potent and selective 5-HT2A and α1-adrenergic receptor antagonist (Ki = 75 nM and 86 nM, respectively).[11] It is virtually inactive at 5-HT1A, 5-HT2B, D2, and β-adrenergic, as well as at SERT and VMAT (Ki = all > 1 μM), but it does have some weak affinity for the α2-adrenergic receptor (Ki = 730 nM),[11] likely acting as an antagonist there as well.
Niaprazine has been shown to metabolize to the compound pFPP in a similar manner to how trazodone and nefazodone metabolize to mCPP.[12][13] It is unclear what role, if any, pFPP plays in the clinical effects of niaprazine.[11] However, from animal studies it is known that pFPP, unlike niaprazine, does not produce sedative effects, and instead exerts a behavioral profile indicative of serotonergic activation.[12] | https://www.wikidoc.org/index.php/Niaprazine | |
aca13b48cda89e6efe1be4687893bad7de5a551f | wikidoc | Nicorandil | Nicorandil
# Overview
Nicorandil is a drug used to treat angina. It is marketed under the trade names Ikorel (in the United Kingdom, Australia and most of Europe), Zynicor (in India) and Sigmart (in Japan, South Korea and Taiwan). Nicorandil is not available in the United States.
# Mechanism of Action
Nicorandil acts by relaxing the smooth muscle of the blood vessels, especially those of the venous system. It does this through two methods. Firstly, by activating potassium channels, and secondly by donating nitric oxide to activate the enzyme guanylate cyclase. Guanylate cyclase causes activation of GMP leading to both arterial and venous vasodilatation. As it is selective for vascular potassium channels, it has no significant action on cardiac contractility and conduction.
Although it can dilate the coronary vessels of a healthy individual, its effects on the coronary vessels of someone with ischaemic heart disease will be little as they will already be completely dilated. Instead, it dilates the venous system, reducing preload and the work of the heart.
# Side Effects
Common side effects include flushing, palpitation, weakness, headache, mouth ulcers, nausea and vomiting. More recently peri-anal, ileal and peri-stomal ulceration has been reported as a side effect. Anal ulceration is now included in the British National Formulary as a recognised side effect. | Nicorandil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nicorandil is a drug used to treat angina. It is marketed under the trade names Ikorel (in the United Kingdom, Australia and most of Europe), Zynicor (in India) and Sigmart (in Japan, South Korea and Taiwan). Nicorandil is not available in the United States.
# Mechanism of Action
Nicorandil acts by relaxing the smooth muscle of the blood vessels, especially those of the venous system. It does this through two methods. Firstly, by activating potassium channels, and secondly by donating nitric oxide to activate the enzyme guanylate cyclase. Guanylate cyclase causes activation of GMP leading to both arterial and venous vasodilatation. As it is selective for vascular potassium channels, it has no significant action on cardiac contractility and conduction.
Although it can dilate the coronary vessels of a healthy individual, its effects on the coronary vessels of someone with ischaemic heart disease will be little as they will already be completely dilated. Instead, it dilates the venous system, reducing preload and the work of the heart.
# Side Effects
Common side effects include flushing, palpitation, weakness, headache, mouth ulcers, nausea and vomiting. More recently peri-anal, ileal and peri-stomal ulceration has been reported as a side effect. Anal ulceration is now included in the British National Formulary as a recognised side effect. | https://www.wikidoc.org/index.php/Nicorandil | |
7a333788b5d7e47fc886e2540277f170bda49dc6 | wikidoc | Niels Bohr | Niels Bohr
Niels Henrik David Bohr (Template:Pronounced in Danish; October 7, 1885 – November 18, 1962) was a Danish physicist who made fundamental contributions to understanding atomic structure and quantum mechanics, for which he received the Nobel Prize in Physics in 1922. Bohr mentored and collaborated with many of the top physicists of the century at his institute in Copenhagen. He was also part of the team of physicists working on the Manhattan Project. Bohr married Margrethe Nørlund in 1912, and one of their sons, Aage Niels Bohr, grew up to be an important physicist who, like his father, received the Nobel prize, in 1975. Bohr has been described as one of the most influential physicists of the 20th century.
# Biography
## Early life
Niels Henrik David Bohr was born in Copenhagen, Denmark in 1885. His father, Christian Bohr, a devout Lutheran, was professor of physiology at the University of Copenhagen, while his mother, Ellen Adler Bohr, came from a wealthy Jewish family prominent in Danish banking and parliamentary circles. His brother was Harald Bohr, a mathematician and Olympic soccer player who played on the Danish national team. Niels Bohr was a passionate soccer player as well, and the two brothers played a number of matches for Akademisk Boldklub.
Bohr studied as an undergraduate, graduate and, under Christian Christiansen, as a doctoral student at Copenhagen University, receiving his doctorate in 1911. As a post-doctoral student, Bohr first conducted experiments under J. J. Thomson at Trinity College, Cambridge. He then went on to study under Ernest Rutherford at the University of Manchester in England. On the basis of Rutherford's theories, Bohr published his model of atomic structure in 1913, introducing the theory of electrons traveling in orbits around the atom's nucleus, the chemical properties of the element being largely determined by the number of electrons in the outer orbits. Bohr also introduced the idea that an electron could drop from a higher-energy orbit to a lower one, emitting a photon (light quantum) of discrete energy. This became a basis for quantum theory.
Niels Bohr and his wife Margrethe Nørlund had six children. Two died young, and most of the others went on to lead successful lives. One, Aage Niels Bohr, also became a very successful physicist; like his father, he won a Nobel Prize in 1975.
## Physics
In 1916, Niels Bohr became a professor at the University of Copenhagen. With the assistance of the Danish government and the Carlsberg Foundation, he succeeded in founding the Institute of Theoretical Physics in 1921, of which he became its director. In 1922, Bohr was awarded the Nobel Prize in physics "for his services in the investigation of the structure of atoms and of the radiation emanating from them." Bohr's institute served as a focal point for theoretical physicists in the 1920s and '30s, and most of the world's best known theoretical physicists of that period spent some time there.
Bohr also conceived the principle of complementarity: that items could be separately analyzed as having several contradictory properties. For example, physicists currently conclude that light is both a wave and a stream of particles — two apparently mutually exclusive properties — on the basis of this principle. Bohr also found philosophical applications for this daringly original principle. Albert Einstein much preferred the determinism of classical physics over the probabilistic new physics of Bohr (to which Max Planck and Einstein himself had contributed). He and Bohr had good-natured arguments over the truth of this principle throughout their lives (see Bohr Einstein debate). One of Bohr's most famous students was Werner Heisenberg, a crucial figure in the development of quantum mechanics, who was also head of the German atomic bomb project.
In 1941, during the German occupation of Denmark in World War II, Bohr was visited by Heisenberg in Copenhagen (see section below). In 1943, shortly before he was to be arrested by the German police, Bohr escaped to Sweden, and then traveled to London.
## Atomic research
He worked at the top-secret Los Alamos laboratory in New Mexico, U.S., on the Manhattan Project, where, according to Richard Feynman, he was known by the assumed name of Nicholas Baker for security reasons. His role in the project was important. He was seen as a knowledgeable consultant or "father confessor" on the project. He was concerned about a nuclear arms race, and is quoted as saying, "That is why I went to America. They didn't need my help in making the atom bomb."
Bohr believed that atomic secrets should be shared by the international scientific community. After meeting with Bohr, J. Robert Oppenheimer suggested Bohr visit President Franklin D. Roosevelt to convince him that the Manhattan Project should be shared with the Russians in the hope of speeding up its results. Roosevelt suggested Bohr return to England to try to win British approval. Winston Churchill disagreed with the idea of openness towards the Russians to the point that he wrote in a letter: "It seems to me Bohr ought to be confined or
at any rate made to see that he is very near the edge of mortal crimes."
After the war Bohr returned to Copenhagen, advocating the peaceful use of nuclear energy. When awarded the Order of the Elephant by the Danish government, he designed his own coat of arms which featured a taijitu (symbol of yin and yang) and the Latin motto contraria sunt complementa: opposites are complementary. He died in Copenhagen in 1962. He is buried in the Assistens Kirkegård in the Nørrebro section of Copenhagen.
# Contributions to physics
- Bohr's model
- The theory that electrons travel in discrete orbits around the atom's nucleus, with the chemical properties of an element being largely determined by the number of electrons in its outer orbit.
- The idea that an electron could in fact drop from a higher-energy orbit to a lower one, emitting a photon (light quantum) of discrete energy (this became the basis for the quantum theory).
- Identified the isotope of uranium that was responsible for slow-neutron fission - U235.
- Much work on the Copenhagen interpretation of quantum mechanics.
- The principle of complementarity: that items could be separately analyzed as having several contradictory properties.
# Kierkegaard's influence on Bohr
It is generally accepted that Bohr read the 19th century Danish philosopher Søren Kierkegaard. Richard Rhodes argues in The Making of the Atomic Bomb that Bohr was influenced by Kierkegaard via the philosopher Harald Høffding, who was strongly influenced by Kierkegaard and who was an old friend of Bohr's father. In 1909, Bohr sent his brother Kierkegaard's Stages on Life's Way as a birthday gift. In the enclosed letter, Bohr wrote, "It is the only thing I have to send home; but I do not believe that it would be very easy to find anything better.... I even think it is one of the most delightful things I have ever read." Bohr enjoyed Kierkegaard's language and literary style, but mentioned that he had some "disagreement with ."
Given this, there has been some dispute over whether Kierkegaard influenced Bohr's philosophy and science. David Favrholdt argues that Kierkegaard had minimal influence over Bohr's work; taking Bohr's statement about disagreeing with Kierkegaard at face value, while Jan Faye endorses the opposing point of view by arguing that one can disagree with the content of a theory while accepting its general premises and structure.
# Relationship with Heisenberg
Bohr and Werner Heisenberg enjoyed a strong mentor/protégé relationship up to the onset of World War II. Heisenberg had made Bohr aware of his talent during a lecture in 1922 in Göttingen. During the mid-1920s Heisenberg worked with Bohr at the institute in Copenhagen. Heisenberg, as most of Bohr's assistants, learned Danish. Heisenberg's uncertainty principle was developed during this period. Bohr's complementarity principle likewise. By the time of World War II, the relationship became strained because, among other reasons Bohr, with his partially-Jewish heritage, remained in occupied Denmark, while Heisenberg remained in Germany and became head of the German nuclear efforts. Heisenberg made a now-famous visit to Bohr in September/October 1941, and during a private moment, it seems that he began to address nuclear energy and morality as well as the war effort. Neither Bohr nor Heisenberg spoke about it in any detail to outsiders nor left written records of this part of the meeting at the time, and they were alone and outside. Bohr seems to have reacted by terminating that conversation abruptly while not giving Heisenberg any hints in any direction. While some suggest that the relationship became strained at this meeting, other evidence shows that the level of contact had been reduced considerably for some time already. One source, Heisenberg himself, suggests that the fracture occurred later. In correspondence to his wife, Heisenberg described the final visit of the trip: "Today I was once more, with Weizsaecker, at Bohr's. In many ways this was especially nice, the conversation revolved for a large part of the evening around purely human concerns, Bohr was reading aloud, I played a Mozart Sonata (A-Major)." Ivan Supek, one of Heisenberg's students and friends, claimed that the main figure of the meeting was actually Weizsäcker who tried to persuade Bohr to mediate for peace between Great Britain and Germany.
## Tube Alloys
"Tube Alloys" was the code-name for the British nuclear weapon program. The British intelligence services inquired about Bohr's availability for work or insights of particular value. Bohr's reply made it clear that he could not help. This reply, like his reaction to Heisenberg, made sure that, if Gestapo intercepted anything attributed to Bohr it would simply point to no particularly relevant knowledge regarding nuclear energy, as it stood in 1941. This does not exclude the possibility that Bohr privately did make calculations going further than his work in 1939 with Wheeler.
After leaving Denmark in the dramatic day and night (October 1943) when most Jews were able to escape to Sweden due to a series of very exceptional circumstances (see Rescue of the Danish Jews), Bohr was quickly asked, again, to join British efforts, and he was flown to the UK for that purpose. He was evacuated from Stockholm in 1943 in an unarmed De Havilland Mosquito bomber (carried in an improvised cabin in the bomb bay) sent by the RAF. The flight almost ended in tragedy as Bohr did not don his oxygen equipment as instructed, and passed out. He would have died had not the pilot, surmising from Bohr's lack of response to intercom communication that he had lost consciousness, descended to a lower altitude for the remainder of the flight. Bohr's comment was that he had slept like a baby for the entire flight.
As part of the UK team on "Tube Alloys" Bohr was also included at Los Alamos. Oppenheimer credited Bohr warmly for his guiding help during certain discussions among scientists there. Discreetly, he met President Franklin D. Roosevelt and later Winston Churchill to warn against the perilous perspectives that would follow from separate development of nuclear weapons by several powers rather than some form of controlled sharing of the basic scientific knowledge, which would spread quickly in any case. Only in the 1950s, after the immense surprise that the Soviets could and did in fact develop the weapons independently, was it possible to create the International Atomic Energy Agency along the lines of Bohr's old suggestion.
## Speculation
In 1957, while the author Robert Jungk was working on the book Brighter Than a Thousand Suns, Heisenberg wrote to Jungk explaining that he had visited Copenhagen to communicate to Bohr his view that scientists on either side should help prevent development of the atomic bomb, that the German attempts were entirely focused on energy production, and that Heisenberg's circle of colleagues tried to keep it that way. However, Heisenberg acknowledged that his cryptic approach of the subject had so alarmed Bohr that the discussion failed. Heisenberg nuanced his claims, though, and avoided the implication that he and his colleagues had purposely sabotaged the bomb effort. However, this nuance was lost in Jungk's original publication of the book, which strongly implied that the German atomic bomb project was rendered purposely stillborn by Heisenberg.
When Bohr saw Jungk's erroneous depiction in the Danish translation of the book, he disagreed wholeheartedly. He drafted (but never sent) a letter to Heisenberg, stating that while Heisenberg had indeed discussed the subject of nuclear weapons in Copenhagen, Heisenberg had never alluded to the fact that he might be resisting efforts to build such weapons. Bohr dismissed the idea of any pact as an after-the-fact construction.
Michael Frayn's play Copenhagen, which was performed in London (for five years), Copenhagen, Gothenburg, Rome, Athens (Greece), Geneva and on Broadway in New York, explores what might have happened at the 1941 meeting between Heisenberg and Bohr. Frayn points in particular to the onus of being one of the few, or the first one, to understand what it would mean in practice to create a nuclear weapon.
# Legacy
## Commemorations
- In 1965, three years after Bohr's death, the Institute of Physics at the University of Copenhagen changed its name to the Niels Bohr Institute.
- The Bohr models semicentennial was commemorated in Denmark on November 21 1963 with a postage stamp depicting Bohr, the hydrogen atom and the formula for the difference of any two hydrogen energy levels: h\nu = \epsilon_{2} - \epsilon_{1}\,.
- Bohrium (a chemical element, atomic number 107) is named in honour of Niels Bohr.
- Hafnium, another chemical element, whose properties were predicted by Niels Bohr, was named by him after Hafnia, Copenhagen's Latin name.
- Asteroid 3948 Bohr is named after him.
- The Centennial of Bohr's birth was commemorated in Denmark on October 3 1985 with a postage stamp depicting Bohr with his wife Margrethe.
- In 1997 the Danish National Bank started circulating the danish five-hundred-kroner bill with the portrait of Niels Bohr smoking a pipe.
## Quotations
- "If quantum mechanics hasn't profoundly shocked you, you haven't understood it yet."
- "Nothing exists until it is measured."
- "A triviality is a statement whose opposite is false. However, a great truth is a statement whose opposite may well be another great truth."
- "Your theory is crazy, but it's not crazy enough to be true."
- "How wonderful that we have met with a paradox. Now we have some hope of making progress!"
- "Einstein, stop telling God what to do." Sometimes quoted including: "...with his dice."
- Alternate version: "Don't you think caution is needed when using ordinary language to ascribe attributes to God?"
- "The complement of truth is clearness."
- "It is very difficult to make an accurate prediction, especially about the future." (Also attributed to Danish cartoonist Robert Storm Petersen, a.k.a. Storm P.)
- "An expert is a person who has made all the mistakes that can be made in a very narrow field."
- "Never talk faster than you think."
- "There are some things so serious you have to laugh at them."
- "It is wrong to think that the task of physics is to find out how nature is. Physics concerns what we can say about nature."
# Further reading
## Primary
- Bohr, N. (1913). On the Constitution of Atoms and Molecules, Philosophical Magazine, Series 6, Vol. 26. pg. 1-25.
- Bohr, N., Causality and Complementarity: Epistemological Lessons of Studies in Atomic Physics, 1999 Ox Bow Press: ISBN 1-881987-13-2, the 1949–50 Gifford lectures
- Bohr, N., Atomic Physics and Human Knowledge (1958), Wiley Interscience, 1987 Ox Bow Press: ISBN 0-91802452-8, seven essays written from 1933 to 1957
## Secondary
- Niels Bohr Collected Works 13-Volume Limited Edition Set, General Editor, Finn Aaserud; ISBN 978-0-444-53286-2
- Niels Bohr: The Man, His Science, and the World They Changed, by Ruth Moore; ISBN 0-262-63101-6
- Niels Bohr's Times, In Physics, Philosophy and Polity, by Abraham Pais; ISBN 0-19-852049-2
- Niels Bohr: His Life and Work As Seen by His Friends and Colleagues, edited by Stefan Rozental, John Wiley & Sons, 1964.
- Suspended In Language: Niels Bohr's Life, Discoveries, And The Century He Shaped by Jim Ottaviani (graphic novel); ISBN 0-9660106-5-5
- Harmony and Unity : The Life of Niel's Bohr, by Niels Blaedel; ISBN 0-910239-14-2
- Niels Bohr: A Centenary Volume, edited by A. P French and P.J. Kennedy. ISBN 0-674-62415-7
- Copenhagen Michael Frayn ISBN 0 413 72490 5
- Faust in Copenhagen: A Struggle for the Soul of Physics by Gino Segre; ISBN 0-670-03858-X | Niels Bohr
Template:Disputed
Template:Infobox Scientist
Niels Henrik David Bohr (Template:Pronounced in Danish; October 7, 1885 – November 18, 1962) was a Danish physicist who made fundamental contributions to understanding atomic structure and quantum mechanics, for which he received the Nobel Prize in Physics in 1922. Bohr mentored and collaborated with many of the top physicists of the century at his institute in Copenhagen. He was also part of the team of physicists working on the Manhattan Project. Bohr married Margrethe Nørlund in 1912, and one of their sons, Aage Niels Bohr, grew up to be an important physicist who, like his father, received the Nobel prize, in 1975. Bohr has been described as one of the most influential physicists of the 20th century.[1]
# Biography
## Early life
Niels Henrik David Bohr was born in Copenhagen, Denmark in 1885. His father, Christian Bohr, a devout Lutheran, was professor of physiology at the University of Copenhagen, while his mother, Ellen Adler Bohr, came from a wealthy Jewish family prominent in Danish banking and parliamentary circles. His brother was Harald Bohr, a mathematician and Olympic soccer player who played on the Danish national team. Niels Bohr was a passionate soccer player as well, and the two brothers played a number of matches for Akademisk Boldklub.
Bohr studied as an undergraduate, graduate and, under Christian Christiansen, as a doctoral student at Copenhagen University, receiving his doctorate in 1911. As a post-doctoral student, Bohr first conducted experiments under J. J. Thomson at Trinity College, Cambridge. He then went on to study under Ernest Rutherford at the University of Manchester in England. On the basis of Rutherford's theories, Bohr published his model of atomic structure in 1913, introducing the theory of electrons traveling in orbits around the atom's nucleus, the chemical properties of the element being largely determined by the number of electrons in the outer orbits. Bohr also introduced the idea that an electron could drop from a higher-energy orbit to a lower one, emitting a photon (light quantum) of discrete energy. This became a basis for quantum theory.
Niels Bohr and his wife Margrethe Nørlund had six children. Two died young, and most of the others went on to lead successful lives. One, Aage Niels Bohr, also became a very successful physicist; like his father, he won a Nobel Prize in 1975.
## Physics
In 1916, Niels Bohr became a professor at the University of Copenhagen. With the assistance of the Danish government and the Carlsberg Foundation, he succeeded in founding the Institute of Theoretical Physics in 1921, of which he became its director.[2] In 1922, Bohr was awarded the Nobel Prize in physics "for his services in the investigation of the structure of atoms and of the radiation emanating from them." Bohr's institute served as a focal point for theoretical physicists in the 1920s and '30s, and most of the world's best known theoretical physicists of that period spent some time there.
Bohr also conceived the principle of complementarity: that items could be separately analyzed as having several contradictory properties. For example, physicists currently conclude that light is both a wave and a stream of particles — two apparently mutually exclusive properties — on the basis of this principle. Bohr also found philosophical applications for this daringly original principle. Albert Einstein much preferred the determinism of classical physics over the probabilistic new physics of Bohr (to which Max Planck and Einstein himself had contributed). He and Bohr had good-natured arguments over the truth of this principle throughout their lives (see Bohr Einstein debate). One of Bohr's most famous students was Werner Heisenberg, a crucial figure in the development of quantum mechanics, who was also head of the German atomic bomb project.
In 1941, during the German occupation of Denmark in World War II, Bohr was visited by Heisenberg in Copenhagen (see section below). In 1943, shortly before he was to be arrested by the German police, Bohr escaped to Sweden, and then traveled to London.
## Atomic research
He worked at the top-secret Los Alamos laboratory in New Mexico, U.S., on the Manhattan Project, where, according to Richard Feynman, he was known by the assumed name of Nicholas Baker for security reasons. His role in the project was important. He was seen as a knowledgeable consultant or "father confessor" on the project. He was concerned about a nuclear arms race, and is quoted as saying, "That is why I went to America. They didn't need my help in making the atom bomb."[3]
Bohr believed that atomic secrets should be shared by the international scientific community. After meeting with Bohr, J. Robert Oppenheimer suggested Bohr visit President Franklin D. Roosevelt to convince him that the Manhattan Project should be shared with the Russians in the hope of speeding up its results. Roosevelt suggested Bohr return to England to try to win British approval. Winston Churchill disagreed with the idea of openness towards the Russians to the point that he wrote in a letter: "It seems to me Bohr ought to be confined or
at any rate made to see that he is very near the edge of mortal crimes."[4]
After the war Bohr returned to Copenhagen, advocating the peaceful use of nuclear energy. When awarded the Order of the Elephant by the Danish government, he designed his own coat of arms which featured a taijitu (symbol of yin and yang) and the Latin motto contraria sunt complementa: opposites are complementary.[5] He died in Copenhagen in 1962. He is buried in the Assistens Kirkegård in the Nørrebro section of Copenhagen.
# Contributions to physics
- Bohr's model
- The theory that electrons travel in discrete orbits around the atom's nucleus, with the chemical properties of an element being largely determined by the number of electrons in its outer orbit.
- The idea that an electron could in fact drop from a higher-energy orbit to a lower one, emitting a photon (light quantum) of discrete energy (this became the basis for the quantum theory).
- Identified the isotope of uranium that was responsible for slow-neutron fission - U235[6].
- Much work on the Copenhagen interpretation of quantum mechanics.
- The principle of complementarity: that items could be separately analyzed as having several contradictory properties.
# Kierkegaard's influence on Bohr
It is generally accepted that Bohr read the 19th century Danish philosopher Søren Kierkegaard. Richard Rhodes argues in The Making of the Atomic Bomb that Bohr was influenced by Kierkegaard via the philosopher Harald Høffding, who was strongly influenced by Kierkegaard and who was an old friend of Bohr's father. In 1909, Bohr sent his brother Kierkegaard's Stages on Life's Way as a birthday gift. In the enclosed letter, Bohr wrote, "It is the only thing I have to send home; but I do not believe that it would be very easy to find anything better.... I even think it is one of the most delightful things I have ever read." Bohr enjoyed Kierkegaard's language and literary style, but mentioned that he had some "disagreement with [Kierkegaard's ideas]."[7]
Given this, there has been some dispute over whether Kierkegaard influenced Bohr's philosophy and science. David Favrholdt[8] argues that Kierkegaard had minimal influence over Bohr's work; taking Bohr's statement about disagreeing with Kierkegaard at face value, while Jan Faye[9] endorses the opposing point of view by arguing that one can disagree with the content of a theory while accepting its general premises and structure.[10]
# Relationship with Heisenberg
Bohr and Werner Heisenberg enjoyed a strong mentor/protégé relationship up to the onset of World War II. Heisenberg had made Bohr aware of his talent during a lecture in 1922 in Göttingen. During the mid-1920s Heisenberg worked with Bohr at the institute in Copenhagen. Heisenberg, as most of Bohr's assistants, learned Danish. Heisenberg's uncertainty principle was developed during this period. Bohr's complementarity principle likewise. By the time of World War II, the relationship became strained because, among other reasons Bohr, with his partially-Jewish heritage, remained in occupied Denmark, while Heisenberg remained in Germany and became head of the German nuclear efforts. Heisenberg made a now-famous visit to Bohr in September/October 1941, and during a private moment, it seems that he began to address nuclear energy and morality as well as the war effort. Neither Bohr nor Heisenberg spoke about it in any detail to outsiders nor left written records of this part of the meeting at the time, and they were alone and outside.[11] Bohr seems to have reacted by terminating that conversation abruptly while not giving Heisenberg any hints in any direction. While some suggest that the relationship became strained at this meeting, other evidence shows that the level of contact had been reduced considerably for some time already. One source, Heisenberg himself, suggests that the fracture occurred later. In correspondence to his wife, Heisenberg described the final visit of the trip: "Today I was once more, with Weizsaecker, at Bohr's. In many ways this was especially nice, the conversation revolved for a large part of the evening around purely human concerns, Bohr was reading aloud, I played a Mozart Sonata (A-Major)."[12] Ivan Supek, one of Heisenberg's students and friends, claimed that the main figure of the meeting was actually Weizsäcker who tried to persuade Bohr to mediate for peace between Great Britain and Germany.[13]
## Tube Alloys
"Tube Alloys" was the code-name for the British nuclear weapon program. The British intelligence services inquired about Bohr's availability for work or insights of particular value. Bohr's reply made it clear that he could not help. This reply, like his reaction to Heisenberg, made sure that, if Gestapo intercepted anything attributed to Bohr it would simply point to no particularly relevant knowledge regarding nuclear energy, as it stood in 1941. This does not exclude the possibility that Bohr privately did make calculations going further than his work in 1939 with Wheeler.
After leaving Denmark in the dramatic day and night (October 1943) when most Jews were able to escape to Sweden due to a series of very exceptional circumstances (see Rescue of the Danish Jews), Bohr was quickly asked, again, to join British efforts, and he was flown to the UK for that purpose. He was evacuated from Stockholm in 1943 in an unarmed De Havilland Mosquito bomber (carried in an improvised cabin in the bomb bay) sent by the RAF. The flight almost ended in tragedy as Bohr did not don his oxygen equipment as instructed, and passed out. He would have died had not the pilot, surmising from Bohr's lack of response to intercom communication that he had lost consciousness, descended to a lower altitude for the remainder of the flight. Bohr's comment was that he had slept like a baby for the entire flight.
As part of the UK team on "Tube Alloys" Bohr was also included at Los Alamos. Oppenheimer credited Bohr warmly for his guiding help during certain discussions among scientists there. Discreetly, he met President Franklin D. Roosevelt and later Winston Churchill to warn against the perilous perspectives that would follow from separate development of nuclear weapons by several powers rather than some form of controlled sharing of the basic scientific knowledge, which would spread quickly in any case. Only in the 1950s, after the immense surprise that the Soviets could and did in fact develop the weapons independently, was it possible to create the International Atomic Energy Agency along the lines of Bohr's old suggestion.
## Speculation
In 1957, while the author Robert Jungk was working on the book Brighter Than a Thousand Suns, Heisenberg wrote to Jungk explaining that he had visited Copenhagen to communicate to Bohr his view that scientists on either side should help prevent development of the atomic bomb, that the German attempts were entirely focused on energy production, and that Heisenberg's circle of colleagues tried to keep it that way.[14] However, Heisenberg acknowledged that his cryptic approach of the subject had so alarmed Bohr that the discussion failed. Heisenberg nuanced his claims, though, and avoided the implication that he and his colleagues had purposely sabotaged the bomb effort. However, this nuance was lost in Jungk's original publication of the book, which strongly implied that the German atomic bomb project was rendered purposely stillborn by Heisenberg.
When Bohr saw Jungk's erroneous depiction in the Danish translation of the book, he disagreed wholeheartedly. He drafted (but never sent) a letter to Heisenberg, stating that while Heisenberg had indeed discussed the subject of nuclear weapons in Copenhagen, Heisenberg had never alluded to the fact that he might be resisting efforts to build such weapons. Bohr dismissed the idea of any pact as an after-the-fact construction.[15]
Michael Frayn's play Copenhagen, which was performed in London (for five years), Copenhagen, Gothenburg, Rome, Athens (Greece), Geneva and on Broadway in New York, explores what might have happened at the 1941 meeting between Heisenberg and Bohr. Frayn points in particular to the onus of being one of the few, or the first one, to understand what it would mean in practice to create a nuclear weapon.
# Legacy
## Commemorations
- In 1965, three years after Bohr's death, the Institute of Physics at the University of Copenhagen changed its name to the Niels Bohr Institute.
- The Bohr models semicentennial was commemorated in Denmark on November 21 1963 with a postage stamp depicting Bohr, the hydrogen atom and the formula for the difference of any two hydrogen energy levels: <math>h\nu = \epsilon_{2} - \epsilon_{1}\,</math>.
- Bohrium (a chemical element, atomic number 107) is named in honour of Niels Bohr.
- Hafnium, another chemical element, whose properties were predicted by Niels Bohr, was named by him after Hafnia, Copenhagen's Latin name.
- Asteroid 3948 Bohr is named after him.
- The Centennial of Bohr's birth was commemorated in Denmark on October 3 1985 with a postage stamp depicting Bohr with his wife Margrethe.
- In 1997 the Danish National Bank started circulating the danish five-hundred-kroner bill with the portrait of Niels Bohr smoking a pipe.[16]
## Quotations
- "If quantum mechanics hasn't profoundly shocked you, you haven't understood it yet."
- "Nothing exists until it is measured."
- "A triviality is a statement whose opposite is false. However, a great truth is a statement whose opposite may well be another great truth."
- "Your theory is crazy, but it's not crazy enough to be true."
- "How wonderful that we have met with a paradox. Now we have some hope of making progress!"
- "Einstein, stop telling God what to do." Sometimes quoted including: "...with his dice."
- Alternate version: "Don't you think caution is needed when using ordinary language to ascribe attributes to God?"
- "The complement of truth is clearness."
- "It is very difficult to make an accurate prediction, especially about the future." (Also attributed to Danish cartoonist Robert Storm Petersen, a.k.a. Storm P.)
- "An expert is a person who has made all the mistakes that can be made in a very narrow field."
- "Never talk faster than you think."
- "There are some things so serious you have to laugh at them."
- "It is wrong to think that the task of physics is to find out how nature is. Physics concerns what we can say about nature."
# Further reading
## Primary
- Bohr, N. (1913). On the Constitution of Atoms and Molecules, Philosophical Magazine, Series 6, Vol. 26. pg. 1-25.
- Bohr, N., Causality and Complementarity: Epistemological Lessons of Studies in Atomic Physics, 1999 Ox Bow Press: ISBN 1-881987-13-2, the 1949–50 Gifford lectures
- Bohr, N., Atomic Physics and Human Knowledge (1958), Wiley Interscience, 1987 Ox Bow Press: ISBN 0-91802452-8, seven essays written from 1933 to 1957
## Secondary
- Niels Bohr Collected Works 13-Volume Limited Edition Set, General Editor, Finn Aaserud; ISBN 978-0-444-53286-2
- Niels Bohr: The Man, His Science, and the World They Changed, by Ruth Moore; ISBN 0-262-63101-6
- Niels Bohr's Times, In Physics, Philosophy and Polity, by Abraham Pais; ISBN 0-19-852049-2
- Niels Bohr: His Life and Work As Seen by His Friends and Colleagues, edited by Stefan Rozental, John Wiley & Sons, 1964.
- Suspended In Language: Niels Bohr's Life, Discoveries, And The Century He Shaped by Jim Ottaviani (graphic novel); ISBN 0-9660106-5-5
- Harmony and Unity : The Life of Niel's Bohr, by Niels Blaedel; ISBN 0-910239-14-2
- Niels Bohr: A Centenary Volume, edited by A. P French and P.J. Kennedy. ISBN 0-674-62415-7
- Copenhagen Michael Frayn ISBN 0 413 72490 5
- Faust in Copenhagen: A Struggle for the Soul of Physics by Gino Segre; ISBN 0-670-03858-X | https://www.wikidoc.org/index.php/Niels_Bohr | |
3ccd9cf56a2f73db702fc0c0ddad75df1c359f81 | wikidoc | Nifurtimox | Nifurtimox
# Overview
Nifurtimox is a 5-nitrofuran and is used to treat diseases caused by trypanosomes (Chagas disease and sleeping sickness). It is given by mouth and not by injection.
# Uses
Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days, but gastrointestinal and neurological side effects have meant that benznidazole is now preferred for that indication.
Nifurtimox has also been used to treat African sleeping sickness and is active in the second stage of African sleeping sickness (CNS disease). Unfortunately, when nifurtimox is given on its own, about half of all patients will relapse, but the combination of melarsoprol with nifurtimox appears to be efficacious. Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.
# Dosing
Nifurtimox is dosed as 15 mg/kg/day in two to three divided doses. It is given by mouth. Refer to the articles on Chagas disease and sleeping sickness for more detailed information on dosing for these diseases.
# Manufacturing and availability
Nifurtimox is sold as Lampit® by Bayer. It was previously known as Bayer 2502.
Nifurtimox is only licensed for use in Argentina and Germany, where it is sold as 120 mg tablets. | Nifurtimox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nifurtimox is a 5-nitrofuran and is used to treat diseases caused by trypanosomes (Chagas disease and sleeping sickness). It is given by mouth and not by injection.
# Uses
Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days,[1] but gastrointestinal and neurological side effects have meant that benznidazole is now preferred for that indication.
Nifurtimox has also been used to treat African sleeping sickness and is active in the second stage of African sleeping sickness (CNS disease). Unfortunately, when nifurtimox is given on its own, about half of all patients will relapse,[2] but the combination of melarsoprol with nifurtimox appears to be efficacious.[3] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[4]
# Dosing
Nifurtimox is dosed as 15 mg/kg/day in two to three divided doses. It is given by mouth. Refer to the articles on Chagas disease and sleeping sickness for more detailed information on dosing for these diseases.
# Manufacturing and availability
Nifurtimox is sold as Lampit® by Bayer. It was previously known as Bayer 2502.
Nifurtimox is only licensed for use in Argentina and Germany, where it is sold as 120 mg tablets. | https://www.wikidoc.org/index.php/Nifurtimox | |
f303ab472c20a6d235949e5db8232345bde80e68 | wikidoc | Nilutamide | Nilutamide
# 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
Nilutamide is an antiandrogen that is FDA approved for the treatment of metastatic prostate cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, hot sweats, constipation, nausea, dizziness an abnormal vision.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: The recommended dosage is 300 mg once a day for 30 days, followed thereafter by 150 mg once a day. Nilutamide tablets can be taken with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nilutamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilutamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nilutamide 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 Nilutamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilutamide in pediatric patients.
# Contraindications
Nilutamide tablets are contraindicated:
- In patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment)
- In patients with severe respiratory insufficiency
- In patients with hypersensitivity to nilutamide or any component of this preparation.
# Warnings
- Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Nilutamide. Hepatotoxicity in these reports generally occurred within the first 3 to 4 months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in 1% of Nilutamide patients in controlled clinical trials.
- Serum transaminase levels should be measured prior to starting treatment with Nilutamide at regular intervals for the first 4 months of treatment, and periodically thereafter. Liver function tests should also be obtained at the first sign or symptom suggestive of liver dysfunction, e.g. nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, Nilutamide should be immediately discontinued with close followup of liver function tests until resolution.
- Nilutamide has no indication for women, and should not be used in this population, particularly for non-serious or non-life threatening conditions.
- Foreign postmarketing surveillance has revealed isolated cases of aplastic anemia in which a causal relationship with Nilutamide could not be ascertained.
# Adverse Reactions
## Clinical Trials Experience
he following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide + surgical castration versus placebo + surgical castration. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilutamide tablets in combination with surgical castration are listed below. For comparison, adverse experiences seen with surgical castration and placebo are also listed.
The overall incidence of adverse experiences was 86% (194/225) for the Nilutamide group and 81% (188/232) for the placebo group.
The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide + leuprolide versus placebo + leuprolide. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilutamide tablets in combination with leuprolide are listed below. For comparison, adverse experiences seen with leuprolide and placebo are also listed.
The overall incidence of adverse experiences is 99.5% (208/209) for the Nilutamide group and 98.5% (199/202) for the placebo group.
Some frequently occurring adverse experiences, for example hot flushes, impotence, and decreased libido, are known to be associated with low serum androgen levels and known to occur with medical or surgical castration alone. Notable was the higher incidence of visual disturbances (variously described as impaired adaptation to darkness, abnormal vision, and colored vision), which led to treatment discontinuation in 1% to 2% of patients.
Interstitial pneumonitis occurred in one (<1%) patient receiving Nilutamide in combination with surgical castration and in seven patients (3%) receiving Nilutamide in combination with leuprolide and one patient receiving placebo in combination with leuprolide. Overall, it has been reported in 2% of patients receiving Nilutamide This included a report of interstitial pneumonitis in 8 of 47 patients (17%) in a small study performed in Japan.
In addition, the following adverse experiences were reported in 2 to 5% of patients treated with Nilutamide in combination with leuprolide or orchiectomy.
- Body as a Whole: Malaise
- Cardiovascular System: Angina, heart failure, syncope.
- Digestive System: Diarrhea, gastrointestinal disorder, gastrointestinal hemorrhage, melena.
- Metabolic and Nutritional System: Alcohol intolerance, edema, weight loss.
- Musculoskeletal System: Arthritis
- Nervous System: Dry mouth, nervousness, paresthesia.
- Respiratory System: Cough increased, interstitial lung disease, lung disorder, rhinitis.
- Skin and Appendages: Pruritus
- Special Senses: Cataract, photophobia
- Laboratory Values: Haptoglobin increased (2%), leukopenia, alkaline phosphatase increased, BUN increased, creatinine increased, hyperglycemia.
## Postmarketing Experience
There is limited information regarding Nilutamide Postmarketing Experience in the drug label.
# Drug Interactions
- In vitro, nilutamide has been shown to inhibit the activity of liver cytochrome P-450 isoenzymes and, therefore, may reduce the metabolism of compounds requiring these systems.
- Consequently, drugs with a low therapeutic margin, such as vitamin K antagonists, phenytoin, and theophylline, could have a delayed elimination and increases in their serum half-life leading to a toxic level. The dosage of these drugs or others with a similar metabolism may need to be modified if they are administered concomitantly with nilutamide. For example, when vitamin K antagonists are administered concomitantly with nilutamide, prothrombin time should be carefully monitored and, if necessary, the dosage of vitamin K antagonists should be reduced.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with nilutamide. It is also not known whether nilutamide can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Nilutamide should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nilutamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nilutamide during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Nilutamide in women who are nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been determined.
### Geriatic Use
There is no FDA guidance on the use of Nilutamide in geriatric settings.
### Gender
There is no FDA guidance on the use of Nilutamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nilutamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nilutamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nilutamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nilutamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nilutamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Nilutamide Administration in the drug label.
### Monitoring
There is limited information regarding Nilutamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Nilutamide and IV administrations.
# Overdosage
- One case of massive overdosage has been published. A 79-year-old man attempted suicide by ingesting 13 g of nilutamide (i.e., 43 times the maximum recommended dose). Despite immediate gastric lavage and oral administration of activated charcoal, plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion. There were no clinical signs or symptoms or changes in parameters such as transaminases or chest X-ray. Maintenance treatment (150 mg/day) was resumed 30 days later.
- In repeated-dose tolerance studies, doses of 600 mg/day and 900 mg/day were administered to 9 and 4 patients, respectively. The ingestion of these doses was associated with gastrointestinal disorders, including nausea and vomiting, malaise, headache, and dizziness. In addition, a transient elevation in hepatic enzyme levels was noted in one patient.
- Since nilutamide is protein bound, dialysis may not be useful as treatment for overdose. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.
# Pharmacology
## Mechanism of Action
- Prostate cancer is known to be androgen sensitive and responds to androgen ablation. In animal studies, nilutamide has demonstrated antiandrogenic activity without other hormonal (estrogen, progesterone, mineralocorticoid, and glucocorticoid) effects. In vitro, nilutamide blocks the effects of testosterone at the androgen receptor level. In vivo, nilutamide interacts with the androgen receptor and prevents the normal androgenic response.
## Structure
- Nilutamide tablets contain nilutamide, a nonsteroidal, orally active antiandrogen having the chemical name 5,5-dimethyl-3-4-nitro-3-(trifluoromethyl)phenyl-2,4-imidazolidinedione with the following structural formula:
## Pharmacodynamics
There is limited information regarding Nilutamide Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
- Analysis of blood, urine, and feces samples following a single oral 150-mg dose of -nilutamide in patients with metastatic prostate cancer showed that the drug is rapidly and completely absorbed and that it yields high and persistent plasma concentrations.
### Distribution
- After absorption of the drug, there is a detectable distribution phase. There is moderate binding of the drug to plasma proteins and low binding to erythrocytes. The binding is nonsaturable except in the case of alpha-1-glycoprotein, which makes a minor contribution to the total concentration of proteins in the plasma. The results of binding studies do not indicate any effects that would cause nonlinear pharmacokinetics.
### Metabolism
- The results of a human metabolism study using 14C-radiolabelled tablets show that nilutamide is extensively metabolized and less than 2% of the drug is excreted unchanged in urine after 5 days. Five metabolites have been isolated from human urine. Two metabolites display an asymmetric center, due to oxidation of a methyl group, resulting in the formation of D- and L-isomers. One of the metabolites was shown, in vitro, to possess 25 to 50% of the pharmacological activity of the parent drug, and the D-isomer of the active metabolite showed equal or greater potency compared to the L-isomer. However, the pharmacokinetics and the pharmacodynamics of the metabolites have not been fully investigated.
### Elimination
- The majority (62%) of orally administered -nilutamide is eliminated in the urine during the first 120 hours after a single 150-mg dose. Fecal elimination is negligible, ranging from 1.4% to 7% of the dose after 4 to 5 days. Excretion of radioactivity in urine likely continues beyond 5 days. The mean elimination half-life of nilutamide determined in studies in which subjects received a single dose of 100–300 mg ranged from 38.0 to 59.1 hours with most values between 41 and 49 hours. The elimination of at least one metabolite is generally longer than that of unchanged nilutamide (59–126 hours). During multiple dosing of 150 mg nilutamide (given as 3 × 50 mg) twice a day, steady state was reached within 2 to 4 weeks for most patients, and mean steady state AUC0–12 was 110% higher than the AUC0–∞obtained from the first 150 mg dose. These data and in vitro metabolism data suggest that, upon multiple dosing, metabolic enzyme inhibition may occur for this drug.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Administration of nilutamide to rats for 18 months at doses of 0, 5, 15, or 45 mg/kg/day produced benign Leydig cell tumors in 35% of the high-dose male rats (AUC exposures in high-dose rats were approximately 1–2 times human AUC exposures with therapeutic doses). The increased incidence of Leydig cell tumors is secondary to elevated luteinizing hormone (LH) concentrations resulting from loss of feedback inhibition at the pituitary. Elevated LH and testosterone concentrations are not observed in castrated men receiving Nilutamide. Nilutamide had no effect on the incidence, size, or time of onset of any spontaneous tumor in rats.
- Nilutamide displayed no mutagenic effects in a variety of in vitro and in vivo tests (Ames test, mouse micronucleus test, and two chromosomal aberration tests).
- In reproduction studies in rats, nilutamide had no effect on the reproductive function of males and females, and no lethal, teratogenic, or growth-suppressive effects on fetuses were found. The maximal dose at which nilutamide did not affect reproductive function in either sex or have an effect on fetuses was estimated to be 45 mg/kg orally (AUC exposures in rats approximately 1–2 times human therapeutic AUC exposures).
# Clinical Studies
- Nilutamide through its antiandrogenic activity can complement surgical castration, which suppresses only testicular androgens. The effects of the combined therapy were studied in patients with previously untreated metastatic prostate cancer.
- In a double-blind, randomized, multicenter study that enrolled 457 patients (225 treated with orchiectomy and Nilutamide 232 treated with orchiectomy and placebo), the Nilutamide group showed a statistically significant benefit in time to progression and time to death. The results are summarized below.
# How Supplied
Nilutamide 150 mg tablets are supplied in boxes of 30 tablets. Each box contains 3 child-resistant, PVC, aluminum foil-backed blisters of 10 tablets (NDC 24987-111-14). Each white, biconvex, cylindrical (10 mm in diameter) tablet has a triangular logo on one side and an internal reference number (168D) on the other.
## Storage
Store at 25°C (77°F); excursions permitted between 15–30°C (59–86°F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Nilutamide Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Nilutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nilandron
# Look-Alike Drug Names
There is limited information regarding Nilutamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nilutamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Nilutamide is an antiandrogen that is FDA approved for the treatment of metastatic prostate cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, hot sweats, constipation, nausea, dizziness an abnormal vision.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: The recommended dosage is 300 mg once a day for 30 days, followed thereafter by 150 mg once a day. Nilutamide tablets can be taken with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nilutamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilutamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nilutamide 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 Nilutamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nilutamide in pediatric patients.
# Contraindications
Nilutamide tablets are contraindicated:
- In patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment)
- In patients with severe respiratory insufficiency
- In patients with hypersensitivity to nilutamide or any component of this preparation.
# Warnings
- Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of Nilutamide. Hepatotoxicity in these reports generally occurred within the first 3 to 4 months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in 1% of Nilutamide patients in controlled clinical trials.
- Serum transaminase levels should be measured prior to starting treatment with Nilutamide at regular intervals for the first 4 months of treatment, and periodically thereafter. Liver function tests should also be obtained at the first sign or symptom suggestive of liver dysfunction, e.g. nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or right upper quadrant tenderness. If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, Nilutamide should be immediately discontinued with close followup of liver function tests until resolution.
- Nilutamide has no indication for women, and should not be used in this population, particularly for non-serious or non-life threatening conditions.
- Foreign postmarketing surveillance has revealed isolated cases of aplastic anemia in which a causal relationship with Nilutamide could not be ascertained.
# Adverse Reactions
## Clinical Trials Experience
he following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide + surgical castration versus placebo + surgical castration. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilutamide tablets in combination with surgical castration are listed below. For comparison, adverse experiences seen with surgical castration and placebo are also listed.
The overall incidence of adverse experiences was 86% (194/225) for the Nilutamide group and 81% (188/232) for the placebo group.
The following adverse experiences were reported during a multicenter clinical trial comparing Nilutamide + leuprolide versus placebo + leuprolide. The most frequently reported (greater than 5%) adverse experiences during treatment with Nilutamide tablets in combination with leuprolide are listed below. For comparison, adverse experiences seen with leuprolide and placebo are also listed.
The overall incidence of adverse experiences is 99.5% (208/209) for the Nilutamide group and 98.5% (199/202) for the placebo group.
Some frequently occurring adverse experiences, for example hot flushes, impotence, and decreased libido, are known to be associated with low serum androgen levels and known to occur with medical or surgical castration alone. Notable was the higher incidence of visual disturbances (variously described as impaired adaptation to darkness, abnormal vision, and colored vision), which led to treatment discontinuation in 1% to 2% of patients.
Interstitial pneumonitis occurred in one (<1%) patient receiving Nilutamide in combination with surgical castration and in seven patients (3%) receiving Nilutamide in combination with leuprolide and one patient receiving placebo in combination with leuprolide. Overall, it has been reported in 2% of patients receiving Nilutamide This included a report of interstitial pneumonitis in 8 of 47 patients (17%) in a small study performed in Japan.
In addition, the following adverse experiences were reported in 2 to 5% of patients treated with Nilutamide in combination with leuprolide or orchiectomy.
- Body as a Whole: Malaise
- Cardiovascular System: Angina, heart failure, syncope.
- Digestive System: Diarrhea, gastrointestinal disorder, gastrointestinal hemorrhage, melena.
- Metabolic and Nutritional System: Alcohol intolerance, edema, weight loss.
- Musculoskeletal System: Arthritis
- Nervous System: Dry mouth, nervousness, paresthesia.
- Respiratory System: Cough increased, interstitial lung disease, lung disorder, rhinitis.
- Skin and Appendages: Pruritus
- Special Senses: Cataract, photophobia
- Laboratory Values: Haptoglobin increased (2%), leukopenia, alkaline phosphatase increased, BUN increased, creatinine increased, hyperglycemia.
## Postmarketing Experience
There is limited information regarding Nilutamide Postmarketing Experience in the drug label.
# Drug Interactions
- In vitro, nilutamide has been shown to inhibit the activity of liver cytochrome P-450 isoenzymes and, therefore, may reduce the metabolism of compounds requiring these systems.
- Consequently, drugs with a low therapeutic margin, such as vitamin K antagonists, phenytoin, and theophylline, could have a delayed elimination and increases in their serum half-life leading to a toxic level. The dosage of these drugs or others with a similar metabolism may need to be modified if they are administered concomitantly with nilutamide. For example, when vitamin K antagonists are administered concomitantly with nilutamide, prothrombin time should be carefully monitored and, if necessary, the dosage of vitamin K antagonists should be reduced.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with nilutamide. It is also not known whether nilutamide can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Nilutamide should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nilutamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nilutamide during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Nilutamide in women who are nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been determined.
### Geriatic Use
There is no FDA guidance on the use of Nilutamide in geriatric settings.
### Gender
There is no FDA guidance on the use of Nilutamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nilutamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nilutamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nilutamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nilutamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nilutamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Nilutamide Administration in the drug label.
### Monitoring
There is limited information regarding Nilutamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Nilutamide and IV administrations.
# Overdosage
- One case of massive overdosage has been published. A 79-year-old man attempted suicide by ingesting 13 g of nilutamide (i.e., 43 times the maximum recommended dose). Despite immediate gastric lavage and oral administration of activated charcoal, plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion. There were no clinical signs or symptoms or changes in parameters such as transaminases or chest X-ray. Maintenance treatment (150 mg/day) was resumed 30 days later.
- In repeated-dose tolerance studies, doses of 600 mg/day and 900 mg/day were administered to 9 and 4 patients, respectively. The ingestion of these doses was associated with gastrointestinal disorders, including nausea and vomiting, malaise, headache, and dizziness. In addition, a transient elevation in hepatic enzyme levels was noted in one patient.
- Since nilutamide is protein bound, dialysis may not be useful as treatment for overdose. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.
# Pharmacology
## Mechanism of Action
- Prostate cancer is known to be androgen sensitive and responds to androgen ablation. In animal studies, nilutamide has demonstrated antiandrogenic activity without other hormonal (estrogen, progesterone, mineralocorticoid, and glucocorticoid) effects. In vitro, nilutamide blocks the effects of testosterone at the androgen receptor level. In vivo, nilutamide interacts with the androgen receptor and prevents the normal androgenic response.
## Structure
- Nilutamide tablets contain nilutamide, a nonsteroidal, orally active antiandrogen having the chemical name 5,5-dimethyl-3-4-nitro-3-(trifluoromethyl)phenyl-2,4-imidazolidinedione with the following structural formula:
## Pharmacodynamics
There is limited information regarding Nilutamide Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
- Analysis of blood, urine, and feces samples following a single oral 150-mg dose of [14C]-nilutamide in patients with metastatic prostate cancer showed that the drug is rapidly and completely absorbed and that it yields high and persistent plasma concentrations.
### Distribution
- After absorption of the drug, there is a detectable distribution phase. There is moderate binding of the drug to plasma proteins and low binding to erythrocytes. The binding is nonsaturable except in the case of alpha-1-glycoprotein, which makes a minor contribution to the total concentration of proteins in the plasma. The results of binding studies do not indicate any effects that would cause nonlinear pharmacokinetics.
### Metabolism
- The results of a human metabolism study using 14C-radiolabelled tablets show that nilutamide is extensively metabolized and less than 2% of the drug is excreted unchanged in urine after 5 days. Five metabolites have been isolated from human urine. Two metabolites display an asymmetric center, due to oxidation of a methyl group, resulting in the formation of D- and L-isomers. One of the metabolites was shown, in vitro, to possess 25 to 50% of the pharmacological activity of the parent drug, and the D-isomer of the active metabolite showed equal or greater potency compared to the L-isomer. However, the pharmacokinetics and the pharmacodynamics of the metabolites have not been fully investigated.
### Elimination
- The majority (62%) of orally administered [14C]-nilutamide is eliminated in the urine during the first 120 hours after a single 150-mg dose. Fecal elimination is negligible, ranging from 1.4% to 7% of the dose after 4 to 5 days. Excretion of radioactivity in urine likely continues beyond 5 days. The mean elimination half-life of nilutamide determined in studies in which subjects received a single dose of 100–300 mg ranged from 38.0 to 59.1 hours with most values between 41 and 49 hours. The elimination of at least one metabolite is generally longer than that of unchanged nilutamide (59–126 hours). During multiple dosing of 150 mg nilutamide (given as 3 × 50 mg) twice a day, steady state was reached within 2 to 4 weeks for most patients, and mean steady state AUC0–12 was 110% higher than the AUC0–∞obtained from the first 150 mg dose. These data and in vitro metabolism data suggest that, upon multiple dosing, metabolic enzyme inhibition may occur for this drug.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Administration of nilutamide to rats for 18 months at doses of 0, 5, 15, or 45 mg/kg/day produced benign Leydig cell tumors in 35% of the high-dose male rats (AUC exposures in high-dose rats were approximately 1–2 times human AUC exposures with therapeutic doses). The increased incidence of Leydig cell tumors is secondary to elevated luteinizing hormone (LH) concentrations resulting from loss of feedback inhibition at the pituitary. Elevated LH and testosterone concentrations are not observed in castrated men receiving Nilutamide. Nilutamide had no effect on the incidence, size, or time of onset of any spontaneous tumor in rats.
- Nilutamide displayed no mutagenic effects in a variety of in vitro and in vivo tests (Ames test, mouse micronucleus test, and two chromosomal aberration tests).
- In reproduction studies in rats, nilutamide had no effect on the reproductive function of males and females, and no lethal, teratogenic, or growth-suppressive effects on fetuses were found. The maximal dose at which nilutamide did not affect reproductive function in either sex or have an effect on fetuses was estimated to be 45 mg/kg orally (AUC exposures in rats approximately 1–2 times human therapeutic AUC exposures).
# Clinical Studies
- Nilutamide through its antiandrogenic activity can complement surgical castration, which suppresses only testicular androgens. The effects of the combined therapy were studied in patients with previously untreated metastatic prostate cancer.
- In a double-blind, randomized, multicenter study that enrolled 457 patients (225 treated with orchiectomy and Nilutamide 232 treated with orchiectomy and placebo), the Nilutamide group showed a statistically significant benefit in time to progression and time to death. The results are summarized below.
# How Supplied
Nilutamide 150 mg tablets are supplied in boxes of 30 tablets. Each box contains 3 child-resistant, PVC, aluminum foil-backed blisters of 10 tablets (NDC 24987-111-14). Each white, biconvex, cylindrical (10 mm in diameter) tablet has a triangular logo on one side and an internal reference number (168D) on the other.
## Storage
Store at 25°C (77°F); excursions permitted between 15–30°C (59–86°F). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Nilutamide Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Nilutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nilandron
# Look-Alike Drug Names
There is limited information regarding Nilutamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nilandron | |
165eb9a8248982abd53dad8b940073f96924b807 | wikidoc | Nimesulide | Nimesulide
# Overview
Nimesulide is a relatively COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old. It has a multifactorial mode of action and is characterized by a fast onset of action.
# History
It was launched in Italy for the first time as Aulin and Mesulid in 1985 and is available in more than 50 countries worldwide, including among others France, Portugal, Greece, Switzerland, Belgium, Russia Thailand and Brazil. Nimesulide has never been filed for Food and Drug Administration (FDA) evaluation in the United States, where it is not marketed.
Due to concerns about the risk of hepatotoxicity, nimesulide has been withdrawn from market in many countries.Template:Which
# Advantages
- Nimesulide has similar gastrointestinal safety as compared to other NSAIDs.
- Its multifactorial mode of action gives it a unique and broad action on inflammatory processes.
- It may be taken through prescription in the treatment of Acute (short term) pain, and Primary dysmenorrhea (Period Pains). It should never be taken in Painful osteoarthritis (Swelling in the joints) .
# Availability
It is available in a variety of forms: tablets, powder for dissolution in water, suppositories, mouth dissolving tablets and topical gel.
A recent evaluation from the European Medicines Agency (EMA) concluded that the overall benefit/risk profile of nimesulide is favourable and in line with that of the other NSAIDs such as diclofenac, ibuprofen, and naproxen.
# Trade names
Nimesulide is available through the world as original product with the following trademarks: Sulide, Nimalox, Mesulid (Novartis, Brazil, Boehringer Ingelheim, Greece), Coxtal (Sanofi, China, Czech, Bulgaria),Sintalgin (Abbott, Brazil), Eskaflam (GSK, Brazil, Mexico), Octaprin, Nimside (Teva,Pakistan), Nise (Dr. Reddy’s Laboratories, India, Russia, Venezuela, Vietnam, Ukraine), Nilsid (Egypt); Aulin, Ainex, Drexel, Donulide, Edrigyl, Enetra, Heugan, Mesulid, Minapon, NeRelid, Nexen, Nidolon, Nilden (Mexico); Nimed, Nimedex, Nimesil, Nimulid, Nimutab, Nimdase, Nimopen-MP (India), Nisulid, Nodard Plus, Nicip, Nimcap, Nic-P, Nic-Spas (India); Novolid, Relmex (Ecuador); Remisid (Ukraine); Scaflam, Scaflan, Sulidin (Turkey), Xilox (Hungary); Modact-IR (Pakistan); Sulidene and Zolan for veterinary use. Many generic and copy-products also exist (Lusemin, Medicox, Nidol, Nimalox, Nimesil, Nimotas, Nimulid, Nizer, Sorini, Ventor, Vionim, Neolide, Willgo among others), new-aid (S.A.R.), Nims (Nepal).
# Pharmacokinetics
Nimesulide is rapidly absorbed following oral administration.
Nimesulide undergoes extensive biotransformation, mainly to 4-hydroxynimesulide (which also appears to be biologically active).
Food, gender and advanced age have negligible effects on nimesulide pharmacokinetics.
Moderate renal impairment does not necessitate dosage adjustment while patients with severe renal impairment or hepatic impairment are contraindicated.
Nimesulide has a relatively rapid onset of action, with meaningful reductions in pain and inflammation observed within 15 minutes from drug intake.
The therapeutic effects of Nimesulide are the result of its complete mode of action which targets a number of key mediators of the inflammatory process such as: COX-2 mediated prostaglandins, free radicals, proteolytic enzymes and histamine.
Clinical evidence is available to support a particularly good profile in terms of gastrointestinal tolerability.
# Nimesulide Events
## Madras High Court revokes suspension on manufacture and sale of Nimesulide in India
On September 13, 2011 Madras High Court revoked a suspension on manufacture and sale of paediatric drugs nimesulide and phenylpropanolamine (PPA).
## EMEA re-confirms efficacy of Nimesulide
On 23 June 2011, the European Medicines Agency concluded the review of systemic nimesulide-containing medicine. They concluded that the benefits of systemic nimesulide continue to outweigh their risks in the treatment of patients with acute pain and primary dysmenorrhea.
## Central Drugs Standard Control Organization of India Restricts use of Nimesulide under 12 years of age.
Several reports have been made of adverse drug reactions in India. On Feb 12, 2011, Express India that the Union Ministry of Health and Family Welfare had finally decided to suspend the pediatric use of the analgesic, Nimesulide suspension. From 10 March 2011 onwards Nimesulide formulations not indicated for human use in children below 12 years of age.
## EMA confirms the positive benefit/risk ratio
On September 21, 2007 the EMA released a press release on their review on the liver-related safety of nimesulide. The EMA has concluded that the benefits of these medicines outweigh their risks, but that there is a need to limit the duration of use to ensure that the risk of patients developing liver problems is kept to a minimum. Therefore the EMA has limited the use of systemic formulations (tablets, solutions, suppositories) of nimesulide to 15 days.
## Irish Medicines Board (IMB) suspends Nimesulide containing drugs (15 May 2007)
The Irish Medicines Board (IMB) has decided to suspend Nimesulide from the Irish market and refer it to the EU Committee for Human Medicinal Products (CHMP) for a review of its benefit/risk profile. The decision is due to the reporting of six (6) cases of potentially related liver failures to the IMB by the National Liver Transplant Unit, St Vincent Hospital. These cases occurred in the period from 1999 to 2006.
## Delhi High Court verdict
In response to a petition against Nimesulide filed in May 2004, the Delhi High Court passed a verdict that Nimesulide will continue to be marketed in India since the concerns over its side effect profile are unsubstantiated. The High court sought the help of leading pediatricians and medical agencies from India to arrive at the conclusion that Nimesulide is a safe NSAID with a side effect profile that is comparable to the other NSAIDs.
## Bribes allegedly paid in Italy to spare few drugs from official scrutiny
In May 2008, Italy's leading daily paper Corriere della Sera and other media outlets reported that a top-ranking official at Italy's medicines agency AIFA had been filmed by police while accepting bribes from employees of pharmaceutical companies. The money was allegedly being paid to ensure that certain drugs would be spared scrutiny from the drugs watchdog. The investigation had started in 2005 following suspicions that some AIFA drug tests had been faked. Eight arrests were made. Nimesulide can be bought carrying a prescription from a physician that is kept as a receipt at the chemist shop, nominally allowing strong control over selling.
The original manufacturer of Nimesulide is Helsinn Healthcare SA, Switzerland, which acquired the rights for the drug in 1976. After the patent protection had terminated, a number of other companies have started production and marketing of Nimesulide.
## European Medicines Agency reports increased risk of liver toxicity
The Committee noted that the studies looking into the effectiveness of nimesulide in acute pain relief have shown that it is as effective as other NSAID pain killers such as diclofenac, ibuprofen and naproxen.
In terms of safety, the Committee noted that nimesulide has the same risk of causing stomach and gut problems as other NSAIDs. To limit the risk of side effects affecting the liver, several restrictions have already been introduced in the past, including restriction to second line treatment, the use of lowest effective doses for the shortest possible duration, and a maximum duration of treatment for acute pain.
The CHMP concluded that nimesulide was associated with an increased risk of liver toxicity compared with other anti-inflammatory treatments. The CHMP is now recommending, as a further restriction, that systemic nimesulide should no longer be used for treating painful osteoarthritis. The Committee considered that the use of systemic nimesulide for the treatment of painful osteoarthritis, which is a chronic condition, will increase the risk of the medicines being used for long-term treatment with a consequent increase in the risk of liver injury.
# Side effects
The use of nimesulide in children under the age of 12 is contraindicated. Continuous use of nimesulide (more than 15 days) can cause the following side effects:
- Diarrhea
- Vomiting
- Skin rash
- Pruritis
- Dizziness
- Bitterness in mouth
Women should use the drug with caution during lactation and it is contraindicated during pregnancy. | Nimesulide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Nimesulide is a relatively COX-2 selective, non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old. It has a multifactorial mode of action and is characterized by a fast onset of action.
# History
It was launched in Italy for the first time as Aulin and Mesulid in 1985 and is available in more than 50 countries worldwide, including among others France, Portugal, Greece, Switzerland, Belgium, Russia Thailand and Brazil. Nimesulide has never been filed for Food and Drug Administration (FDA) evaluation in the United States, where it is not marketed.[1]
Due to concerns about the risk of hepatotoxicity, nimesulide has been withdrawn from market in many countries.Template:Which
# Advantages
- Nimesulide has similar gastrointestinal safety as compared to other NSAIDs.[citation needed]
- Its multifactorial mode of action gives it a unique and broad action on inflammatory processes.[citation needed]
- It may be taken through prescription in the treatment of Acute (short term) pain, and Primary dysmenorrhea (Period Pains). It should never be taken in Painful osteoarthritis (Swelling in the joints) .[2]
# Availability
It is available in a variety of forms: tablets, powder for dissolution in water, suppositories, mouth dissolving tablets and topical gel.
A recent evaluation from the European Medicines Agency (EMA) concluded that the overall benefit/risk profile of nimesulide is favourable and in line with that of the other NSAIDs such as diclofenac, ibuprofen, and naproxen.
# Trade names
Nimesulide is available through the world as original product with the following trademarks: Sulide, Nimalox, Mesulid (Novartis, Brazil, Boehringer Ingelheim, Greece), Coxtal (Sanofi, China, Czech, Bulgaria),Sintalgin (Abbott, Brazil), Eskaflam (GSK, Brazil, Mexico), Octaprin, Nimside (Teva,Pakistan), Nise (Dr. Reddy’s Laboratories, India, Russia, Venezuela, Vietnam, Ukraine), Nilsid (Egypt); Aulin, Ainex, Drexel, Donulide, Edrigyl, Enetra, Heugan, Mesulid, Minapon, NeRelid, Nexen, Nidolon, Nilden (Mexico); Nimed, Nimedex, Nimesil, Nimulid, Nimutab, Nimdase, Nimopen-MP (India), Nisulid, Nodard Plus, Nicip, Nimcap, Nic-P, Nic-Spas (India); Novolid, Relmex (Ecuador); Remisid (Ukraine); Scaflam, Scaflan, Sulidin (Turkey), Xilox (Hungary); Modact-IR (Pakistan);[3] Sulidene and Zolan for veterinary use. Many generic and copy-products also exist (Lusemin, Medicox, Nidol, Nimalox, Nimesil, Nimotas, Nimulid, Nizer, Sorini, Ventor, Vionim, Neolide, Willgo among others), new-aid (S.A.R.), Nims (Nepal).
# Pharmacokinetics
Nimesulide is rapidly absorbed following oral administration.[4]
Nimesulide undergoes extensive biotransformation, mainly to 4-hydroxynimesulide (which also appears to be biologically active).[4]
Food, gender and advanced age have negligible effects on nimesulide pharmacokinetics.[4]
Moderate renal impairment does not necessitate dosage adjustment while patients with severe renal impairment or hepatic impairment are contraindicated.[5]
Nimesulide has a relatively rapid onset of action, with meaningful reductions in pain and inflammation observed within 15 minutes from drug intake.[6][7]
The therapeutic effects of Nimesulide are the result of its complete mode of action which targets a number of key mediators of the inflammatory process such as: COX-2 mediated prostaglandins, free radicals, proteolytic enzymes and histamine.[6]
Clinical evidence is available to support a particularly good profile in terms of gastrointestinal tolerability.[8]
# Nimesulide Events
## Madras High Court revokes suspension on manufacture and sale of Nimesulide in India
On September 13, 2011 Madras High Court revoked a suspension on manufacture and sale of paediatric drugs nimesulide and phenylpropanolamine (PPA).[9]
## EMEA re-confirms efficacy of Nimesulide
On 23 June 2011, the European Medicines Agency concluded the review of systemic nimesulide-containing medicine. They concluded that the benefits of systemic nimesulide continue to outweigh their risks in the treatment of patients with acute pain and primary dysmenorrhea.
## Central Drugs Standard Control Organization of India Restricts use of Nimesulide under 12 years of age.
Several reports have been made of adverse drug reactions in India.[10][11][12][13] On Feb 12, 2011, Express India that the Union Ministry of Health and Family Welfare had finally decided to suspend the pediatric use of the analgesic, Nimesulide suspension.[14] From 10 March 2011 onwards Nimesulide formulations not indicated for human use in children below 12 years of age.[15]
## EMA confirms the positive benefit/risk ratio
On September 21, 2007 the EMA released a press release on their review on the liver-related safety of nimesulide. The EMA has concluded that the benefits of these medicines outweigh their risks, but that there is a need to limit the duration of use to ensure that the risk of patients developing liver problems is kept to a minimum. Therefore the EMA has limited the use of systemic formulations (tablets, solutions, suppositories) of nimesulide to 15 days.[16]
## Irish Medicines Board (IMB) suspends Nimesulide containing drugs (15 May 2007)
The Irish Medicines Board (IMB) has decided to suspend Nimesulide from the Irish market and refer it to the EU Committee for Human Medicinal Products (CHMP) for a review of its benefit/risk profile. The decision is due to the reporting of six (6) cases of potentially related liver failures to the IMB by the National Liver Transplant Unit, St Vincent Hospital. These cases occurred in the period from 1999 to 2006.[17]
## Delhi High Court verdict
In response to a petition against Nimesulide filed in May 2004, the Delhi High Court passed a verdict that Nimesulide will continue to be marketed in India since the concerns over its side effect profile are unsubstantiated. The High court sought the help of leading pediatricians and medical agencies from India to arrive at the conclusion that Nimesulide is a safe NSAID with a side effect profile that is comparable to the other NSAIDs.
## Bribes allegedly paid in Italy to spare few drugs from official scrutiny
In May 2008, Italy's leading daily paper Corriere della Sera and other media outlets[citation needed] reported that a top-ranking official at Italy's medicines agency AIFA had been filmed by police while accepting bribes from employees of pharmaceutical companies.[18][19] The money was allegedly being paid to ensure that certain drugs would be spared scrutiny from the drugs watchdog. The investigation had started in 2005 following suspicions that some AIFA drug tests had been faked. Eight arrests were made. Nimesulide can be bought carrying a prescription from a physician that is kept as a receipt at the chemist shop, nominally allowing strong control over selling.
The original manufacturer of Nimesulide is Helsinn Healthcare SA, Switzerland, which acquired the rights for the drug in 1976. After the patent protection had terminated, a number of other companies have started production and marketing of Nimesulide.
## European Medicines Agency reports increased risk of liver toxicity
The Committee noted that the studies looking into the effectiveness of nimesulide in acute pain relief have shown that it is as effective as other NSAID pain killers such as diclofenac, ibuprofen and naproxen.
In terms of safety, the Committee noted that nimesulide has the same risk of causing stomach and gut problems as other NSAIDs. To limit the risk of side effects affecting the liver, several restrictions have already been introduced in the past, including restriction to second line treatment, the use of lowest effective doses for the shortest possible duration, and a maximum duration of treatment for acute pain.
The CHMP concluded that nimesulide was associated with an increased risk of liver toxicity compared with other anti-inflammatory treatments. The CHMP is now recommending, as a further restriction, that systemic nimesulide should no longer be used for treating painful osteoarthritis. The Committee considered that the use of systemic nimesulide for the treatment of painful osteoarthritis, which is a chronic condition, will increase the risk of the medicines being used for long-term treatment with a consequent increase in the risk of liver injury.
# Side effects
The use of nimesulide in children under the age of 12 is contraindicated. Continuous use of nimesulide (more than 15 days) can cause the following side effects:
- Diarrhea
- Vomiting
- Skin rash
- Pruritis
- Dizziness
- Bitterness in mouth
Women should use the drug with caution during lactation and it is contraindicated during pregnancy.[20] | https://www.wikidoc.org/index.php/Nimesulide | |
2199c7b4aeccff531ced93da226097568d035149 | wikidoc | Nimodipine | Nimodipine
# 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
Nimodipine is a Calcium Channel Blocker that is FDA approved for the treatment of improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Hypotension， Diarrhea， Nausea， Headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Subarachnoid Hemorrhage
- Indication (For both capsule and solution)
- Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).
- Dosing information (In capsule)
- DO NOT ADMINISTER NIMODIPINE CAPSULES INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES (see WARNINGS). If Nimodipine is inadvertently administered intravenously, clinically significant hypotension may require cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly.
- Nimodipine is given orally in the form of soft gelatin 30 mg capsules for subarachnoid hemorrhage.
- Recommended dosage: 60 mg (two 30 mg capsules) PO q4h for 21 consecutive days.
- In general, the capsules should be swallowed whole with a little liquid, preferably not less than one hour before or two hours after meals. Grapefruit juice is to be avoided. Oral nimodipine therapy should commence as soon as possible within 96 hours of the onset of subarachnoid hemorrhage.
- If the capsule cannot be swallowed, e.g., at the time of surgery, or if the patient is unconscious, a hole should be made in both ends of the capsule with an 18 gauge needle, and the contents of the capsule extracted into a syringe. A parenteral syringe can be used to extract the liquid inside the capsule, but the liquid should always be transferred to a syringe that cannot accept a needle and that is designed for administration orally or via a naso-gastric tube or PEG. To help minimize administration errors, it is recommended that the syringe used for administration be labeled “Not for IV Use”. The contents should then be emptied into the patient’s in situ naso-gastric tube and washed down the tube with 30 mL of normal saline (0.9%).
- Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first pass capacity and a reduced metabolic clearance. The reduction in blood pressure and other adverse effects may be more pronounced in these patients.
- Dosage should be reduced to one 30 mg capsule every 4 hours with close monitoring of blood pressure and heart rate; if necessary, discontinuation of the treatment should be considered.
- Strong inhibitors of CYP3A4 should not be administered concomitantly with nimodipine . Strong inducers of CYP3A4 should generally not be administered with nimodipine. Patients on moderate and weak inducers of CYP3A4 should be closely monitored for lack of effectiveness, and a nimodipine dose increase may be required. Patients on moderate and weak CYP3A4 inhibitors may require a nimodipine dose reduction in case of hypotension
- Dosing information （In solution）
- Administration Instructions
- Administer only enterally (e.g., oral, nasogastric tube, or gastric tube route). Do not administer intravenously or by other parenteral routes. For all routes of administration, begin Nimodipine within 96 hours of the onset of SAH. Administer one hour before a meal or two hours after a meal for all routes of administration.
- Administration by Oral Route
- Recommended oral dosage: 20 mL (60 mg) PO q4h for 21 consecutive days.
- Administration Via Nasogastric or Gastric Tube
- Using the supplied oral syringe labeled "ORAL USE ONLY", administer 20 mL (60 mg) every 4 hours into a nasogastric or gastric tube for 21 consecutive days. For each dose, refill the syringe with 20 mL of 0.9% saline solution and then flush any remaining contents from nasogastric or gastric tube into the stomach.
- Dosage Adjustments in Patients with Cirrhosis
- In patients with cirrhosis, reduce the dosage to 10 mL (30 mg) every 4 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nimodipine sandbox in adult patients.
### Non–Guideline-Supported Use
### Cluster headache
- Dosing information
- Total daily doses of 60 to 120 mg
### Adjunct treatment of Dementia
- Dosing information
- 180 mg/day
- 30 mg PO tid
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nimodipine sandbox in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nimodipine sandbox in pediatric patients.
# Contraindications
The concomitant use of nimodipine with strong inhibitors of CYP3A4 such as some macrolide antibiotics (e.g., clarithromycin, telithromycin), some anti-HIV protease inhibitors (e.g., delaviridine, indinavir, nelfinavir, ritonavir, saquinavir), some azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole) and some antidepressants (e.g., nefazadone) is contraindicated because of a risk of significant hypotension
# Warnings
# Warning (capsule)
DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION: DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION).
Reduced Efficacy with CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenobarbital, phenytoin, carbamazepine, St John’s wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be very significantly reduced.
Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine to a lesser extent. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inhibitors include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.
## PRECAUTIONS (capsule)
### General
Blood Pressure: Nimodipine has the hemodynamic effects expected of a calcium channel blocker, although they are generally not marked. However, intravenous administration of the contents of nimodipine capsules has resulted in serious adverse consequences including death, cardiac arrest, cardiovascular collapse, hypotension, and bradycardia. In patients with subarachnoid hemorrhage given nimodipine in clinical studies, about 5% were reported to have had lowering of the blood pressure and about 1% left the study because of this (not all could be attributed to nimodipine). Nevertheless, blood pressure should be carefully monitored during treatment with nimodipine based on its known pharmacology and the known effects of calcium channel blockers.
Hepatic Disease: The metabolism of nimodipine is decreased in patients with impaired hepatic function. Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose.
- Intestinal pseudo-obstruction and ileus have been reported rarely in patients treated with nimodipine. A causal relationship has not been established. The condition has responded to conservative management.
# WARNINGS AND PRECAUTIONS
## Hypotension
- Blood pressure should be carefully monitored during treatment with Nimodipine. In clinical studies of patients with subarachnoid hemorrhage, about 5% of nimodipine-treated patients compared to 1% of placebo-treated patients had hypotension and about 1% of nimodipine-treated patients left the study because of this.
## Possible Increased Risk of Adverse Reactions in Patients with Cirrhosis
- Given that the plasma levels of nimodipine are increased in patients with cirrhosis, these patients are at higher risk of adverse reactions. Therefore, monitor blood pressure and pulse rate closely and administer a lower dosage.
## Possible Increased Risk of Hypotension with Strong CYP3A4 Inhibitors
- Concomitant use of strong inhibitors of CYP3A4, such as some macrolide antibiotics (e.g., clarithromycin, telithromycin), some HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (e.g., boceprevir, telaprevir), some azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan, delaviridine, and nefazadone with nimodipine should generally be avoided because of a risk of significant hypotension.
## Possible Reduced Efficacy with Strong CYP3A4 Inducers
- Concomitant use of strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, St John's wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be significantly reduced.
# 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.
- In clinical trials of nimodipine oral capsules in patients with SAH, eleven percent (92 of 823) of nimodipine-treated patients reported adverse events compared to six percent (29 of 479) of placebo-treated patients. The most common adverse event was decreased blood pressure in 4.4% of nimodipine-treated patients. The events reported with a frequency greater than 1% are displayed in Table 1 by dose.
- SAH is frequently accompanied by alterations in consciousness that may lead to an under-reporting of adverse experiences. As a calcium channel blocker, nimodipine may have the potential to exacerbate heart failure in susceptible patients or to interfere with A-V conduction, but these events were not observed in SAH trials.
## Postmarketing Experience
FDA Package Insert for Nimodipine contains no information regarding Adverse Reactions.
# Drug Interactions
- Nimodipine is metabolized via the cytochrome P450 3A4 system located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine.
- In addition, the blood pressure lowering effects of antihypertensives could be enhanced when taken concomitantly with nimodipine.
## Inducers of CYP3A4
- Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers. Therefore strong CYP3A4 inducers (e.g. rifampin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) should generally not be administered concomitantly with nimodipine.
- Other moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine, although the magnitude of decrease in nimodipine plasma concentrations is not known. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inducers include: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, Echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.
## Inhibitors of CYP3A4
- Nimodipine plasma concentration can be significantly increased when concomitantly administered with strong inhibitors of the CYP3A4 system. As a consequence, the blood pressure lowering effect may be increased. Therefore strong CYP3A4 inhibitors should not be coadministered with nimodipine. Strong CYP3A4 inhibitors include some members of the following classes:
- macrolide antibiotics (e.g., clarithromycin, telithromycin,),
- HIV protease inhibitors (e.g., delavirdine, indinavir, nelfinavir, ritonavir, saquinavir),
- azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole),
- antidepressants (e.g. nefazodone)
- grapefruit juice: after intake of grapefruit juice and nimodipine, the blood pressure lowering effect may last for at least 4 days after the last ingestion of grapefruit juice. Ingestion of grapefruit / grapefruit juice is therefore not recommended while taking nimodipine.
Nimodipine plasma concentration can also be increased in the presence of moderate and weak inhibitors of CYP3A4. If nimodipine is concomitantly administered with these drugs, blood pressure should be monitored, and a reduction of the nimodipine dose may be necessary. Moderate and weak CYP3A4 inhibitors include amprenavir, aprepitant, atazanavir, amiodarone, alprozalam, cyclosporine, cimetidine, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalforpristin, and valproic acid.
Blood pressure lowering drugs:
Nimodipine may increase the blood pressure lowering effect of concomitantly administered anti-hypertensives, such as:
– diuretics,
– β-blockers,
– ACE inhibitors,
– A1-antagonists,
– other calcium antagonists,
– α-adrenergic blocking agents,
– PDE5 inhibitors,
– α-methyldopa.
Blood pressure should be carefully monitored, and dose adjustment of the blood pressure lowering drug(s) may be necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Pregnancy Category C. Nimodipine has been shown to have a teratogenic effect in Himalayan rabbits. Incidences of malformations and stunted fetuses were increased at oral doses of 1 and 10 mg/kg/day administered (by gavage) from day 6 through day 18 of pregnancy but not at 3 mg/kg/day in one of two identical rabbit studies. In the second study an increased incidence of stunted fetuses was seen at 1 mg/kg/day but not at higher doses. Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses, in Long Evans rats at 100 mg/kg/day administered by gavage from day 6 through day 15 of pregnancy. In two other rat studies, doses of 30 mg/kg/day nimodipine administered by gavage from day 16 of gestation and continued until sacrifice (day 20 of pregnancy or day 21 post partum) were associated with higher incidences of skeletal variation, stunted fetuses and stillbirths but no malformations. There are no adequate and well controlled studies in pregnant women to directly assess the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nimodipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nimodipine during labor and delivery.
### Nursing Mothers
- Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than in maternal plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, nursing mothers are advised not to breast feed their babies when taking the drug.
### Pediatric Use
Safety and effectiveness in children have not been established.
### Geriatic Use
- Clinical studies of nimodipine 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, dosing in elderly patients 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 Nimodipine with respect to specific gender populations.
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Nimodipine contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
- There have been no reports of overdosage from the oral administration of nimodipine. Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. Clinically significant hypotension due to nimodipine overdosage may require active cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly. Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.
# Pharmacology
## Mechanism of Action
- Nimodipine is a calcium channel blocker. The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine-treated subarachnoid hemorrhage (SAH) patients.
- The precise mechanism of action of nimodipine in humans is unknown. Although the clinical studies described below demonstrate a favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries. However, whether or not the arteriographic methodology utilized was adequate to detect a clinically meaningful effect, if any, on vasospasm is unknown.
## Structure
- Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is isopropyl 2 -methoxyethyl 1,4 –dihydro -2,6 –dimethyl -4-(m-nitrophenyl) -3,5-pyridinedicarboxylate. It has a molecular weight of 418.5 and a molecular formula of C21H26N2O7. The structural formula is:
- Nimodipine is a yellow crystalline substance, practically insoluble in water.
## Pharmacodynamics
FDA Package Insert for Nimodipine contains no information regarding pharmacodynamics.
## Pharmacokinetics
- In man, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. The terminal elimination half-life is approximately 8 to 9 hours but earlier elimination rates are much more rapid, equivalent to a half-life of 1-2 hours; a consequence is the need for frequent (every 4 hours) dosing. There were no signs of accumulation when nimodipine was given three times a day for seven days. Nimodipine is over 95% bound to plasma proteins. The binding was concentration independent over the range of 10 ng/mL to 10 µg/ml. Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. The metabolism of nimodipine is mediated by CYP3A4. Because of a high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration. The bioavailability is significantly increased in patients with hepatic cirrhosis, with Cmax approximately double that in normals which necessitates lowering the dose in this group of patients. In a study of 24 healthy male volunteers, administration of nimodipine capsules following a standard breakfast resulted in a 68% lower peak plasma concentration and 38% lower bioavailability relative to dosing under fasted conditions.
- In a single parallel-group study involving 24 elderly subjects (aged 59-79) and 24 younger subjects (aged 22-40), the observed AUC and Cmax of nimodipine was approximately 2-fold higher in the elderly population compared to the younger study subjects following oral administration (given as a single dose of 30 mg and dosed to steady-state with 30 mg t.i.d. for 6 days). The clinical response to these age-related pharmacokinetic differences, however, was not considered significant. (See PRECAUTIONS, Geriatric Use.)
## Nonclinical Toxicology
- In a two-year study, higher incidences of adenocarcinoma of the uterus and Leydig-cell adenoma of the testes were observed in rats given a diet containing 1800 ppm nimodipine (equivalent to 91 to 121 mg/kg/day nimodipine) than in placebo controls. The differences were not statistically significant, however, and the higher rates were well within historical control range for these tumors in the Wistar strain. Nimodipine was found not to be carcinogenic in a 91-week mouse study but the high dose of 1800 ppm nimodipine-in-feed (546 to 774 mg/kg/day) shortened the life expectancy of the animals. Mutagenicity studies, including the Ames, micronucleus and dominant lethal tests were negative.
- Nimodipine did not impair the fertility and general reproductive performance of male and female Wistar rats following oral doses of up to 30 mg/kg/day when administered daily for more than 10 weeks in the males and 3 weeks in the females prior to mating and continued to day 7 of pregnancy. This dose in a rat is about 4 times the equivalent clinical dose of 60 mg q4h in a 50 kg patient.
# Clinical Studies
# Clinical Studies (capsule)
- Nimodipine has been shown, in 4 randomized, double-blind, placebo-controlled trials, to reduce the severity of neurological deficits resulting from vasospasm in patients who have had a recent subarachnoid hemorrhage (SAH). The trials used doses ranging from 20-30 mg to 90 mg every 4 hours, with drug given for 21 days in 3 studies, and for at least 18 days in the other. Three of the four trials followed patients for 3-6 months. Three of the trials studied relatively well patients, with all or most patients in Hunt and Hess Grades I - III (essentially free of focal deficits after the initial bleed) the fourth studied much sicker patients, Hunt and Hess Grades III - V. Two studies, one U.S., one French, were similar in design, with relatively unimpaired SAH patients randomized to nimodipine or placebo. In each, a judgment was made as to whether any late-developing deficit was due to spasm or other causes, and the deficits were graded. Both studies showed significantly fewer severe deficits due to spasm in the nimodipine group; the second (French) study showed fewer spasm-related deficits of all severities. No effect was seen on deficits not related to spasm.
- A third, large, study was performed in the United Kingdom in SAH patients with all grades of severity (but 89% were in Grades I-III). Nimodipine was dosed 60 mg every 4 hours. Outcomes were not defined as spasm related or not but there was a significant reduction in the overall rate of infarction and severely disabling neurological outcome at 3 months:
- A Canadian study entered much sicker patients, (Hunt and Hess Grades III-V), who had a high rate of death and disability, and used a dose of 90 mg every 4 hours, but was otherwise similar to the first two studies. Analysis of delayed ischemic deficits, many of which result from spasm, showed a significant reduction in spasm-related deficits. Among analyzed patients (72 nimodipine, 82 placebo), there were the following outcomes.
- When data were combined for the Canadian and the United Kingdom studies, the treatment difference on success rate (i.e., good recovery) on the Glasgow Outcome Scale was 25.3% (nimodipine) versus 10.9% (placebo) for Hunt and Hess Grades IV or V. The table below demonstrates that nimodipine tends to improve good recovery of SAH patients with poor neurological status post-ictus, while decreasing the numbers with severe disability and vegetative survival.
- A dose-ranging study comparing 30, 60 and 90 mg doses found a generally low rate of spasm-related neurological deficits but no dose response relationship.
# Clinical Studies (solution)
- The safety and efficacy of Nimodipine (nimodipine oral solution) in the treatment of patients with SAH is based on adequate and well-controlled studies of nimodipine oral capsules in patients with SAH. Nimodipine (nimodipine oral solution) has comparable bioavailability to nimodipine oral capsules.
- Nimodipine has been shown in 4 randomized, double-blind, placebo-controlled trials to reduce the severity of neurological deficits resulting from vasospasm in patients who have had a recent SAH (Studies 1, 2, 3, and 4).
- The trials used doses ranging from 20-30 mg to 90 mg every 4 hours, with drug given for 21 days in 3 studies, and for at least 18 days in the other. Three of the four trials followed patients for 3-6 months. Three of the trials studied relatively well patients, with all or most patients in Hunt and Hess Grades I - III (essentially free of focal deficits after the initial bleed). Study 4 studied much sicker patients with Hunt and Hess Grades III - V. Studies 1 and 2 were similar in design, with relatively unimpaired SAH patients randomized to nimodipine or placebo. In each, a judgment was made as to whether any late-developing deficit was due to spasm or other causes, and the deficits were graded. Both studies showed significantly fewer severe deficits due to spasm in the nimodipine group; Study 2 showed fewer spasm-related deficits of all severities. No effect was seen on deficits not related to spasm. See Table 2.
- Study 3 was a 554-patient trial that included SAH patients with all grades of severity (89% were in Hunt and Hess Grades I-III). In Study 3, patients were treated with placebo or 60 mg of nimodipine every 4 hours. Outcomes were not defined as spasm related or not but there was a significant reduction in the overall rate of brain infarction and severely disabling neurological outcome at 3 months (Table 3):
- Study 4 enrolled much sicker patients, (Hunt and Hess Grades III-V), who had a high rate of death and disability, and used a dose of 90 mg every 4 hours, but was otherwise similar to Study 1 and Study 2. Analysis of delayed ischemic deficits, many of which result from spasm, showed a significant reduction in spasm-related deficits. Among analyzed patients (72 nimodipine, 82 placebo), there were the following outcomes (Table 4).
- When data were combined for Study 3 and Study 4, the treatment difference on success rate (i.e., good recovery) on the Glasgow Outcome Scale was 25.3% (nimodipine) versus 10.9% (placebo) for Hunt and Hess Grades IV or V. Table 5 demonstrates that nimodipine tends to improve good recovery of SAH patients with poor neurological status post-ictus, while decreasing the numbers with severe disability and vegetative survival.
- A dose-ranging study comparing 30 mg, 60 mg, and 90 mg doses found a generally low rate of spasm-related neurological deficits but no dose response relationship.
# How Supplied
# Nimodipine Capsules
30 mg - Oblong, white opaque, soft gelatin capsules in
Unit Dose Package of 30 NDC 23155-108-30
Unit Dose Package of 100 NDC 23155-108-00
Printed H108 in black ink.
The capsules should be stored in the manufacturer’s original package.
# Nimodipine Solution
- NDC 24338-200-16: 16 oz. bottle (473 mL)
- NDC 24338-200-12: Carton containing 12 individually wrapped packages. Each package contains one 20 mL Unit-Dose cup (NDC 24338-200-20) and one oral syringe.
## Storage
# Nimodipine Capsules
Store at 20°-25°C (68°-77°F) .
Capsules should be protected from light and freezing.
# Nimodipine Solution
Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) .
Protect from light.
Do not refrigerate.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients that the most frequent adverse reaction associated with nimodipine is decreased blood pressure . Inform them that use of Nimodipine with anti-hypertensives can cause increased drop in blood pressure .
Patients should be aware that ingestion of grapefruit or grapefruit juice should be avoided when taking Nimodipine due to its ability to increase nimodipine plasma concentrations and potential to increase the risk of hypotension .
Pregnant women should be advised that a harmful effect of Nimodipine on the fetus cannot be ruled out and the drug should only be used if the potential benefit justifies the potential risk to the fetus .
Manufactured for:
arbor™
PHARMACEUTICALS, LLC.
Atlanta, GA 30328
Manufactured by:
Importfab
Pointe-Claire, QC, Canada
H9R 1C9
Distributed By Arbor Pharmaceuticals, LLC., Atlanta, GA 30328
Nimodipine is a trademark of Arbor Pharmaceuticals, LLC
© 2013 Arbor Pharmaceuticals, LLC
NIM-PI-02
PRINCIPAL DISPLAY PANEL - 473 mL Bottle Label
NDC: 24338-200-16
16 oz.
(473 mL)
Nimodipine®
(nimodipine) oral solution
60 mg/20 mL
For Oral Use Only
Distributed by:
arbor™
PHARMACEUTICALS, LLC.
Atlanta, GA 30328
# Precautions with Alcohol
Alcohol-Nimodipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nimotop
- Nimodipine
# Look-Alike Drug Names
Nimodipine - Nicardipine
Nimodipine - Nifedipine
# Drug Shortage Status
# Price | Nimodipine
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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# Black Box Warning
# Overview
Nimodipine is a Calcium Channel Blocker that is FDA approved for the treatment of improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Hypotension， Diarrhea， Nausea， Headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Subarachnoid Hemorrhage
- Indication (For both capsule and solution)
- Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).
- Dosing information (In capsule)
- DO NOT ADMINISTER NIMODIPINE CAPSULES INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES (see WARNINGS). If Nimodipine is inadvertently administered intravenously, clinically significant hypotension may require cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly.
- Nimodipine is given orally in the form of soft gelatin 30 mg capsules for subarachnoid hemorrhage.
- Recommended dosage: 60 mg (two 30 mg capsules) PO q4h for 21 consecutive days.
- In general, the capsules should be swallowed whole with a little liquid, preferably not less than one hour before or two hours after meals. Grapefruit juice is to be avoided. Oral nimodipine therapy should commence as soon as possible within 96 hours of the onset of subarachnoid hemorrhage.
- If the capsule cannot be swallowed, e.g., at the time of surgery, or if the patient is unconscious, a hole should be made in both ends of the capsule with an 18 gauge needle, and the contents of the capsule extracted into a syringe. A parenteral syringe can be used to extract the liquid inside the capsule, but the liquid should always be transferred to a syringe that cannot accept a needle and that is designed for administration orally or via a naso-gastric tube or PEG. To help minimize administration errors, it is recommended that the syringe used for administration be labeled “Not for IV Use”. The contents should then be emptied into the patient’s in situ naso-gastric tube and washed down the tube with 30 mL of normal saline (0.9%).
- Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first pass capacity and a reduced metabolic clearance. The reduction in blood pressure and other adverse effects may be more pronounced in these patients.
- Dosage should be reduced to one 30 mg capsule every 4 hours with close monitoring of blood pressure and heart rate; if necessary, discontinuation of the treatment should be considered.
- Strong inhibitors of CYP3A4 should not be administered concomitantly with nimodipine . Strong inducers of CYP3A4 should generally not be administered with nimodipine. Patients on moderate and weak inducers of CYP3A4 should be closely monitored for lack of effectiveness, and a nimodipine dose increase may be required. Patients on moderate and weak CYP3A4 inhibitors may require a nimodipine dose reduction in case of hypotension
- Dosing information （In solution）
- Administration Instructions
- Administer only enterally (e.g., oral, nasogastric tube, or gastric tube route). Do not administer intravenously or by other parenteral routes. For all routes of administration, begin Nimodipine within 96 hours of the onset of SAH. Administer one hour before a meal or two hours after a meal for all routes of administration.
- Administration by Oral Route
- Recommended oral dosage: 20 mL (60 mg) PO q4h for 21 consecutive days.
- Administration Via Nasogastric or Gastric Tube
- Using the supplied oral syringe labeled "ORAL USE ONLY", administer 20 mL (60 mg) every 4 hours into a nasogastric or gastric tube for 21 consecutive days. For each dose, refill the syringe with 20 mL of 0.9% saline solution and then flush any remaining contents from nasogastric or gastric tube into the stomach.
- Dosage Adjustments in Patients with Cirrhosis
- In patients with cirrhosis, reduce the dosage to 10 mL (30 mg) every 4 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nimodipine sandbox in adult patients.
### Non–Guideline-Supported Use
### Cluster headache
- Dosing information
- Total daily doses of 60 to 120 mg [1][2]
### Adjunct treatment of Dementia
- Dosing information
- 180 mg/day[3]
- 30 mg PO tid [4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nimodipine sandbox in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nimodipine sandbox in pediatric patients.
# Contraindications
The concomitant use of nimodipine with strong inhibitors of CYP3A4 such as some macrolide antibiotics (e.g., clarithromycin, telithromycin), some anti-HIV protease inhibitors (e.g., delaviridine, indinavir, nelfinavir, ritonavir, saquinavir), some azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole) and some antidepressants (e.g., nefazadone) is contraindicated because of a risk of significant hypotension
# Warnings
# Warning (capsule)
DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION: DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION).
Reduced Efficacy with CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenobarbital, phenytoin, carbamazepine, St John’s wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be very significantly reduced.
Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine to a lesser extent. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inhibitors include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.
## PRECAUTIONS (capsule)
### General
Blood Pressure: Nimodipine has the hemodynamic effects expected of a calcium channel blocker, although they are generally not marked. However, intravenous administration of the contents of nimodipine capsules has resulted in serious adverse consequences including death, cardiac arrest, cardiovascular collapse, hypotension, and bradycardia. In patients with subarachnoid hemorrhage given nimodipine in clinical studies, about 5% were reported to have had lowering of the blood pressure and about 1% left the study because of this (not all could be attributed to nimodipine). Nevertheless, blood pressure should be carefully monitored during treatment with nimodipine based on its known pharmacology and the known effects of calcium channel blockers.
Hepatic Disease: The metabolism of nimodipine is decreased in patients with impaired hepatic function. Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose.
- Intestinal pseudo-obstruction and ileus have been reported rarely in patients treated with nimodipine. A causal relationship has not been established. The condition has responded to conservative management.
# WARNINGS AND PRECAUTIONS
## Hypotension
- Blood pressure should be carefully monitored during treatment with Nimodipine. In clinical studies of patients with subarachnoid hemorrhage, about 5% of nimodipine-treated patients compared to 1% of placebo-treated patients had hypotension and about 1% of nimodipine-treated patients left the study because of this.
## Possible Increased Risk of Adverse Reactions in Patients with Cirrhosis
- Given that the plasma levels of nimodipine are increased in patients with cirrhosis, these patients are at higher risk of adverse reactions. Therefore, monitor blood pressure and pulse rate closely and administer a lower dosage.
## Possible Increased Risk of Hypotension with Strong CYP3A4 Inhibitors
- Concomitant use of strong inhibitors of CYP3A4, such as some macrolide antibiotics (e.g., clarithromycin, telithromycin), some HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (e.g., boceprevir, telaprevir), some azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan, delaviridine, and nefazadone with nimodipine should generally be avoided because of a risk of significant hypotension.
## Possible Reduced Efficacy with Strong CYP3A4 Inducers
- Concomitant use of strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, St John's wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be significantly reduced.
# 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.
- In clinical trials of nimodipine oral capsules in patients with SAH, eleven percent (92 of 823) of nimodipine-treated patients reported adverse events compared to six percent (29 of 479) of placebo-treated patients. The most common adverse event was decreased blood pressure in 4.4% of nimodipine-treated patients. The events reported with a frequency greater than 1% are displayed in Table 1 by dose.
- SAH is frequently accompanied by alterations in consciousness that may lead to an under-reporting of adverse experiences. As a calcium channel blocker, nimodipine may have the potential to exacerbate heart failure in susceptible patients or to interfere with A-V conduction, but these events were not observed in SAH trials.
## Postmarketing Experience
FDA Package Insert for Nimodipine contains no information regarding Adverse Reactions.
# Drug Interactions
- Nimodipine is metabolized via the cytochrome P450 3A4 system located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine.
- In addition, the blood pressure lowering effects of antihypertensives could be enhanced when taken concomitantly with nimodipine.
## Inducers of CYP3A4
- Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers. Therefore strong CYP3A4 inducers (e.g. rifampin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) should generally not be administered concomitantly with nimodipine.
- Other moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine, although the magnitude of decrease in nimodipine plasma concentrations is not known. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inducers include: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, Echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.
## Inhibitors of CYP3A4
- Nimodipine plasma concentration can be significantly increased when concomitantly administered with strong inhibitors of the CYP3A4 system. As a consequence, the blood pressure lowering effect may be increased. Therefore strong CYP3A4 inhibitors should not be coadministered with nimodipine. Strong CYP3A4 inhibitors include some members of the following classes:
- macrolide antibiotics (e.g., clarithromycin, telithromycin,),
- HIV protease inhibitors (e.g., delavirdine, indinavir, nelfinavir, ritonavir, saquinavir),
- azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole),
- antidepressants (e.g. nefazodone)
- grapefruit juice: after intake of grapefruit juice and nimodipine, the blood pressure lowering effect may last for at least 4 days after the last ingestion of grapefruit juice. Ingestion of grapefruit / grapefruit juice is therefore not recommended while taking nimodipine.
Nimodipine plasma concentration can also be increased in the presence of moderate and weak inhibitors of CYP3A4. If nimodipine is concomitantly administered with these drugs, blood pressure should be monitored, and a reduction of the nimodipine dose may be necessary. Moderate and weak CYP3A4 inhibitors include amprenavir, aprepitant, atazanavir, amiodarone, alprozalam, cyclosporine, cimetidine, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalforpristin, and valproic acid.
Blood pressure lowering drugs:
Nimodipine may increase the blood pressure lowering effect of concomitantly administered anti-hypertensives, such as:
– diuretics,
– β-blockers,
– ACE inhibitors,
– A1-antagonists,
– other calcium antagonists,
– α-adrenergic blocking agents,
– PDE5 inhibitors,
– α-methyldopa.
Blood pressure should be carefully monitored, and dose adjustment of the blood pressure lowering drug(s) may be necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Pregnancy Category C. Nimodipine has been shown to have a teratogenic effect in Himalayan rabbits. Incidences of malformations and stunted fetuses were increased at oral doses of 1 and 10 mg/kg/day administered (by gavage) from day 6 through day 18 of pregnancy but not at 3 mg/kg/day in one of two identical rabbit studies. In the second study an increased incidence of stunted fetuses was seen at 1 mg/kg/day but not at higher doses. Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses, in Long Evans rats at 100 mg/kg/day administered by gavage from day 6 through day 15 of pregnancy. In two other rat studies, doses of 30 mg/kg/day nimodipine administered by gavage from day 16 of gestation and continued until sacrifice (day 20 of pregnancy or day 21 post partum) were associated with higher incidences of skeletal variation, stunted fetuses and stillbirths but no malformations. There are no adequate and well controlled studies in pregnant women to directly assess the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nimodipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nimodipine during labor and delivery.
### Nursing Mothers
- Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than in maternal plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, nursing mothers are advised not to breast feed their babies when taking the drug.
### Pediatric Use
Safety and effectiveness in children have not been established.
### Geriatic Use
- Clinical studies of nimodipine 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, dosing in elderly patients 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 Nimodipine with respect to specific gender populations.
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Females of Reproductive Potential and Males
(Description)
### Immunocompromised Patients
(Description)
### Others
(Description)
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Nimodipine contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
- There have been no reports of overdosage from the oral administration of nimodipine. Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. Clinically significant hypotension due to nimodipine overdosage may require active cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly. Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.
# Pharmacology
## Mechanism of Action
- Nimodipine is a calcium channel blocker. The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine-treated subarachnoid hemorrhage (SAH) patients.
- The precise mechanism of action of nimodipine in humans is unknown. Although the clinical studies described below demonstrate a favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries. However, whether or not the arteriographic methodology utilized was adequate to detect a clinically meaningful effect, if any, on vasospasm is unknown.
## Structure
- Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is isopropyl 2 -methoxyethyl 1,4 –dihydro -2,6 –dimethyl -4-(m-nitrophenyl) -3,5-pyridinedicarboxylate. It has a molecular weight of 418.5 and a molecular formula of C21H26N2O7. The structural formula is:
- Nimodipine is a yellow crystalline substance, practically insoluble in water.
## Pharmacodynamics
FDA Package Insert for Nimodipine contains no information regarding pharmacodynamics.
## Pharmacokinetics
- In man, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. The terminal elimination half-life is approximately 8 to 9 hours but earlier elimination rates are much more rapid, equivalent to a half-life of 1-2 hours; a consequence is the need for frequent (every 4 hours) dosing. There were no signs of accumulation when nimodipine was given three times a day for seven days. Nimodipine is over 95% bound to plasma proteins. The binding was concentration independent over the range of 10 ng/mL to 10 µg/ml. Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. The metabolism of nimodipine is mediated by CYP3A4. Because of a high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration. The bioavailability is significantly increased in patients with hepatic cirrhosis, with Cmax approximately double that in normals which necessitates lowering the dose in this group of patients. In a study of 24 healthy male volunteers, administration of nimodipine capsules following a standard breakfast resulted in a 68% lower peak plasma concentration and 38% lower bioavailability relative to dosing under fasted conditions.
- In a single parallel-group study involving 24 elderly subjects (aged 59-79) and 24 younger subjects (aged 22-40), the observed AUC and Cmax of nimodipine was approximately 2-fold higher in the elderly population compared to the younger study subjects following oral administration (given as a single dose of 30 mg and dosed to steady-state with 30 mg t.i.d. for 6 days). The clinical response to these age-related pharmacokinetic differences, however, was not considered significant. (See PRECAUTIONS, Geriatric Use.)
## Nonclinical Toxicology
- In a two-year study, higher incidences of adenocarcinoma of the uterus and Leydig-cell adenoma of the testes were observed in rats given a diet containing 1800 ppm nimodipine (equivalent to 91 to 121 mg/kg/day nimodipine) than in placebo controls. The differences were not statistically significant, however, and the higher rates were well within historical control range for these tumors in the Wistar strain. Nimodipine was found not to be carcinogenic in a 91-week mouse study but the high dose of 1800 ppm nimodipine-in-feed (546 to 774 mg/kg/day) shortened the life expectancy of the animals. Mutagenicity studies, including the Ames, micronucleus and dominant lethal tests were negative.
- Nimodipine did not impair the fertility and general reproductive performance of male and female Wistar rats following oral doses of up to 30 mg/kg/day when administered daily for more than 10 weeks in the males and 3 weeks in the females prior to mating and continued to day 7 of pregnancy. This dose in a rat is about 4 times the equivalent clinical dose of 60 mg q4h in a 50 kg patient.
# Clinical Studies
# Clinical Studies (capsule)
- Nimodipine has been shown, in 4 randomized, double-blind, placebo-controlled trials, to reduce the severity of neurological deficits resulting from vasospasm in patients who have had a recent subarachnoid hemorrhage (SAH). The trials used doses ranging from 20-30 mg to 90 mg every 4 hours, with drug given for 21 days in 3 studies, and for at least 18 days in the other. Three of the four trials followed patients for 3-6 months. Three of the trials studied relatively well patients, with all or most patients in Hunt and Hess Grades I - III (essentially free of focal deficits after the initial bleed) the fourth studied much sicker patients, Hunt and Hess Grades III - V. Two studies, one U.S., one French, were similar in design, with relatively unimpaired SAH patients randomized to nimodipine or placebo. In each, a judgment was made as to whether any late-developing deficit was due to spasm or other causes, and the deficits were graded. Both studies showed significantly fewer severe deficits due to spasm in the nimodipine group; the second (French) study showed fewer spasm-related deficits of all severities. No effect was seen on deficits not related to spasm.
- A third, large, study was performed in the United Kingdom in SAH patients with all grades of severity (but 89% were in Grades I-III). Nimodipine was dosed 60 mg every 4 hours. Outcomes were not defined as spasm related or not but there was a significant reduction in the overall rate of infarction and severely disabling neurological outcome at 3 months:
- A Canadian study entered much sicker patients, (Hunt and Hess Grades III-V), who had a high rate of death and disability, and used a dose of 90 mg every 4 hours, but was otherwise similar to the first two studies. Analysis of delayed ischemic deficits, many of which result from spasm, showed a significant reduction in spasm-related deficits. Among analyzed patients (72 nimodipine, 82 placebo), there were the following outcomes.
- When data were combined for the Canadian and the United Kingdom studies, the treatment difference on success rate (i.e., good recovery) on the Glasgow Outcome Scale was 25.3% (nimodipine) versus 10.9% (placebo) for Hunt and Hess Grades IV or V. The table below demonstrates that nimodipine tends to improve good recovery of SAH patients with poor neurological status post-ictus, while decreasing the numbers with severe disability and vegetative survival.
- A dose-ranging study comparing 30, 60 and 90 mg doses found a generally low rate of spasm-related neurological deficits but no dose response relationship.
# Clinical Studies (solution)
- The safety and efficacy of Nimodipine (nimodipine oral solution) in the treatment of patients with SAH is based on adequate and well-controlled studies of nimodipine oral capsules in patients with SAH. Nimodipine (nimodipine oral solution) has comparable bioavailability to nimodipine oral capsules.
- Nimodipine has been shown in 4 randomized, double-blind, placebo-controlled trials to reduce the severity of neurological deficits resulting from vasospasm in patients who have had a recent SAH (Studies 1, 2, 3, and 4).
- The trials used doses ranging from 20-30 mg to 90 mg every 4 hours, with drug given for 21 days in 3 studies, and for at least 18 days in the other. Three of the four trials followed patients for 3-6 months. Three of the trials studied relatively well patients, with all or most patients in Hunt and Hess Grades I - III (essentially free of focal deficits after the initial bleed). Study 4 studied much sicker patients with Hunt and Hess Grades III - V. Studies 1 and 2 were similar in design, with relatively unimpaired SAH patients randomized to nimodipine or placebo. In each, a judgment was made as to whether any late-developing deficit was due to spasm or other causes, and the deficits were graded. Both studies showed significantly fewer severe deficits due to spasm in the nimodipine group; Study 2 showed fewer spasm-related deficits of all severities. No effect was seen on deficits not related to spasm. See Table 2.
- Study 3 was a 554-patient trial that included SAH patients with all grades of severity (89% were in Hunt and Hess Grades I-III). In Study 3, patients were treated with placebo or 60 mg of nimodipine every 4 hours. Outcomes were not defined as spasm related or not but there was a significant reduction in the overall rate of brain infarction and severely disabling neurological outcome at 3 months (Table 3):
- Study 4 enrolled much sicker patients, (Hunt and Hess Grades III-V), who had a high rate of death and disability, and used a dose of 90 mg every 4 hours, but was otherwise similar to Study 1 and Study 2. Analysis of delayed ischemic deficits, many of which result from spasm, showed a significant reduction in spasm-related deficits. Among analyzed patients (72 nimodipine, 82 placebo), there were the following outcomes (Table 4).
- When data were combined for Study 3 and Study 4, the treatment difference on success rate (i.e., good recovery) on the Glasgow Outcome Scale was 25.3% (nimodipine) versus 10.9% (placebo) for Hunt and Hess Grades IV or V. Table 5 demonstrates that nimodipine tends to improve good recovery of SAH patients with poor neurological status post-ictus, while decreasing the numbers with severe disability and vegetative survival.
- A dose-ranging study comparing 30 mg, 60 mg, and 90 mg doses found a generally low rate of spasm-related neurological deficits but no dose response relationship.
# How Supplied
# Nimodipine Capsules
30 mg - Oblong, white opaque, soft gelatin capsules in
Unit Dose Package of 30 NDC 23155-108-30
Unit Dose Package of 100 NDC 23155-108-00
Printed H108 in black ink.
The capsules should be stored in the manufacturer’s original package.
# Nimodipine Solution
- NDC 24338-200-16: 16 oz. bottle (473 mL)
- NDC 24338-200-12: Carton containing 12 individually wrapped packages. Each package contains one 20 mL Unit-Dose cup (NDC 24338-200-20) and one oral syringe.
## Storage
# Nimodipine Capsules
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].
Capsules should be protected from light and freezing.
# Nimodipine Solution
Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].
Protect from light.
Do not refrigerate.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients that the most frequent adverse reaction associated with nimodipine is decreased blood pressure [see Warnings and Precautions (5.1)]. Inform them that use of Nimodipine with anti-hypertensives can cause increased drop in blood pressure [see Drug Interactions (7.1)].
Patients should be aware that ingestion of grapefruit or grapefruit juice should be avoided when taking Nimodipine due to its ability to increase nimodipine plasma concentrations and potential to increase the risk of hypotension [see Drug Interactions (7.2)].
Pregnant women should be advised that a harmful effect of Nimodipine on the fetus cannot be ruled out and the drug should only be used if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations, Pregnancy (8.1)].
Manufactured for:
arbor™
PHARMACEUTICALS, LLC.
Atlanta, GA 30328
Manufactured by:
Importfab
Pointe-Claire, QC, Canada
H9R 1C9
Distributed By Arbor Pharmaceuticals, LLC., Atlanta, GA 30328
Nimodipine is a trademark of Arbor Pharmaceuticals, LLC
© 2013 Arbor Pharmaceuticals, LLC
NIM-PI-02
PRINCIPAL DISPLAY PANEL - 473 mL Bottle Label
NDC: 24338-200-16
16 oz.
(473 mL)
Nimodipine®
(nimodipine) oral solution
60 mg/20 mL
For Oral Use Only
Distributed by:
arbor™
PHARMACEUTICALS, LLC.
Atlanta, GA 30328
# Precautions with Alcohol
Alcohol-Nimodipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nimotop
- Nimodipine
# Look-Alike Drug Names
Nimodipine - Nicardipine
Nimodipine - Nifedipine[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nimodipine | |
d97e1ef3019e1ba0c76539629aa210e552bd689e | wikidoc | Nintedanib | Nintedanib
- Nintedanib is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
# Dosage
## Testing Prior to Nintedanib Administration
- Conduct liver function tests prior to initiating treatment with nintedanib.
## Recommended Dosage
- The recommended dosage of nintedanib is 150 mg twice daily administered approximately 12 hours apart.
- Nintedanib capsules should be taken with food and swallowed whole with liquid. Nintedanib capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.
- If a dose of nintedanib is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.
## Dosage Modification due to Adverse Reactions
- In addition to symptomatic treatment, if applicable, the management of adverse reactions of nintedanib may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with nintedanib.
- Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to 5 times ULN or >3 times ULN with signs or symptoms of severe liver damage.
- The safety and efficacy of nintedanib has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with nintedanib is not recommended in patients with moderate or severe hepatic impairment.
- In clinical trials, administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT). Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. Administration of nintedanib was also associated with elevations of bilirubin. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN.
- Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with nintedanib, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations.
# Gastrointestinal Disorders
## Diarrhea
- Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with nintedanib compared to 0 placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 5% of the patients compared to <1% of placebo-treated patients.
- Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with nintedanib.
## Nausea and Vomiting
- Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with nintedanib and placebo, respectively. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of nintedanib in 2% of patients. Vomiting led to discontinuation of nintedanib in 1% of the patients.
- For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with nintedanib.
# Embryofetal Toxicity
- Nintedanib can cause fetal harm when administered to a pregnant woman. Nintedanib was teratogenic and embryofetocidal in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on an AUC basis at oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). If nintedanib is used during pregnancy, or if the patient becomes pregnant while taking nintedanib, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with nintedanib and to use adequate contraception during treatment and at least 3 months after the last dose of nintedanib.
# Arterial Thromboembolic Events
- Arterial thromboembolic events have been reported in patients taking nintedanib. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with nintedanib and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of nintedanib-treated patients compared to 0.4% of placebo-treated patients.
- Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.
# Risk of Bleeding
- Based on the mechanism of action (VEGFR inhibition), nintedanib may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with nintedanib and in 7% of patients treated with placebo.
- Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
# Gastrointestinal Perforation
- Based on the mechanism of action, nintedanib may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with nintedanib, compared to 0 cases in the placebo-treated patients.
- Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with nintedanib in patients who develop gastrointestinal perforation. Only use nintedanib in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.
The safety of nintedanib was evaluated in over 1000 IPF patients with over 200 patients exposed to nintedanib for more than 2 years in clinical trials.
Nintedanib was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 3) trials, 723 patients with IPF received nintedanib 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with nintedanib and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%).
The most frequent serious adverse reactions reported in patients treated with nintedanib, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with nintedanib, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of nintedanib-treated patients and 1.8% of placebo-treated patients.
Adverse reactions leading to permanent dose reductions were reported in 16% of nintedanib-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib was diarrhea (11%).
Adverse reactions leading to discontinuation were reported in 21% of nintedanib-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).
The most common adverse reactions with an incidence of ≥5% and more frequent in the nintedanib than placebo treatment group are listed in Table 1.
In addition, hypothyroidism was reported in patients treated with nintedanib, more than placebo (1.1% vs. 0.6%).
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with nintedanib may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with nintedanib.
Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with nintedanib should be avoided as these drugs may decrease exposure to nintedanib.
# Anticoagulants
Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
In animal reproduction toxicity studies, nintedanib caused embryofetal deaths and teratogenic effects in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
## Smokers
Smoking was associated with decreased exposure to nintedanib, which may alter the efficacy profile of nintedanib. Encourage patients to stop smoking prior to treatment with nintedanib and to avoid smoking when using nintedanib.
- Monitor patients closely for tolerability of nintedanib with coadministration of P-gp and CYP3A4 inhibitors.
- Monitor for adverse reactions and consider dose modification or discontinuation of nintedanib as needed for patients with mild hepatic impairment.
- Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
In a study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.
## Absorption
Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median tmax fasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.
## Distribution
Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (Vss: 1050 L) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.
## Elimination
The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.
## Metabolism
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
## Excretion
The major route of elimination of drug-related radioactivity after oral administration of nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of nintedanib was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.
## Specific Populations
Age, Body Weight, and Sex
Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However, their effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.
Renal Impairment
Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.
Hepatic Impairment
No dedicated PK study was conducted in patients with hepatic impairment. As nintedanib is eliminated primarily by biliary/fecal excretion (>90%), hepatic impairment is likely to increase plasma nintedanib concentrations. Clinical studies excluded patients with AST or ALT greater than 1.5 times ULN. Patients with total bilirubin greater than 1.5 times ULN were also excluded. Therefore, monitor for adverse reactions and consider dose modification or discontinuation of nintedanib as needed for patients with mild hepatic impairment.
Smokers
In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.
## Drug Interaction Studies
Potential for Nintedanib to Affect Other Drugs
Effect of nintedanib coadministration on pirfenidone AUC and Cmax was evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.
In in vitro studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2. In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.
Potential for Other Drugs to Affect Nintedanib
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon coadministration with rifampicin compared to administration of nintedanib alone.
Based on a multiple-dose study in Japanese IPF patients, exposure to nintedanib decreased to 68.3% based on AUC and to 59.2% based on Cmax upon coadministration with pirfenidone compared to administration of nintedanib alone.
Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH<3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.
In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP. In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
Two-year oral carcinogenicity studies of nintedanib in rats and mice have not revealed any evidence of carcinogenic potential. Nintedanib was dosed up to 10 and 30 mg/kg/day in rats and mice, respectively. These doses were less than and approximately 4 times the MRHD on a plasma drug AUC basis.
Nintedanib was negative for genotoxicity in the in vitro bacterial reverse mutation assay, the mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus assay.
In rats, nintedanib reduced female fertility at exposure levels approximately 3 times the MRHD (on an AUC basis at an oral dose of 100 mg/kg/day). Effects included increases in resorption and post-implantation loss, and a decrease in gestation index. Changes in the number and size of corpora lutea in the ovaries were observed in chronic toxicity studies in rats and mice. An increase in the number of females with resorptions only was observed at exposures approximately equal to the MRHD (on an AUC basis at an oral dose of 20 mg/kg/day). Nintedanib had no effects on male fertility in rats at exposure levels approximately 3 times the MRHD (on an AUC basis at an oral dose of 100 mg/kg/day).
Studies 2 and 3 were identical in design. Study 1 was very similar in design. Patients were randomized in a 3:2 ratio (1:1 for Study 1) to either nintedanib 150 mg or placebo twice daily for 52 weeks. Study 1 also included other treatment arms (50 mg daily, 50 mg twice daily, and 100 mg twice daily) that are not further discussed. The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). Time to first acute IPF exacerbation was a key secondary endpoint in Studies 2 and 3 and a secondary endpoint in Study 1. Change from baseline in FVC percent predicted and survival were additional secondary endpoints in all studies.
Patients were required to have a diagnosis of IPF (ATS/ERS/JRS/ALAT criteria) for 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the studies. Patients were also excluded if they received other investigational therapy, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks of entry into this trial, or n-acetyl cysteine and prednisone (>15 mg/day or equivalent) within 2 weeks. The majority of patients were Caucasian (60%) or Asian (30%) and male (79%). Patients had a mean age of 67 years and a mean FVC percent predicted of 80%.
Annual Rate of Decline in FVC
A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving nintedanib compared to patients receiving placebo based on the random coefficient regression model, adjusted for gender, height, and age. The treatment effect on FVC was consistent in all 3 studies. See Table 2 for individual study results.
Figure 1 displays the change from baseline over time in both treatment groups for Study 2. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Similar plots were seen for Studies 1 and 3.
Change from Baseline in Percent Predicted Forced Vital Capacity
Figure 2 presents the cumulative distribution for all cut-offs for the change from baseline in FVC percent predicted at Week 52 for Study 2. For all categorical declines in lung function, the proportion of patients declining was lower on nintedanib than on placebo. Study 3 showed similar results.
Time to First Acute IPF Exacerbation
Acute IPF exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new high-resolution CT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute IPF exacerbation was adjudicated in Studies 2 and 3. In Studies 1 (investigator-reported) and 3 (adjudicated), the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving nintedanib compared to placebo (hazard ratio : 0.16, 95% CI: 0.04, 0.71) and (HR:0.20, 95% CI: 0.07, 0.56), respectively. In Study 2 (adjudicated), there was no difference between the treatment groups (HR: 0.55, 95% CI: 0.20, 1.54).
Survival
Survival was evaluated for nintedanib compared to placebo in Studies 2 and 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (See Figure 3).
Bottles of 60 NDC: 0597-0145-60
- 100 mg: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100". They are packaged in HDPE bottles with a child-resistant closure, available as follows:
Bottles of 60 NDC: 0597-0143-60
NDC 0597-0145-60
NDC 0597-0143-60
OFEV 150 mg Carton
NDC 0597-0145-60
OFEV 100 mg Label
NDC 0597-0143-60
OFEV 100 mg Carton
NDC 0597-0143-60
- ↑ "OFEV- nintedanib capsule"..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} | Nintedanib
- Nintedanib is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
## Dosage
### Testing Prior to Nintedanib Administration
- Conduct liver function tests prior to initiating treatment with nintedanib.
### Recommended Dosage
- The recommended dosage of nintedanib is 150 mg twice daily administered approximately 12 hours apart.
- Nintedanib capsules should be taken with food and swallowed whole with liquid. Nintedanib capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.
- If a dose of nintedanib is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.
### Dosage Modification due to Adverse Reactions
- In addition to symptomatic treatment, if applicable, the management of adverse reactions of nintedanib may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with nintedanib.
- Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to <5 times the upper limit of normal (ULN) without signs of severe liver damage, interrupt treatment or reduce nintedanib to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with nintedanib may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily). Discontinue nintedanib for AST or ALT elevations >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage.
- The safety and efficacy of nintedanib has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with nintedanib is not recommended in patients with moderate or severe hepatic impairment.
- In clinical trials, administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT). Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. Administration of nintedanib was also associated with elevations of bilirubin. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN.
- Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with nintedanib, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations.
## Gastrointestinal Disorders
### Diarrhea
- Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with nintedanib compared to 0 placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 5% of the patients compared to <1% of placebo-treated patients.
- Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with nintedanib.
### Nausea and Vomiting
- Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with nintedanib and placebo, respectively. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of nintedanib in 2% of patients. Vomiting led to discontinuation of nintedanib in 1% of the patients.
- For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. Nintedanib treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with nintedanib.
## Embryofetal Toxicity
- Nintedanib can cause fetal harm when administered to a pregnant woman. Nintedanib was teratogenic and embryofetocidal in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on an AUC basis at oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). If nintedanib is used during pregnancy, or if the patient becomes pregnant while taking nintedanib, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with nintedanib and to use adequate contraception during treatment and at least 3 months after the last dose of nintedanib.
## Arterial Thromboembolic Events
- Arterial thromboembolic events have been reported in patients taking nintedanib. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with nintedanib and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of nintedanib-treated patients compared to 0.4% of placebo-treated patients.
- Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.
## Risk of Bleeding
- Based on the mechanism of action (VEGFR inhibition), nintedanib may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with nintedanib and in 7% of patients treated with placebo.
- Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
## Gastrointestinal Perforation
- Based on the mechanism of action, nintedanib may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with nintedanib, compared to 0 cases in the placebo-treated patients.
- Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with nintedanib in patients who develop gastrointestinal perforation. Only use nintedanib in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.
The safety of nintedanib was evaluated in over 1000 IPF patients with over 200 patients exposed to nintedanib for more than 2 years in clinical trials.
Nintedanib was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 3) trials, 723 patients with IPF received nintedanib 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with nintedanib and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%).
The most frequent serious adverse reactions reported in patients treated with nintedanib, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with nintedanib, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of nintedanib-treated patients and 1.8% of placebo-treated patients.
Adverse reactions leading to permanent dose reductions were reported in 16% of nintedanib-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib was diarrhea (11%).
Adverse reactions leading to discontinuation were reported in 21% of nintedanib-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).
The most common adverse reactions with an incidence of ≥5% and more frequent in the nintedanib than placebo treatment group are listed in Table 1.
In addition, hypothyroidism was reported in patients treated with nintedanib, more than placebo (1.1% vs. 0.6%).
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with nintedanib may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with nintedanib.
Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with nintedanib should be avoided as these drugs may decrease exposure to nintedanib.
## Anticoagulants
Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
In animal reproduction toxicity studies, nintedanib caused embryofetal deaths and teratogenic effects in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
### Smokers
Smoking was associated with decreased exposure to nintedanib, which may alter the efficacy profile of nintedanib. Encourage patients to stop smoking prior to treatment with nintedanib and to avoid smoking when using nintedanib.
- Monitor patients closely for tolerability of nintedanib with coadministration of P-gp and CYP3A4 inhibitors.
- Monitor for adverse reactions and consider dose modification or discontinuation of nintedanib as needed for patients with mild hepatic impairment.
- Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
In a study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.
### Absorption
Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median tmax fasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.
### Distribution
Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (Vss: 1050 L) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.
### Elimination
The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.
### Metabolism
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
### Excretion
The major route of elimination of drug-related radioactivity after oral administration of [14C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of nintedanib was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.
### Specific Populations
Age, Body Weight, and Sex
Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However, their effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.
Renal Impairment
Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.
Hepatic Impairment
No dedicated PK study was conducted in patients with hepatic impairment. As nintedanib is eliminated primarily by biliary/fecal excretion (>90%), hepatic impairment is likely to increase plasma nintedanib concentrations. Clinical studies excluded patients with AST or ALT greater than 1.5 times ULN. Patients with total bilirubin greater than 1.5 times ULN were also excluded. Therefore, monitor for adverse reactions and consider dose modification or discontinuation of nintedanib as needed for patients with mild hepatic impairment.
Smokers
In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.
### Drug Interaction Studies
Potential for Nintedanib to Affect Other Drugs
Effect of nintedanib coadministration on pirfenidone AUC and Cmax was evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.
In in vitro studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2. In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.
Potential for Other Drugs to Affect Nintedanib
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon coadministration with rifampicin compared to administration of nintedanib alone.
Based on a multiple-dose study in Japanese IPF patients, exposure to nintedanib decreased to 68.3% based on AUC and to 59.2% based on Cmax upon coadministration with pirfenidone compared to administration of nintedanib alone.
Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH<3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.
In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP. In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
Two-year oral carcinogenicity studies of nintedanib in rats and mice have not revealed any evidence of carcinogenic potential. Nintedanib was dosed up to 10 and 30 mg/kg/day in rats and mice, respectively. These doses were less than and approximately 4 times the MRHD on a plasma drug AUC basis.
Nintedanib was negative for genotoxicity in the in vitro bacterial reverse mutation assay, the mouse lymphoma cell forward mutation assay, and the in vivo rat micronucleus assay.
In rats, nintedanib reduced female fertility at exposure levels approximately 3 times the MRHD (on an AUC basis at an oral dose of 100 mg/kg/day). Effects included increases in resorption and post-implantation loss, and a decrease in gestation index. Changes in the number and size of corpora lutea in the ovaries were observed in chronic toxicity studies in rats and mice. An increase in the number of females with resorptions only was observed at exposures approximately equal to the MRHD (on an AUC basis at an oral dose of 20 mg/kg/day). Nintedanib had no effects on male fertility in rats at exposure levels approximately 3 times the MRHD (on an AUC basis at an oral dose of 100 mg/kg/day).
Studies 2 and 3 were identical in design. Study 1 was very similar in design. Patients were randomized in a 3:2 ratio (1:1 for Study 1) to either nintedanib 150 mg or placebo twice daily for 52 weeks. Study 1 also included other treatment arms (50 mg daily, 50 mg twice daily, and 100 mg twice daily) that are not further discussed. The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). Time to first acute IPF exacerbation was a key secondary endpoint in Studies 2 and 3 and a secondary endpoint in Study 1. Change from baseline in FVC percent predicted and survival were additional secondary endpoints in all studies.
Patients were required to have a diagnosis of IPF (ATS/ERS/JRS/ALAT criteria) for <5 years. Diagnoses were centrally adjudicated based on radiologic and, if applicable, histopathologic confirmation. Patients were required to be ≥40 years of age with an FVC ≥50% of predicted and a carbon monoxide diffusing capacity (DLCO, corrected for hemoglobin) 30% to 79% of predicted. Patients with relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC <0.7) or, in the opinion of the investigator, likely to receive a lung transplant during the studies were excluded (being listed for lung transplant was acceptable for inclusion). Patients with >1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the studies. Patients were also excluded if they received other investigational therapy, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks of entry into this trial, or n-acetyl cysteine and prednisone (>15 mg/day or equivalent) within 2 weeks. The majority of patients were Caucasian (60%) or Asian (30%) and male (79%). Patients had a mean age of 67 years and a mean FVC percent predicted of 80%.
Annual Rate of Decline in FVC
A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving nintedanib compared to patients receiving placebo based on the random coefficient regression model, adjusted for gender, height, and age. The treatment effect on FVC was consistent in all 3 studies. See Table 2 for individual study results.
Figure 1 displays the change from baseline over time in both treatment groups for Study 2. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Similar plots were seen for Studies 1 and 3.
Change from Baseline in Percent Predicted Forced Vital Capacity
Figure 2 presents the cumulative distribution for all cut-offs for the change from baseline in FVC percent predicted at Week 52 for Study 2. For all categorical declines in lung function, the proportion of patients declining was lower on nintedanib than on placebo. Study 3 showed similar results.
Time to First Acute IPF Exacerbation
Acute IPF exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new high-resolution CT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute IPF exacerbation was adjudicated in Studies 2 and 3. In Studies 1 (investigator-reported) and 3 (adjudicated), the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving nintedanib compared to placebo (hazard ratio [HR]: 0.16, 95% CI: 0.04, 0.71) and (HR:0.20, 95% CI: 0.07, 0.56), respectively. In Study 2 (adjudicated), there was no difference between the treatment groups (HR: 0.55, 95% CI: 0.20, 1.54).
Survival
Survival was evaluated for nintedanib compared to placebo in Studies 2 and 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (See Figure 3).
Bottles of 60 NDC: 0597-0145-60
- 100 mg: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100". They are packaged in HDPE bottles with a child-resistant closure, available as follows:
Bottles of 60 NDC: 0597-0143-60
NDC 0597-0145-60
NDC 0597-0143-60
OFEV 150 mg Carton
NDC 0597-0145-60
OFEV 100 mg Label
NDC 0597-0143-60
OFEV 100 mg Carton
NDC 0597-0143-60
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fa4dd740fdc88a7f7fcaf8b4082dc1e4690d8dba | wikidoc | Nitrazepam | Nitrazepam
Nitrazepam is a type of benzodiazepine drug. It is a powerful hypnotic drug with strong sedative and motor impairing properties, anxiolytic, amnestic, anticonvulsant, and skeletal muscle relaxant properties.
Nitrazepam is available in 5mg and 10mg tablets. In Australia, Israel and the United Kingdom it is only available in 5mg tablets.
# Pharmacology
Nitrazepam is a nitrobenzodiazepine. It is a 1,4 benzodiazepine, with the chemical name 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4- benzodiazepin-2-one.
It is long acting, is lipophilic and is metabolised hepatically via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA (gamma amino butyric acid) to GABAA receptors. GABA is a major inhibitory neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system. The mechanism of action of nitrazepam is the same as other benzodiazepine drugs and zopiclone. The anticonvulsant properties of nitrazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation. The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord. It is a full agonist of the benzodiazepine receptor. The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats. Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and aspartic acid in the mouse brain. The decrease may be due to activation of benzodiazepine receptors. At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain. Nitrazepam possesses antipruritic properties. It possesses antipruritic properties, which are believed to be due to a central mechanism of action rather than a peripheral mechanism of action. Nitrazepam has demonstrated cortisol suppressing properties in man.
Nitrazepam is an agonist for both central and peripheral type benzodiazepine receptors in rat neuroblastoma cells.
# EEG and sleep
In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric in-patients nitrazepam was found to be no more effective than placebo tablets in increasing total time spent asleep, was found to significantly impair trial subjects abilities to move and carry out everyday activities the next day and it was concluded that nitrazepam should not be used as a sleep aid in psychogeriatric in-patients.
Stage 2 NREM sleep is significantly increased by nitrazepam but SWS stage sleep is significantly decreased by nitrazepam. There is delay in the onset, and decrease in the duration of REM sleep. Following discontinuation of the drug, REM sleep rebound has been reported in some studies. Nitrazepam is reported to significantly affect stages of sleep: a decrease stage 1, 3 and 4 sleep and to increase stage 2. In young volunteers the pharmacological properties of nitrazepam was found to produce sedation, impaired psychomotor performance and standing steadiness. EEG tests showed a decrease of alpha activity and increased the beta activity. These effects increased according to blood plasma levels of nitrazepam. Performance was significantly impaired 13 hours after dosing with nitrazepam as was decision-making skills. EEG tests show more drowsiness and light sleep 18 hours after nitrazepam intake more so than amylobarbitone. Fast activity was recorded via EEG 18 hours after nitrazepam dosing. An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is also suppressed by nitrazepam. Estazolam was found to be more potent however. Nitrazepam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages, when benzodiazepines such as nitrazepam are used. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.
# Pharmacokinetics
Nitrazepam is largely bound to plasma proteins. Benzodiazepines such as nitrazepam are lipid soluble and have a high cerebral uptake. The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours).The half life which is the time taken for a dose to decrease by half is 16.5 to 48.3 (mean 28.8) hours. Both low dose (5 mg) and high dose (10 mg) of nitrazepam significantly increases growth hormone levels in humans. Nitrazepam has a much longer half life in the cerebrospinal fluid. The half life in the cerebrospinal fluid is 68 hours which indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid.
Nitrazepam has a half life of about 29 hours in young people and a much longer half life in the elderly. In the elderly the half life is about 40 hours. Concomitant food intake has no influence on the rate of absorption of nitrazepam nor on its bioavailability. Therefore nitrazepam can be taken with or without food.
# Uses
Nitrazepam is most often used to treat short-term sleeping problems (insomnia), namely difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Nitrazepam is long acting and is sometimes used in patients who have difficulty in maintaining sleep. Nitrazepam shortens the time required to fall asleep and lengthens the duration of sleep. It is also useful for the management of myoclonic seizures and has been used in the management of seizure disorders in children and also for infantile spasms. However, the usefulness of nitrazepam is limited due to dose limiting sedative side effects.
Nitrazepam is sometimes used for refractory epilepsies. However, long term prophylactic treatment of epilepsy has considerable drawbacks. Most importantly the loss of antiepileptic effects due to tolerance which renders prolonged nitrazepam therapy ineffective. Nitrazepam also has the draw back of significant side effects such as sedation, which is why nitrazepam and benzodiazepines in general are only prescribed in the acute management of epilepsies. Nitrazepam has been found to be more effective than clonazepam in the treatment of west syndrome which is an age dependent epilepsy, affecting the very young. However, as with other epilepies treated with benzodiazepines, long term therapy becomes ineffective with prolonged therapy and the side effects of hypotonia and drowsiness are troublesome with nitrazepam therapy, other antiepileptic agents are therefore recommended for long term therapy, possibly Corticotropin (ACTH) or vigabatrin.
## Utilisation
Nitrazepam along with diazepam, oxazepam and temazepam 1993 represented 82% of the benzodiazepine market in Australia. The rate of benzodiazepine prescribing in Tasmania is higher than in other Australian states; Nitrazepam and flunitrazepam prescribing levels in Tasmania are disturbingly high. Prescribing of hypnotics in Norway is quite restrictive with only 4 hypnotics which are prescribable; nitrazepam, flunitrazepam, zolpidem and zopiclone. The usage of benzodiazepine hypnotics in local authority homes for the elderly 1982 in Edinburgh, established via a clinical survey, was that 34% of residents were taking sleeping medication. However, the number varied between the homes, with some homes reporting only 2.3% of residents to be on hypnotic medication and others up to 56.5% on hypnotic drugs. Nitrazepam was the most frequently prescribed hypnotic medication accounting for a third of hypnotic use in Edinburgh residential homes in 1982.
# Dosage
When used for treatment of insomnia, the usual dose for adults is 2.5mg to 10mg, taken at bedtime. Typically, it works within the hour and allows the individual to maintain sleep for 4 to 8 hours.
When used for treatment of myoclonic seizures, the dose is based on body weight. The dose for children (30kg or less) is anywhere from 0.3mg/kg to 1mg/kg, daily in three divided doses.
# Tolerance dependence and withdrawal
## Tolerance
Tolerance to a drugs effects occurs after regular exposure to a drug. The mechanism of nitrazepam tolerance may be due to down-regulation of benzodiazepine receptors. When tolerance and habituation occurs to nitrazepam its pharmacokinetic profile changes with absorption of the drug slowing down, elimination time increasing and brain concentration of nitrazepam increasing significantly. Increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occurs as a result of nitrazepam tolerance.
After 6 days of use tolerance to nitrazepam's but not temazepams sleep inducing effects and performance impairing effects occurred in a study. One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration in 19 elderly inpatients. Self reported quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 self reported quality of sleep was found to have returned to baseline in these patients, suggesting the development of tolerance after 7 days use. The effect was more pronounced in patients of lower intelligence. In mice tolerance to the anticonvulsant properties of nitrazepam developed profoundly and rapidly over 6 days, and then did not proceed. Some anticonvulsant effects were still apparent after 6 days administration. In humans tolerance to the anticonvulsant effects of nitrazepam is a frequent occurrence.
### Dependence and withdrawal
See also benzodiazepine withdrawal syndrome
Benzodiazepine drugs such as nitrazepam can cause dependence and addiction and is what is known as the benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen with alcohol and barbiturates, including delirium tremens. The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur at standard dosages and also after short term treatment. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
Frequent use of nitrazepam may cause dependence and when the drug is reduced or stopped, withdrawal symptoms occur. Withdrawal symptoms including a worsening of insomnia compared to baseline typically occurs after discontinuation of nitrazepam even after short term single nightly dose therapy. Dependence on benzodiazepines such as nitrazepam or temazepam often occurs due to discharging patients from hospital on benzodiazepines who were started on benzodiazepine hypnotics in hospital. It is recommended that hypnotic use in hospital be limited to 5 days to avoid the development of drug dependence and withdrawal insomnia.
After discontinuation of nitrazepam a rebound effect may occur about 4 days after stopping medication. Nitrazepam has more side effects than other hypnotic drugs and tolerance to sedative properties and rebound insomnia after discontinuation occurs after only 7 days administration. Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.
Abrupt withdrawal after long term use from therapeutic doses of nitrazepam may result in a severe benzodiazepine withdrawal syndrome. Reports in the medical literature report of two psychotic states developing after abrupt withdrawal from nitrazepam including delirium after abrupt withdrawal of 10 mg of nitrazepam and in another case auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage was recommended to prevent severe withdrawal syndromes from developing. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Depersonalisation has also been reported as a benzodiazepine withdrawal effect from nitrazepam.
# Toxicity
## Animals
Genotoxicity
Nitrazepam may be carcinogenic in hamster cells under the influence of UV-light and has been found to be both photogenotoxic and photocytotoxic in hamster cells under UV light. Some studies on some animals have demonstrated teratogenic and also carcinogenic effects of nitrazepam and some other benzodiazepines in these animals and the wide spread use of these drugs world wide was of major concern for human health. A review and update of existing results was therefore attempted. However, since 1996 no further research for this concern has been carried out.
Genotoxic drugs have the potential to cause genetic mutations, DNA damage and promote the development of cancer including tumors.
Reproductive Toxicity
Nitrazepam has been reported in the medical literature by researchers as a drug which is well known for inducing testicular and reproductive toxicities. Nitrazepam decreases the number of motile sperm, curilinear velocity, beat cross frequency, maximum and mean amplitude of lateral head displacement and causes testicular lesions. Nitrazepam may result in low fertility.
In studies of Sprague-Dawley rats, nitrazepam induced reproductive toxicity has been demonstrated after 2 weeks of therapy, with significant decreases in fertility in nitrazepam treated male rats. Testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads was found after 2 weeks treatment with the higher dose nitrazepam and after 4 weeks in the lower dosed rats. The doses used however in the toxicology tests were sigificantly higher than standard therapeutic doses. Nitrazepam has also been shown at high doses to affect sperm motion in laboratory tests via causing lesions in spermatids.
Nitrazepam has been shown in Sprague-Dawley rats to cause testicular damage. A decrease in the weight of the testis, weight of the epididymis, number of sperm in the testis and sperm motility was shown in very high dose of nitrazepam treated rats, i.e. 20mg/kg to 80mg/kg. Rats treated with such extreme doses of nitrazepam show a significant decrease in pregnancy rate. Localised necrosis in the seminiferous epithelium and Leydig cell hyperplasia occurs in the testis of rats treated with nitrazepam and morphological changes occur in spermatocytes with necrosis of the cytoplasm. Laboratory tests assessing the toxicity of nitrazepam, diazepam and chlordiazepoxide on mice spermatozoa found that nitrazepam produced the most toxicities on sperm including abnormalities involving both shape and size of the sperm head.
In female rats nitrazepam has been shown to inhibit ovulation.
Fetal Toxicity
In a rat study nitrazepam showed much greater damage to the fetus than other benzodiazepines, as did nimetazepam. High levels of nitrazepam were found in the maternal serum and in the whole fetus which may account for the increased toxicity. Diazepam showed relatively weak fetal toxicities. Rats treated with a single very high dose of nitrazepam on day 12 of gestation significant increase in malformation in rats. However, mice seem more resistant to the teratogenic effects which may be related to differences in metabolism of nitrazepam between the two species. Exencephaly, cleft palate, micrognathia, short or kinky tail and limb reduction defects occurred in rats treated with a single very high dose of nitrazepam, with limb buds revealing hemorrhage and mesenchymal cell necrosis. Another fetal toxicity study in rats at 100mg/kg demonstrated that nitrazepam has embryocidal activity in vitro and that nitrazepam is teratogenic in vivo in rats.
Nitrazepam is much more teratogenic in rats, but not mice, than other benzodiazepines probably due to its extensive nitro reduction to 7-aminonitrazepam by rat intestinal microflora. Nitrazepam undergoes enterocyte metabolism to form oxidative free radicals. Superoxide is intracellularly produced during nitrazepam metabolism and this oxidative metabolism can lead to cellular dysfunction.
## Humans
The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry sponsored trials on their own results showing that use of hypnotics is correlated with depression. The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that "major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia.
Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department.
Cancer
Benzodiazepine usage for more than 1 - 6 months at prescribed doses is associated with an increased risk of the development of ovarian cancer. There have been 15 epidemiologic studies which have shown that hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. Not only are benzodiazepines associated with an increased risk of cancer, the benzodiazepine receptor agonist Z-drugs also are associated with cancer in humans in these studies. Initially FDA reviewers did not want to approve the Z drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer.
The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer". It has to be seen if other reviewers and the FDA come to the same result.
Mortality
Nitrazepam therapy compared with other drug therapies increases risk of death when used for intractable epilepsy in an analysis of 302 patients. The risk of death from nitrazepam therapy may be greater in younger patients (children below 3.4 years in the study) with intractable epilepsy. In older children (above 3.4 years) the tendency appears to be reversed in this study. Nitrazepam may cause sudden death in children. Nitrazepam therapy can cause swallowing incoordination, high-peaked esophageal peristalsis, bronchospasm, delayed cricopharyngeal relaxation and severe respiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia leading to potentially fatal respiratory distress in children.
# Abuse potential
Nitrazepam is a drug which is very frequently involved in drug intoxication. Nitrazepam was the most commonly detected benzodiazepine in urine samples in the UK in 1997 suggesting a high liking and preference amongst drug abusers. However, it has been superseded by temazepam, despite the fact that temazepam is much more highly regulated in the UK. Temazepam is Class B drug, while nitrazepam is a Class C drug. In Nepal, nitrazepam is a major drug of abuse as is codeine, heroin, buprenorphine and cannabis.
Nitrazepam in animal studies has been shown to increase reward seeking which may suggest increased risk of addictive behavioural patterns.
A study found that nitrazepam caused significant euphoria as against placebos and was identified as an active drug by freshly detoxified experienced drug abusers of heroin and other drugs. Nitrazepam resembled diazepam (Valium), however, on certain parameters the effects produced by nitrazepam were more pronounced in these drug abusers. Nitrazepam was found to be an abusable drug and has similar abuse liability like diazepam, if not slightly higher in these drug abusers. Treatment with nitrazepam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply. Dependence can occur in as little as four weeks.
Benzodiazepines, including diazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse.
Nitrazepam is detected frequently in cases of people suspected of driving under the influence of drugs in Sweden. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers in suspected impaired drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were found in tests on impaired drivers, benzodiazepines were found to be present in 87% of cases.
# Side Effects
## Common Side Effects
CNS depression including, somnolence, dizziness, depressed mood, rage, violence, fatigue, ataxia, headache, vertigo, impairment of memory, impairment of motor functions, hangover feeling in the morning, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, double vision and inattention have been reported. Unpleasant dreams and rebound insomnia has also been reported. High levels of confusion, clumsiness also occurs after administration of nitrazepam. Increased reaction time, co-ordination problems and impaired learning and memory.
Impaired learning and memory occurs due to the action of the drug on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system. Nitrazepam causes a reduced output of serotonin which is closely involved in regulating mood and may be the cause of feelings of depression in users of nitrazepam or other benzodiazepines.
Nitrazepam is a long acting benzodiazepine with an elimination half life of 15-38 (mean elimination half life 26 hours). Residual 'hangover' effects after nighttime administration of nitrazepam 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 increases the risk of falls and hip fractures. Significant impairment of visual perception and sedative effects persisting into the next day typically occurs with nitrazepam administration as was demonstrated in a human clinical trial assessing the effect of nitrazepam on peak saccade velocity.
Impairment of psychomotor function may especially occur after repeated administration, with the elderly being more vulnerable to this adverse effect. Overall accuracy of completing tasks is impaired after repeated administration of nitrazepam and is due to drug accumulation of nitrazepam. The elderly are more vulnerable to these side effects.
## Less Common Side Effects
Hypotension, faintness, palpitation, rash or pruritus, gastrointestinal disturbances, changes in libido. Very infrequently, paradoxical reactions may occur, e.g. excitement, stimulation, hallucinations, hyperactivity and insomnia. Also depressed or increased dreaming, disorientation, severe sedation, retrograde amnesia, headache, hypothermia, delirium tremens. Acroparaesthesia has been reported as a side effect from nitrazepam with symptoms including, pins and needles in hands and loss of power of fingers and clumsiness of the fingers.
# Interactions
Nitrazepam interacts with the antibiotic erythromycin which is a strong inhibitor of CYP3A4, which affects concentration peak time. This interaction is not to believed to be clinically important. However, anxiety, tremor and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin to the patient, repetitive hallucinations and abnormal bodily sensations developed. The patient had however acute pneumonia and renal failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms especially in those with other significant physical complications.
Oral contraceptive pills, reduce the clearance of nitrazepam which may lead to increased plasma levels of nitrazepam and accumulation.
Rifampin increases the clearance of nitrazepam significantly and probenecid decreases the clearance of nitrazepam significantly. Cimetidine slows down the elimination rate of nitrazepam leading to more prolonged effects of nitrazepam and increased risk of accumulation. Alcohol (ethanol) in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol.
Benzodiazepines including nitrazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine in rat experiments.
# Special precautions
It has been recommended in the medical literature that caution should be exercised in prescribing nitrazepam to anyone who is of working age due to the significant impairment of psychomotor skills. This impairment is greater the higher the dosage that is prescribed.
Nitrazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness. Doses as low as 5 mg of nitrazepam can impair driving skills. Therefore people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it all together.
Caution in the elderly. Nitrazepam has been found to be dangerous in elderly patients due to a significant increased risk of falls. This increased risk is probably due to the persisting drug effects of nitrazepam well into the next day. Nitrazepam is a particularly unsuitable hypnotic for the elderly as it induces a disability characterised by general mental deterioration, inability to walk, incontinence, dysarthric, confusion, prone to stumbling, falls and disoriention which can occur from doses as low as 5 mg. The nitrazepam induced symptomatology can lead to a misdiagnosis of brain disease in the elderly eg dementia and can also lead to the symptoms of postural hypotension which may also get misdiagnosed. It was reported that a geriatric unit was seeing as many as 7 patients a month with nitrazepam induced disabilities and health problems. It was recommended that nitrazepam should join the barbiturates in not being prescribed to the elderly. Only nitrazepam and lorazepam were found to increase the risk of falls and fractures in the elderly. CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam. Both young and old patients report sleeping better after 3 nights use of nitrazepam however they also report feeling less awake and are slower on psychomotor testing up to 36 hours after intake of nitrazepam. The elderly showed cognitive deficits, making significantly more mistakes in psychomotor testing than younger patients despite similar plasma levels of the drug, suggesting that the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to nitrazepam. Confusion and disorientation can result from chronic nitrazepam administration to elderly subjects. Also the effects of a single dose of nitrazepam may last up to 60 hours after administration.
Caution in children. Nitrazepam is not recommended for use in those under 18. Use in very young children may be especially danagerous. Children treated with nitrazepam for epilepsies may develop tolerance within months of continued use, with dose escalation often occurring with prolonged use. Sleepiness, deterioration in motor skills and ataxia were common side effects in children with tuberous sclerosis treated with nitrazepam. The side effects of nitrazepam may impair the development of motor and cognitive skills in children treated with nitrazepam. Withdrawal of nitrazepam only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, eg able to walk at 5 years was impaired in many children taking nitrazepam but was not impaired with several other non benzodiazepine antiepileptic agents. It has been recommended that children being treated with nitrazepam should be reviewed and have their nitrazepam gradually discontinued whenever appropriate.
Caution in hypotension. Caution in those suffering from hypotension, nitrazepam may worsen hypotension.
Caution in hypothyroidism. Caution should be exercised by people who have hypothyroidism as this condition may cause a long delay in the metabolism of nitrazepam leading to significant drug accumulation.
## Pregnancy
Nitrazepam is a long acting benzodiazepine and there is a risk of drug accumulation, even though no active metabolites are formed during metabolism. Accumulation can occur in various body organs including the heart, accumulation is even greater in babies. Nitrazepam rapidly crosses the placenta and also is present in breast milk in high quantities. Therefore nitrazepam and benzodiazepines should be avoided during pregnancy and breast feeding. In early pregnancy nitrazepam levels are lower in the baby than in the mother and in the later stages of pregnancy nitrazepam is found in equal levels in both the mother and the unborn child. Internationally benzodiazepines are known to cause harm when used during pregnancy and nitrazepam is a category D drug during pregnancy.
Benzodiazepines are lipophilic and rapidly penetrate membranes and therefore rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines eg nitrazepam in late pregnancy especially high doses may result in floppy infant syndrome. Use in the third trimester stage of pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.
# Contraindications
Nitrazepam should be avoided in patients with chronic obstructive pulmonary disease (COPD), especially during acute exacerbations of COPD, due to the fact that serious respiratory depression may occur in patients who are receiving hypnotics.
Nitrazepam should be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found that users of nitrazepam were found to be significantly impaired up to 17 hours after dosing, whereas users of temazepam did not show significant impairments of driving ability. These results reflect the long acting nature of nitrazepam.
# Overdose
Nitrazepam overdose may result in stereotypical symptoms of benzodiazepine overdose including intoxication, impaired balance and slurred speech. In cases of severe overdose this may progress to a comatose state with the possibility of death.
The risk of nitrazepam overdose is increased significantly if nitrazepam is abused in conjunction with opiates, as was highlighted in a review of deaths of users of the opiate buprenorphine. Severe nitrazepam overdose resulting in coma causes the central somatosensory conduction time (CCT) after median nerve stimulation to be prolonged and the N20 to be dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of nitrazepam cause prolonged CCT and IPLs.
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class in suicides in this review of Swedish death certificates. In 72% of the cases benzodiazepines were the only drug consumed. Benzodiazepines and in particular nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.
In a brain sample of a fatal nitrazepam poisoning high concentrations of nitrazepam and its metabolite were found in the brain of the deceased person.
In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam and flunitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths related to drug addiction in this study of causes of deaths. Nitrazepam and flunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death. In Australia, nitrazepam and temazepam were the benzodiazepines most commonly detected in overdose drug related deaths. In a third of cases benzodiazepines were the sole cause of death.
Individuals with chronic illnesses are much more vulnerable to lethal overdose with nitrazepam, as fatal overdoses can occur at relatively low doses in these individuals.
# Trade names
Mogadon, Alodorm, Apodorm, Remnos, Somnite, Apodorm, Arem, Cavodan, Dima, Dormalon, Dormigen, Dormo-Puren, Dumolid, Eatan N, Eunoctin, Hypnotex, Imeson, Insoma, Insomin, Ipersed, Mitidin, Mogadan, Nilandron, Nitavan, Nitepam, Nitrados, Nitrapan, Nitravet, Nitrazadon, Nitrazep, Nitrazepan, Nitrazepol, Nitredon, Nitrosun, Novanox, Numbon, Onirema, Ormodon, Pacisyn, Paxadorm, Pelson, Pelsonfilina, Protraz, Radedorm, Remnos, Serenade, Somnibel N, Somnipar, Somnite, Sonebon, Sonotrat, Surem, Tri, Unisomnia, Nitrazepam Capsules BP 1993, Nitrazepam Oral Suspension BP 1993, Nitrazepam Tablets BP 1993.
# In Popular Culture
- Marillion refers to the drug in the song Punch & Judy on their second album Fugazi, with lyricist Fish writing Curling tongs, mogadons, "I got a headache baby, don't take so long"
- Porcupine Tree reference the drug in their song Fear of a Blank Planet from the album of the same name with the line "My face is Mogadon." | Nitrazepam
Nitrazepam is a type of benzodiazepine drug. It is a powerful hypnotic drug with strong sedative and motor impairing properties,[1] anxiolytic, amnestic, anticonvulsant, and skeletal muscle relaxant properties.
Nitrazepam is available in 5mg and 10mg tablets. In Australia, Israel and the United Kingdom it is only available in 5mg tablets.
# Pharmacology
Nitrazepam is a nitrobenzodiazepine.[2][3] It is a 1,4 benzodiazepine, with the chemical name 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4- benzodiazepin-2-one.
It is long acting, is lipophilic and is metabolised hepatically via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors, causing an enhanced binding of GABA (gamma amino butyric acid) to GABAA receptors.[4] GABA is a major inhibitory neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system. The mechanism of action of nitrazepam is the same as other benzodiazepine drugs and zopiclone.[5] The anticonvulsant properties of nitrazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.[6] The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[7] It is a full agonist of the benzodiazepine receptor.[8] The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats.[9] Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and aspartic acid in the mouse brain. The decrease may be due to activation of benzodiazepine receptors.[10] At high doses decreases in histamine turnover occur as a result of nitrazepam's action at the benzodiazepine-GABA receptor complex in mouse brain. [11] Nitrazepam possesses antipruritic properties. It possesses antipruritic properties, which are believed to be due to a central mechanism of action rather than a peripheral mechanism of action.[12] Nitrazepam has demonstrated cortisol suppressing properties in man.[13]
Nitrazepam is an agonist for both central and peripheral type benzodiazepine receptors in rat neuroblastoma cells.[14]
# EEG and sleep
In sleep laboratory studies, nitrazepam decreased sleep onset latency. In psychogeriatric in-patients nitrazepam was found to be no more effective than placebo tablets in increasing total time spent asleep, was found to significantly impair trial subjects abilities to move and carry out everyday activities the next day and it was concluded that nitrazepam should not be used as a sleep aid in psychogeriatric in-patients.[15]
Stage 2 NREM sleep is significantly increased by nitrazepam but SWS stage sleep is significantly decreased by nitrazepam.[16] There is delay in the onset, and decrease in the duration of REM sleep. Following discontinuation of the drug, REM sleep rebound has been reported in some studies.[17] Nitrazepam is reported to significantly affect stages of sleep: a decrease stage 1, 3 and 4 sleep and to increase stage 2.[18] In young volunteers the pharmacological properties of nitrazepam was found to produce sedation, impaired psychomotor performance and standing steadiness. EEG tests showed a decrease of alpha activity and increased the beta activity. These effects increased according to blood plasma levels of nitrazepam.[19] Performance was significantly impaired 13 hours after dosing with nitrazepam as was decision-making skills. EEG tests show more drowsiness and light sleep 18 hours after nitrazepam intake more so than amylobarbitone. Fast activity was recorded via EEG 18 hours after nitrazepam dosing.[20] An animal study demonstrated that nitrazepam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is also suppressed by nitrazepam. Estazolam was found to be more potent however.[21] Nitrazepam increases the slow wave light sleep (SWLS) in a dose-dependent manner whilst suppressing deep sleep stages. Less time is spent in stages 3 and 4 which are the deep sleep stages, when benzodiazepines such as nitrazepam are used. Benzodiazepines are therefore not good hypnotics in the treatment of insomnia. The suppression of deep sleep stages by benzodiazepines may be especially problematic to the elderly as they naturally spend less time in the deep sleep stage.[22]
# Pharmacokinetics
Nitrazepam is largely bound to plasma proteins.[23] Benzodiazepines such as nitrazepam are lipid soluble and have a high cerebral uptake.[24] The time for nitrazepam to reach peak plasma concentrations following oral administration is about 2 hours (0.5 to 5 hours).The half life which is the time taken for a dose to decrease by half is 16.5 to 48.3 (mean 28.8) hours. Both low dose (5 mg) and high dose (10 mg) of nitrazepam significantly increases growth hormone levels in humans.[25] Nitrazepam has a much longer half life in the cerebrospinal fluid. The half life in the cerebrospinal fluid is 68 hours which indicates that nitrazepam is eliminated extremely slowly from the cerebrospinal fluid.[26]
Nitrazepam has a half life of about 29 hours in young people and a much longer half life in the elderly. In the elderly the half life is about 40 hours.[27][28] Concomitant food intake has no influence on the rate of absorption of nitrazepam nor on its bioavailability. Therefore nitrazepam can be taken with or without food.[29]
# Uses
Nitrazepam is most often used to treat short-term sleeping problems (insomnia), namely difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Nitrazepam is long acting and is sometimes used in patients who have difficulty in maintaining sleep. Nitrazepam shortens the time required to fall asleep and lengthens the duration of sleep. It is also useful for the management of myoclonic seizures and has been used in the management of seizure disorders in children and also for infantile spasms. However, the usefulness of nitrazepam is limited due to dose limiting sedative side effects.
Nitrazepam is sometimes used for refractory epilepsies. However, long term prophylactic treatment of epilepsy has considerable drawbacks. Most importantly the loss of antiepileptic effects due to tolerance which renders prolonged nitrazepam therapy ineffective. Nitrazepam also has the draw back of significant side effects such as sedation, which is why nitrazepam and benzodiazepines in general are only prescribed in the acute management of epilepsies.[30] Nitrazepam has been found to be more effective than clonazepam in the treatment of west syndrome which is an age dependent epilepsy, affecting the very young. However, as with other epilepies treated with benzodiazepines, long term therapy becomes ineffective with prolonged therapy and the side effects of hypotonia and drowsiness are troublesome with nitrazepam therapy, other antiepileptic agents are therefore recommended for long term therapy, possibly Corticotropin (ACTH) or vigabatrin.[31]
## Utilisation
Nitrazepam along with diazepam, oxazepam and temazepam 1993 represented 82% of the benzodiazepine market in Australia.[32] The rate of benzodiazepine prescribing in Tasmania is higher than in other Australian states; Nitrazepam and flunitrazepam prescribing levels in Tasmania are disturbingly high.[33] Prescribing of hypnotics in Norway is quite restrictive with only 4 hypnotics which are prescribable; nitrazepam, flunitrazepam, zolpidem and zopiclone.[34] The usage of benzodiazepine hypnotics in local authority homes for the elderly 1982 in Edinburgh, established via a clinical survey, was that 34% of residents were taking sleeping medication. However, the number varied between the homes, with some homes reporting only 2.3% of residents to be on hypnotic medication and others up to 56.5% on hypnotic drugs. Nitrazepam was the most frequently prescribed hypnotic medication accounting for a third of hypnotic use in Edinburgh residential homes in 1982.[35]
# Dosage
When used for treatment of insomnia, the usual dose for adults is 2.5mg to 10mg, taken at bedtime. Typically, it works within the hour and allows the individual to maintain sleep for 4 to 8 hours.
When used for treatment of myoclonic seizures, the dose is based on body weight. The dose for children (30kg or less) is anywhere from 0.3mg/kg to 1mg/kg, daily in three divided doses.
# Tolerance dependence and withdrawal
## Tolerance
Tolerance to a drugs effects occurs after regular exposure to a drug. The mechanism of nitrazepam tolerance may be due to down-regulation of benzodiazepine receptors.[36] When tolerance and habituation occurs to nitrazepam its pharmacokinetic profile changes with absorption of the drug slowing down, elimination time increasing and brain concentration of nitrazepam increasing significantly.[37] Increased levels of GABA in cerebral tissue and alterations in the activity state of the serotoninergic system occurs as a result of nitrazepam tolerance.[38]
After 6 days of use tolerance to nitrazepam's but not temazepams sleep inducing effects and performance impairing effects occurred in a study.[39] One study demonstrated tolerance to the sleep promoting effects of nitrazepam and temazepam after 7 days nightly administration in 19 elderly inpatients. Self reported quality of sleep was found to be increased after the first nights administration of either nitrazepam or temazepam but by day 7 self reported quality of sleep was found to have returned to baseline in these patients, suggesting the development of tolerance after 7 days use. The effect was more pronounced in patients of lower intelligence. [40] In mice tolerance to the anticonvulsant properties of nitrazepam developed profoundly and rapidly over 6 days, and then did not proceed. Some anticonvulsant effects were still apparent after 6 days administration.[41] In humans tolerance to the anticonvulsant effects of nitrazepam is a frequent occurrence.[42]
### Dependence and withdrawal
See also benzodiazepine withdrawal syndrome
Benzodiazepine drugs such as nitrazepam can cause dependence and addiction and is what is known as the benzodiazepine withdrawal syndrome. Withdrawal from nitrazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen with alcohol and barbiturates, including delirium tremens.[43][44] The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur at standard dosages and also after short term treatment. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.[45]
Frequent use of nitrazepam may cause dependence and when the drug is reduced or stopped, withdrawal symptoms occur. Withdrawal symptoms including a worsening of insomnia compared to baseline typically occurs after discontinuation of nitrazepam even after short term single nightly dose therapy.[46] Dependence on benzodiazepines such as nitrazepam or temazepam often occurs due to discharging patients from hospital on benzodiazepines who were started on benzodiazepine hypnotics in hospital. It is recommended that hypnotic use in hospital be limited to 5 days to avoid the development of drug dependence and withdrawal insomnia.[47]
After discontinuation of nitrazepam a rebound effect may occur about 4 days after stopping medication.[48] Nitrazepam has more side effects than other hypnotic drugs and tolerance to sedative properties and rebound insomnia after discontinuation occurs after only 7 days administration.[49] Tolerance to the anticonvulsant and anxiolytic effects also develops rapidly during daily administration.[50]
Abrupt withdrawal after long term use from therapeutic doses of nitrazepam may result in a severe benzodiazepine withdrawal syndrome. Reports in the medical literature report of two psychotic states developing after abrupt withdrawal from nitrazepam including delirium after abrupt withdrawal of 10 mg of nitrazepam and in another case auditory hallucinations and visual cognitive disorder developed after abrupt withdrawal from 5 mg of nitrazepam and 0.5 mg of triazolam. Gradual and careful reduction of the dosage was recommended to prevent severe withdrawal syndromes from developing.[51] Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions.[52] Depersonalisation has also been reported as a benzodiazepine withdrawal effect from nitrazepam.[53]
# Toxicity
## Animals
Genotoxicity
Nitrazepam may be carcinogenic in hamster cells under the influence of UV-light and has been found to be both photogenotoxic and photocytotoxic in hamster cells under UV light.[54] Some studies on some animals have demonstrated teratogenic and also carcinogenic effects of nitrazepam and some other benzodiazepines in these animals and the wide spread use of these drugs world wide was of major concern for human health. A review and update of existing results was therefore attempted.[55] However, since 1996 no further research for this concern has been carried out.
Genotoxic drugs have the potential to cause genetic mutations, DNA damage and promote the development of cancer including tumors.[1]
Reproductive Toxicity
Nitrazepam has been reported in the medical literature by researchers as a drug which is well known for inducing testicular and reproductive toxicities. Nitrazepam decreases the number of motile sperm, curilinear velocity, beat cross frequency, maximum and mean amplitude of lateral head displacement and causes testicular lesions. Nitrazepam may result in low fertility.[56]
In studies of Sprague-Dawley rats, nitrazepam induced reproductive toxicity has been demonstrated after 2 weeks of therapy, with significant decreases in fertility in nitrazepam treated male rats. Testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads was found after 2 weeks treatment with the higher dose nitrazepam and after 4 weeks in the lower dosed rats. The doses used however in the toxicology tests were sigificantly higher than standard therapeutic doses.[57] Nitrazepam has also been shown at high doses to affect sperm motion in laboratory tests via causing lesions in spermatids.[58]
Nitrazepam has been shown in Sprague-Dawley rats to cause testicular damage. A decrease in the weight of the testis, weight of the epididymis, number of sperm in the testis and sperm motility was shown in very high dose of nitrazepam treated rats, i.e. 20mg/kg to 80mg/kg. Rats treated with such extreme doses of nitrazepam show a significant decrease in pregnancy rate. Localised necrosis in the seminiferous epithelium and Leydig cell hyperplasia occurs in the testis of rats treated with nitrazepam and morphological changes occur in spermatocytes with necrosis of the cytoplasm.[59] Laboratory tests assessing the toxicity of nitrazepam, diazepam and chlordiazepoxide on mice spermatozoa found that nitrazepam produced the most toxicities on sperm including abnormalities involving both shape and size of the sperm head.[60]
In female rats nitrazepam has been shown to inhibit ovulation.[61]
Fetal Toxicity
In a rat study nitrazepam showed much greater damage to the fetus than other benzodiazepines, as did nimetazepam. High levels of nitrazepam were found in the maternal serum and in the whole fetus which may account for the increased toxicity. Diazepam showed relatively weak fetal toxicities.[62] Rats treated with a single very high dose of nitrazepam on day 12 of gestation significant increase in malformation in rats. However, mice seem more resistant to the teratogenic effects which may be related to differences in metabolism of nitrazepam between the two species.[63] Exencephaly, cleft palate, micrognathia, short or kinky tail and limb reduction defects occurred in rats treated with a single very high dose of nitrazepam, with limb buds revealing hemorrhage and mesenchymal cell necrosis.[64] Another fetal toxicity study in rats at 100mg/kg demonstrated that nitrazepam has embryocidal activity in vitro and that nitrazepam is teratogenic in vivo in rats.[65]
Nitrazepam is much more teratogenic in rats, but not mice, than other benzodiazepines probably due to its extensive nitro reduction to 7-aminonitrazepam by rat intestinal microflora.[66] Nitrazepam undergoes enterocyte metabolism to form oxidative free radicals. Superoxide is intracellularly produced during nitrazepam metabolism and this oxidative metabolism can lead to cellular dysfunction.[67]
## Humans
The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry sponsored trials on their own results showing that use of hypnotics is correlated with depression. The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that "major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia.[68]
Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department.[69]
Cancer
Benzodiazepine usage for more than 1 - 6 months at prescribed doses is associated with an increased risk of the development of ovarian cancer.[70] There have been 15 epidemiologic studies which have shown that hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. Not only are benzodiazepines associated with an increased risk of cancer, the benzodiazepine receptor agonist Z-drugs also are associated with cancer in humans in these studies. Initially FDA reviewers did not want to approve the Z drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer.
The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer".[71] It has to be seen if other reviewers and the FDA come to the same result.
Mortality
Nitrazepam therapy compared with other drug therapies increases risk of death when used for intractable epilepsy in an analysis of 302 patients. The risk of death from nitrazepam therapy may be greater in younger patients (children below 3.4 years in the study) with intractable epilepsy. In older children (above 3.4 years) the tendency appears to be reversed in this study. [72] Nitrazepam may cause sudden death in children. Nitrazepam therapy can cause swallowing incoordination, high-peaked esophageal peristalsis, bronchospasm, delayed cricopharyngeal relaxation and severe respiratory distress necessitating ventilatory support in children. Nitrazepam may promote the development of parasympathetic overactivity or vagotonia leading to potentially fatal respiratory distress in children.[73]
# Abuse potential
Nitrazepam is a drug which is very frequently involved in drug intoxication.[74] Nitrazepam was the most commonly detected benzodiazepine in urine samples in the UK in 1997 suggesting a high liking and preference amongst drug abusers. However, it has been superseded by temazepam, despite the fact that temazepam is much more highly regulated in the UK. Temazepam is Class B drug, while nitrazepam is a Class C drug.[75][76] In Nepal, nitrazepam is a major drug of abuse as is codeine, heroin, buprenorphine and cannabis.[77]
Nitrazepam in animal studies has been shown to increase reward seeking which may suggest increased risk of addictive behavioural patterns.[78]
A study found that nitrazepam caused significant euphoria as against placebos and was identified as an active drug by freshly detoxified experienced drug abusers of heroin and other drugs. Nitrazepam resembled diazepam (Valium), however, on certain parameters the effects produced by nitrazepam were more pronounced in these drug abusers. Nitrazepam was found to be an abusable drug and has similar abuse liability like diazepam, if not slightly higher in these drug abusers. Treatment with nitrazepam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for nitrazepam should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply. Dependence can occur in as little as four weeks.[2][3]
Benzodiazepines, including diazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse.[79]
Nitrazepam is detected frequently in cases of people suspected of driving under the influence of drugs in Sweden. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers in suspected impaired drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.[80] In Northern Ireland in cases where drugs were found in tests on impaired drivers, benzodiazepines were found to be present in 87% of cases.[81]
# Side Effects
## Common Side Effects
CNS depression including, somnolence, dizziness, depressed mood, rage, violence, fatigue, ataxia, headache, vertigo, impairment of memory, impairment of motor functions, hangover feeling in the morning, slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, double vision and inattention have been reported. Unpleasant dreams and rebound insomnia has also been reported. High levels of confusion, clumsiness also occurs after administration of nitrazepam.[82] Increased reaction time, co-ordination problems and impaired learning and memory.[83]
Impaired learning and memory occurs due to the action of the drug on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system.[84] Nitrazepam causes a reduced output of serotonin which is closely involved in regulating mood and may be the cause of feelings of depression in users of nitrazepam or other benzodiazepines.[85]
Nitrazepam is a long acting benzodiazepine with an elimination half life of 15-38 (mean elimination half life 26 hours).[4] Residual 'hangover' effects after nighttime administration of nitrazepam 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 increases the risk of falls and hip fractures.[86] Significant impairment of visual perception and sedative effects persisting into the next day typically occurs with nitrazepam administration as was demonstrated in a human clinical trial assessing the effect of nitrazepam on peak saccade velocity.[87]
Impairment of psychomotor function may especially occur after repeated administration, with the elderly being more vulnerable to this adverse effect.[88] Overall accuracy of completing tasks is impaired after repeated administration of nitrazepam and is due to drug accumulation of nitrazepam. The elderly are more vulnerable to these side effects.[89]
## Less Common Side Effects
Hypotension,[90] faintness, palpitation, rash or pruritus, gastrointestinal disturbances, changes in libido. Very infrequently, paradoxical reactions may occur, e.g. excitement, stimulation, hallucinations, hyperactivity and insomnia. Also depressed or increased dreaming, disorientation, severe sedation, retrograde amnesia, headache, hypothermia, delirium tremens.[91] Acroparaesthesia has been reported as a side effect from nitrazepam with symptoms including, pins and needles in hands and loss of power of fingers and clumsiness of the fingers.[92]
# Interactions
Nitrazepam interacts with the antibiotic erythromycin which is a strong inhibitor of CYP3A4, which affects concentration peak time. This interaction is not to believed to be clinically important.[93] However, anxiety, tremor and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin to the patient, repetitive hallucinations and abnormal bodily sensations developed. The patient had however acute pneumonia and renal failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms especially in those with other significant physical complications.[94]
Oral contraceptive pills, reduce the clearance of nitrazepam which may lead to increased plasma levels of nitrazepam and accumulation.[95]
Rifampin increases the clearance of nitrazepam significantly and probenecid decreases the clearance of nitrazepam significantly.[96] Cimetidine slows down the elimination rate of nitrazepam leading to more prolonged effects of nitrazepam and increased risk of accumulation.[97] Alcohol (ethanol) in combination with nitrazepam may cause a synergistic enhancement of the hypotensive properties of both benzodiazepines and alcohol.[98]
Benzodiazepines including nitrazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine in rat experiments.[99]
# Special precautions
It has been recommended in the medical literature that caution should be exercised in prescribing nitrazepam to anyone who is of working age due to the significant impairment of psychomotor skills. This impairment is greater the higher the dosage that is prescribed.[100]
Nitrazepam in doses of 5 mg or more causes significant deterioration in vigilance performance combined with increased feelings of sleepiness.[101] Doses as low as 5 mg of nitrazepam can impair driving skills.[102] Therefore people driving or conducting activities which require vigilance should exercise caution in using nitrazepam or possibly avoid it all together.[103]
Caution in the elderly. Nitrazepam has been found to be dangerous in elderly patients due to a significant increased risk of falls.[104] This increased risk is probably due to the persisting drug effects of nitrazepam well into the next day.[105] Nitrazepam is a particularly unsuitable hypnotic for the elderly as it induces a disability characterised by general mental deterioration, inability to walk, incontinence, dysarthric, confusion, prone to stumbling, falls and disoriention which can occur from doses as low as 5 mg. The nitrazepam induced symptomatology can lead to a misdiagnosis of brain disease in the elderly eg dementia and can also lead to the symptoms of postural hypotension which may also get misdiagnosed. It was reported that a geriatric unit was seeing as many as 7 patients a month with nitrazepam induced disabilities and health problems. It was recommended that nitrazepam should join the barbiturates in not being prescribed to the elderly.[106] Only nitrazepam and lorazepam were found to increase the risk of falls and fractures in the elderly.[107] CNS depression occurs much more frequently in the elderly and is especially common in doses above 5 mg of nitrazepam.[108] Both young and old patients report sleeping better after 3 nights use of nitrazepam however they also report feeling less awake and are slower on psychomotor testing up to 36 hours after intake of nitrazepam. The elderly showed cognitive deficits, making significantly more mistakes in psychomotor testing than younger patients despite similar plasma levels of the drug, suggesting that the elderly are more sensitive to nitrazepam due to increased sensitivity of the aging brain to nitrazepam. Confusion and disorientation can result from chronic nitrazepam administration to elderly subjects. Also the effects of a single dose of nitrazepam may last up to 60 hours after administration.[109]
Caution in children. Nitrazepam is not recommended for use in those under 18. Use in very young children may be especially danagerous. Children treated with nitrazepam for epilepsies may develop tolerance within months of continued use, with dose escalation often occurring with prolonged use. Sleepiness, deterioration in motor skills and ataxia were common side effects in children with tuberous sclerosis treated with nitrazepam. The side effects of nitrazepam may impair the development of motor and cognitive skills in children treated with nitrazepam. Withdrawal of nitrazepam only occasionally resulted in a return of seizures and some children withdrawn from nitrazepam appeared to improve. Development, eg able to walk at 5 years was impaired in many children taking nitrazepam but was not impaired with several other non benzodiazepine antiepileptic agents. It has been recommended that children being treated with nitrazepam should be reviewed and have their nitrazepam gradually discontinued whenever appropriate.[110]
Caution in hypotension. Caution in those suffering from hypotension, nitrazepam may worsen hypotension.[90]
Caution in hypothyroidism. Caution should be exercised by people who have hypothyroidism as this condition may cause a long delay in the metabolism of nitrazepam leading to significant drug accumulation.[111]
## Pregnancy
Nitrazepam is a long acting benzodiazepine and there is a risk of drug accumulation, even though no active metabolites are formed during metabolism. Accumulation can occur in various body organs including the heart, accumulation is even greater in babies. Nitrazepam rapidly crosses the placenta and also is present in breast milk in high quantities. Therefore nitrazepam and benzodiazepines should be avoided during pregnancy and breast feeding.[112] In early pregnancy nitrazepam levels are lower in the baby than in the mother and in the later stages of pregnancy nitrazepam is found in equal levels in both the mother and the unborn child.[113] Internationally benzodiazepines are known to cause harm when used during pregnancy and nitrazepam is a category D drug during pregnancy.
Benzodiazepines are lipophilic and rapidly penetrate membranes and therefore rapidly penetrate the placenta with significant uptake of the drug. Use of benzodiazepines eg nitrazepam in late pregnancy especially high doses may result in floppy infant syndrome.[114] Use in the third trimester stage of pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.[115]
# Contraindications
Nitrazepam should be avoided in patients with chronic obstructive pulmonary disease (COPD), especially during acute exacerbations of COPD, due to the fact that serious respiratory depression may occur in patients who are receiving hypnotics.[116]
Nitrazepam should be avoided in patients who drive or operate machinery. A study assessing driving skills of sedative hypnotic users found that users of nitrazepam were found to be significantly impaired up to 17 hours after dosing, whereas users of temazepam did not show significant impairments of driving ability. These results reflect the long acting nature of nitrazepam.[117]
# Overdose
Nitrazepam overdose may result in stereotypical symptoms of benzodiazepine overdose including intoxication, impaired balance and slurred speech. In cases of severe overdose this may progress to a comatose state with the possibility of death.
The risk of nitrazepam overdose is increased significantly if nitrazepam is abused in conjunction with opiates, as was highlighted in a review of deaths of users of the opiate buprenorphine.[118] Severe nitrazepam overdose resulting in coma causes the central somatosensory conduction time (CCT) after median nerve stimulation to be prolonged and the N20 to be dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. Toxic overdoses therefore of nitrazepam cause prolonged CCT and IPLs.[119]
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class in suicides in this review of Swedish death certificates. In 72% of the cases benzodiazepines were the only drug consumed. Benzodiazepines and in particular nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.[120]
In a brain sample of a fatal nitrazepam poisoning high concentrations of nitrazepam and its metabolite were found in the brain of the deceased person.[121]
In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines nitrazepam and flunitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths related to drug addiction in this study of causes of deaths. Nitrazepam and flunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death.[122] In Australia, nitrazepam and temazepam were the benzodiazepines most commonly detected in overdose drug related deaths. In a third of cases benzodiazepines were the sole cause of death.[123]
Individuals with chronic illnesses are much more vulnerable to lethal overdose with nitrazepam, as fatal overdoses can occur at relatively low doses in these individuals.[124]
# Trade names
Mogadon, Alodorm, Apodorm, Remnos, Somnite, Apodorm, Arem, Cavodan, Dima, Dormalon, Dormigen, Dormo-Puren, Dumolid, Eatan N, Eunoctin, Hypnotex, Imeson, Insoma, Insomin, Ipersed, Mitidin, Mogadan, Nilandron, Nitavan, Nitepam, Nitrados, Nitrapan, Nitravet, Nitrazadon, Nitrazep, Nitrazepan, Nitrazepol, Nitredon, Nitrosun, Novanox, Numbon, Onirema, Ormodon, Pacisyn, Paxadorm, Pelson, Pelsonfilina, Protraz, Radedorm, Remnos, Serenade, Somnibel N, Somnipar, Somnite, Sonebon, Sonotrat, Surem, Tri, Unisomnia, Nitrazepam Capsules BP 1993, Nitrazepam Oral Suspension BP 1993, Nitrazepam Tablets BP 1993.[5]
# In Popular Culture
- Marillion refers to the drug in the song Punch & Judy on their second album Fugazi, with lyricist Fish writing Curling tongs, mogadons, "I got a headache baby, don't take so long"
- Porcupine Tree reference the drug in their song Fear of a Blank Planet from the album of the same name with the line "My face is Mogadon." | https://www.wikidoc.org/index.php/Nitrazepam | |
fce9a209f6815b221c7022f07f8c43070fc1f2d9 | wikidoc | Nizatidine | Nizatidine
# 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
Nizatidine is a histamine H2-receptor antagonist that is FDA approved for the treatment of active duodenal ulcer, esophagitis, active benign gastric ulcer, GERD, maintenance therapy for duodenal ulcer patients. Common adverse reactions include Diarrhea, Vomiting, Headache,.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Nizatidine is indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks.
- Nizatidine is indicated for maintenance therapy for duodenal ulcer patients, at a reduced dosage of 150 mg h.s. after healing of an active duodenal ulcer. The consequences of continuous therapy with nizatidine for longer than 1 year are not known.
- Nizatidine is indicated for up to 12 weeks for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerative esophagitis, and associated heartburn due to GERD.
- Nizatidine is indicated for up to 8 weeks for the treatment of active benign gastric ulcer. Before initiating therapy, care should be taken to exclude the possibility of malignant gastric ulceration.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nizatidine in adult patients.
### Non–Guideline-Supported Use
- Duodenal ulcer disease - Helicobacter pylori gastrointestinal tract infection
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nizatidine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nizatidine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nizatidine in pediatric patients.
# Contraindications
- Nizatidine is contraindicated in patients with known hypersensitivity to the drug. Because cross sensitivity in this class of compounds has been observed, H2-receptor antagonists, including nizatidine, should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.
# Warnings
### Precautions
- Symptomatic response to nizatidine therapy does not preclude the presence of gastric malignancy.
- Because nizatidine is excreted primarily by the kidney, dosage should be reduced in patients with moderate to severe renal insufficiency.
- Pharmacokinetic studies in patients with hepatorenal syndrome have not been done. Part of the dose of nizatidine is metabolized in the liver. In patients with normal renal function and uncomplicated hepatic dysfunction, the disposition of nizatidine is similar to that in normal subjects.
- False-positive tests for urobilinogen with Multistix® may occur during therapy with nizatidine.
# Adverse Reactions
## Clinical Trials Experience
- Worldwide, controlled clinical trials of nizatidine included over 6,000 patients given nizatidine in studies of varying durations. Placebo-controlled trials in the United States and Canada included over 2,600 patients given nizatidine and over 1,700 given placebo. Among the adverse events in these placebo-controlled trials, anemia (0.2% vs 0%) and urticaria (0.5% vs 0.1%) were significantly more common in the nizatidine group.
- Incidence in Placebo-Controlled Clinical Trials in the United States and Canada – Table 5 lists adverse events that occurred at a frequency of 1% or more among nizatidine-treated patients who participated in placebo-controlled trials. The cited figures provide some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
- A variety of less common events were also reported; it was not possible to determine whether these were caused by nizatidine.
- Hepatocellular injury, evidenced by elevated liver enzyme tests (SGOT/AST, SGPT/ALT, or alkaline phosphatase), occurred in some patients and was possibly or probably related to nizatidine. In some cases there was marked elevation of SGOT, SGPT enzymes (greater than 500 IU/L) and, in a single instance, SGPT was greater than 2,000 IU/L. The overall rate of occurrences of elevated liver enzymes and elevations to 3 times the upper limit of normal, however, did not significantly differ from the rate of liver enzyme abnormalities in placebo-treated patients. All abnormalities were reversible after discontinuation of nizatidine. Since market introduction, hepatitis and jaundice have been reported. Rare cases of cholestatic or mixed hepatocellular and cholestatic injury with jaundice have been reported with reversal of the abnormalities after discontinuation of nizatidine.
- In clinical pharmacology studies, short episodes of asymptomatic ventricular tachycardia occurred in 2 individuals administered nizatidine and in 3 untreated subjects.
- Rare cases of reversible mental confusion have been reported.
- Clinical pharmacology studies and controlled clinical trials showed no evidence of anti-androgenic activity due to nizatidine. Impotence and decreased libido were reported with similar frequency by patients who received nizatidine and by those given placebo. Rare reports of gynecomastia occurred.
- Anemia was reported significantly more frequently in nizatidine- than in placebo-treated patients. Fatal thrombocytopenia was reported in a patient who was treated with nizatidine and another H2-receptor antagonist. On previous occasions, this patient had experienced thrombocytopenia while taking other drugs. Rare cases of thrombocytopenic purpura have been reported.
- Sweating and urticaria were reported significantly more frequently in nizatidine- than in placebo-treated patients. Rash and exfoliative dermatitis were also reported. Vasculitis has been reported rarely.
- As with other H2-receptor antagonists, rare cases of anaphylaxis following administration of nizatidine have been reported. Rare episodes of hypersensitivity reactions (e.g., bronchospasm, laryngeal edema, rash, and eosinophilia) have been reported.
- Serum sickness-like reactions have occurred rarely in conjunction with nizatidine use.
- Reports of impotence have occurred.
- Hyperuricemia unassociated with gout or nephrolithiasis was reported. Eosinophilia, fever, and nausea related to nizatidine administration have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nizatidine in the drug label.
# Drug Interactions
- No interactions have been observed between nizatidine and theophylline, chlordiazepoxide, lorazepam, lidocaine, phenytoin, and warfarin. Nizatidine does not inhibit the cytochrome P-450-linked drug-metabolizing enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are not expected to occur. In patients given very high doses (3,900 mg) of aspirin daily, increases in serum salicylate levels were seen when nizatidine, 150 mg b.i.d., was administered concurrently.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Oral reproduction studies in pregnant rats at doses up to 1500 mg/kg/day (9000 mg/m2/day, 40.5 times the recommended human dose based on body surface area) and in pregnant rabbits at doses up to 275 mg/kg/day (3245 mg/m2/day, 14.6 times the recommended human dose based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus due to nizatidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nizatidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nizatidine during labor and delivery.
### Nursing Mothers
- Studies conducted in lactating women have shown that 0.1% of the administered oral dose of nizatidine is secreted in human milk in proportion to plasma concentrations. Because of the growth depression in pups reared by lactating rats treated with nizatidine, 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
- Of the 955 patients in clinical studies who were treated with nizatidine, 337 (35.3%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. 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.
- 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 Nizatidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nizatidine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nizatidine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nizatidine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nizatidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nizatidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- 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
# IV Compatibility
There is limited information regarding IV Compatibility of Nizatidine in the drug label.
# Overdosage
- Overdoses of nizatidine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.
- There is little clinical experience with overdosage of nizatidine in humans. Test animals that received large doses of nizatidine have exhibited cholinergic-type effects, including lacrimation, salivation, emesis, miosis, and diarrhea. Single oral doses of 800 mg/kg in dogs and of 1,200 mg/kg in monkeys were not lethal. Intravenous median lethal doses in the rat and mouse were 301 mg/kg and 232 mg/kg respectively.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- If overdosage occurs, use of activated charcoal, emesis, or lavage should be considered along with clinical monitoring and supportive therapy. The ability of hemodialysis to remove nizatidine from the body has not been conclusively demonstrated; however, due to its large volume of distribution, nizatidine is not expected to be efficiently removed from the body by this method.
# Pharmacology
## Mechanism of Action
- Nizatidine is a competitive, reversible inhibitor of histamine at the histamine H2-receptors, particularly those in the gastric parietal cells.
- Effects on Acid Secretion: Nizatidine significantly inhibited nocturnal gastric acid secretion for up to 12 hours. Nizatidine also significantly inhibited gastric acid secretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1).
- Effects on Other Gastrointestinal Secretions – Pepsin: Oral administration of 75 to 300 mg of nizatidine did not affect pepsin activity in gastric secretions. Total pepsin output was reduced in proportion to the reduced volume of gastric secretions.
- Intrinsic Factor: Oral administration of 75 to 300 mg of nizatidine increased betazole-stimulated secretion of intrinsic factor.
- Serum Gastrin: Nizatidine had no effect on basal serum gastrin. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of nizatidine.
- Other Pharmacologic Actions
- Hormones: Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or estradiol.
Nizatidine had no demonstrable antiandrogenic action.
## Structure
- Nizatidine USP is a histamine H2-receptor antagonist. Chemically, it is N-2-2--4-thiazolylmethylthioethyl]-N'-methyl-2-nitro-1,1-ethenediamine. The structural formula is represented below:
- It is an off-white to buff crystalline solid that is soluble in water. Nizatidine has a bitter taste and mild sulfur-like odor. Nizatidine Capsules USP, for oral administration, contain 150 mg or 300 mg nizatidine and the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, magnesium stearate and pregelatinized starch. The capsule shells contain: ammonium hydroxide, black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, silicon dioxide, sodium lauryl sulfate and titanium dioxide.
- The 150 mg capsule shell also contains D&C Yellow No. 10 and FD&C Yellow No. 6.
- The 300 mg capsule shell also contains black iron oxide, red iron oxide and yellow iron oxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nizatidine in the drug label.
## Pharmacokinetics
- The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800 mcg/L for a 150 mg dose and 1,400 to 3,600 mcg/L for a 300 mg dose) occur from 0.5 to 3 hours following the dose. A concentration of 1,000 mcg/L is equivalent to 3 mcmol/L; a dose of 300 mg is equivalent to 905 mcmoles. Plasma concentrations 12 hours after administration are less than 10 mcg/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distribution is 0.8 to 1.5 L/kg. Because of the short half-life and rapid clearance of nizatidine, accumulation of the drug would not be expected in individuals with normal renal function who take either 300 mg once daily at bedtime or 150 mg twice daily. Nizatidine exhibits dose proportionality over the recommended dose range.
- The oral bioavailability of nizatidine is unaffected by concomitant ingestion of propantheline. Antacids consisting of aluminum and magnesium hydroxides with simethicone decrease the absorption of nizatidine by about 10%. With food, the AUC and Cmax increase by approximately 10%.
- In humans, less than 7% of an oral dose is metabolized as N2-monodesmethylnizatidine, an H2-receptor antagonist, which is the principal metabolite excreted in the urine. Other likely metabolites are the N2-oxide (less than 5% of the dose) and the S-oxide (less than 6% of the dose).
- More than 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Renal clearance is about 500 mL/min, which indicates excretion by active tubular secretion. Less than 6% of an administered dose is eliminated in the feces.
- Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. In individuals who are functionally anephric, the half-life is 3.5 to 11 hours, and the plasma clearance is 7 to 14 L/h. To avoid accumulation of the drug in individuals with clinically significant renal impairment, the amount and/or frequency of doses of nizatidine should be reduced in proportion to the severity of dysfunction.
- Approximately 35% of nizatidine is bound to plasma protein, mainly to a1-acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro.
- In multicenter, double-blind, placebo-controlled studies in the United States, endoscopically diagnosed duodenal ulcers healed more rapidly following administration of nizatidine, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2). Lower doses, such as 100 mg h.s., had slightly lower effectiveness.
- Treatment with a reduced dose of nizatidine has been shown to be effective as maintenance therapy following healing of active duodenal ulcers. In multicenter, double-blind, placebo-controlled studies conducted in the United States, 150 mg of nizatidine taken at bedtime resulted in a significantly lower incidence of duodenal ulcer recurrence in patients treated for up to 1 year (Table 3).
- In 2 multicenter, double-blind, placebo-controlled clinical trials performed in the United States and Canada, nizatidine was more effective than placebo in improving endoscopically diagnosed esophagitis and in healing erosive and ulcerative esophagitis.
- In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of nizatidine given to 88 patients compared with placebo in 98 patients in Study 1 yielded a higher healing rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P<0.05). Of 99 patients on nizatidine and 94 patients on placebo, Study 2 at the same dosage yielded similar results at 6 weeks (21% vs 11%, P <0.05) and at 12 weeks (29% vs 13%, P<0.01).
- In addition, relief of associated heartburn was greater in patients treated with nizatidine. Patients treated with nizatidine consumed fewer antacids than did patients treated with placebo.
- In a multicenter, double-blind, placebo-controlled study conducted in the United States and Canada, endoscopically diagnosed benign gastric ulcers healed significantly more rapidly following administration of nizatidine than of placebo (Table 4).
- P-values are one-sided, obtained by Chi-square test, and not adjusted for multiple comparisons.
- In a multicenter, double-blind, comparator-controlled study in Europe, healing rates for patients receiving nizatidine (300 mg h.s. or 150 mg b.i.d.) were equivalent to rates for patients receiving a comparator drug, and statistically superior to historical placebo control rates.
## Nonclinical Toxicology
- A 2-year oral carcinogenicity study in rats with doses as high as 500 mg/kg/day (about 80 times the recommended daily therapeutic dose) showed no evidence of a carcinogenic effect. There was a dose-related increase in the density of enterochromaffin-like (ECL) cells in the gastric oxyntic mucosa. In a 2-year study in mice, there was no evidence of a carcinogenic effect in male mice; although hyperplastic nodules of the liver were increased in the high-dose males as compared with placebo. Female mice given the high dose of nizatidine (2,000 mg/kg/day, about 330 times the human dose) showed marginally statistically significant increases in hepatic carcinoma and hepatic nodular hyperplasia with no numerical increase seen in any of the other dose groups. The rate of hepatic carcinoma in the high-dose animals was within the historical control limits seen for the strain of mice used. The female mice were given a dose larger than the maximum tolerated dose, as indicated by excessive (30%) weight decrement as compared with concurrent controls and evidence of mild liver injury (transaminase elevations). The occurrence of a marginal finding at high dose only in animals given an excessive and somewhat hepatotoxic dose, with no evidence of a carcinogenic effect in rats, male mice, and female mice (given up to 360 mg/kg/day, about 60 times the human dose), and a negative mutagenicity battery are not considered evidence of a carcinogenic potential for nizatidine.
- Nizatidine was not mutagenic in a battery of tests performed to evaluate its potential genetic toxicity, including bacterial mutation tests, unscheduled DNA synthesis, sister chromatid exchange, the mouse lymphoma assay, chromosome aberration tests, and a micronucleus test.
- In a 2-generation, perinatal and postnatal fertility study in rats, doses of nizatidine up to 650 mg/kg/day produced no adverse effects on the reproductive performance of parental animals or their progeny.
# Clinical Studies
There is limited information regarding Clinical Studies of Nizatidine in the drug label.
# How Supplied
- Nizatidine Capsules USP, 150 mg are #2, buff opaque capsules imprinted WPI and 3137 supplied in bottles of 60.
- Nizatidine Capsules USP, 300 mg are #0, light brown opaque capsules imprinted WPI and 3138 supplied in bottles of 30.
## Storage
- Store at 20°-25°C (68°-77°F).
- Dispense in a tight, light-resistant container as defined in the USP.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL 150 MG
NDC 0591-3137-60
Nizatidine
Capsules USP
150 mg
Watson® 60 Capsules Rx only
Each capsule contains:
Nizatidine USP, 150 mg
Usual adult dosage. See package insert for
dosage and full prescribing information.
Dispense in a tight, light-resistant
container as defined in the USP.
Store at 20º-25ºC (68º-77ºF).
Manufactured By:
Watson Pharma Private Limited
Verna, Salcette Goa 403 722 INDIA
Code No. GO/DRUGS/741 190936
Distributed By: Watson Pharma, Inc.
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Nizatidine in the drug label.
# Precautions with Alcohol
- Alcohol-Nizatidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Axid®
# Look-Alike Drug Names
There is limited information regarding Nizatidine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nizatidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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
Nizatidine is a histamine H2-receptor antagonist that is FDA approved for the treatment of active duodenal ulcer, esophagitis, active benign gastric ulcer, GERD, maintenance therapy for duodenal ulcer patients. Common adverse reactions include Diarrhea, Vomiting, Headache,.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Nizatidine is indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks.
- Nizatidine is indicated for maintenance therapy for duodenal ulcer patients, at a reduced dosage of 150 mg h.s. after healing of an active duodenal ulcer. The consequences of continuous therapy with nizatidine for longer than 1 year are not known.
- Nizatidine is indicated for up to 12 weeks for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerative esophagitis, and associated heartburn due to GERD.
- Nizatidine is indicated for up to 8 weeks for the treatment of active benign gastric ulcer. Before initiating therapy, care should be taken to exclude the possibility of malignant gastric ulceration.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nizatidine in adult patients.
### Non–Guideline-Supported Use
- Duodenal ulcer disease - Helicobacter pylori gastrointestinal tract infection[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nizatidine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nizatidine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nizatidine in pediatric patients.
# Contraindications
- Nizatidine is contraindicated in patients with known hypersensitivity to the drug. Because cross sensitivity in this class of compounds has been observed, H2-receptor antagonists, including nizatidine, should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.
# Warnings
### Precautions
- Symptomatic response to nizatidine therapy does not preclude the presence of gastric malignancy.
- Because nizatidine is excreted primarily by the kidney, dosage should be reduced in patients with moderate to severe renal insufficiency.
- Pharmacokinetic studies in patients with hepatorenal syndrome have not been done. Part of the dose of nizatidine is metabolized in the liver. In patients with normal renal function and uncomplicated hepatic dysfunction, the disposition of nizatidine is similar to that in normal subjects.
- False-positive tests for urobilinogen with Multistix® may occur during therapy with nizatidine.
# Adverse Reactions
## Clinical Trials Experience
- Worldwide, controlled clinical trials of nizatidine included over 6,000 patients given nizatidine in studies of varying durations. Placebo-controlled trials in the United States and Canada included over 2,600 patients given nizatidine and over 1,700 given placebo. Among the adverse events in these placebo-controlled trials, anemia (0.2% vs 0%) and urticaria (0.5% vs 0.1%) were significantly more common in the nizatidine group.
- Incidence in Placebo-Controlled Clinical Trials in the United States and Canada – Table 5 lists adverse events that occurred at a frequency of 1% or more among nizatidine-treated patients who participated in placebo-controlled trials. The cited figures provide some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.
- A variety of less common events were also reported; it was not possible to determine whether these were caused by nizatidine.
- Hepatocellular injury, evidenced by elevated liver enzyme tests (SGOT/AST, SGPT/ALT, or alkaline phosphatase), occurred in some patients and was possibly or probably related to nizatidine. In some cases there was marked elevation of SGOT, SGPT enzymes (greater than 500 IU/L) and, in a single instance, SGPT was greater than 2,000 IU/L. The overall rate of occurrences of elevated liver enzymes and elevations to 3 times the upper limit of normal, however, did not significantly differ from the rate of liver enzyme abnormalities in placebo-treated patients. All abnormalities were reversible after discontinuation of nizatidine. Since market introduction, hepatitis and jaundice have been reported. Rare cases of cholestatic or mixed hepatocellular and cholestatic injury with jaundice have been reported with reversal of the abnormalities after discontinuation of nizatidine.
- In clinical pharmacology studies, short episodes of asymptomatic ventricular tachycardia occurred in 2 individuals administered nizatidine and in 3 untreated subjects.
- Rare cases of reversible mental confusion have been reported.
- Clinical pharmacology studies and controlled clinical trials showed no evidence of anti-androgenic activity due to nizatidine. Impotence and decreased libido were reported with similar frequency by patients who received nizatidine and by those given placebo. Rare reports of gynecomastia occurred.
- Anemia was reported significantly more frequently in nizatidine- than in placebo-treated patients. Fatal thrombocytopenia was reported in a patient who was treated with nizatidine and another H2-receptor antagonist. On previous occasions, this patient had experienced thrombocytopenia while taking other drugs. Rare cases of thrombocytopenic purpura have been reported.
- Sweating and urticaria were reported significantly more frequently in nizatidine- than in placebo-treated patients. Rash and exfoliative dermatitis were also reported. Vasculitis has been reported rarely.
- As with other H2-receptor antagonists, rare cases of anaphylaxis following administration of nizatidine have been reported. Rare episodes of hypersensitivity reactions (e.g., bronchospasm, laryngeal edema, rash, and eosinophilia) have been reported.
- Serum sickness-like reactions have occurred rarely in conjunction with nizatidine use.
- Reports of impotence have occurred.
- Hyperuricemia unassociated with gout or nephrolithiasis was reported. Eosinophilia, fever, and nausea related to nizatidine administration have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nizatidine in the drug label.
# Drug Interactions
- No interactions have been observed between nizatidine and theophylline, chlordiazepoxide, lorazepam, lidocaine, phenytoin, and warfarin. Nizatidine does not inhibit the cytochrome P-450-linked drug-metabolizing enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are not expected to occur. In patients given very high doses (3,900 mg) of aspirin daily, increases in serum salicylate levels were seen when nizatidine, 150 mg b.i.d., was administered concurrently.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Oral reproduction studies in pregnant rats at doses up to 1500 mg/kg/day (9000 mg/m2/day, 40.5 times the recommended human dose based on body surface area) and in pregnant rabbits at doses up to 275 mg/kg/day (3245 mg/m2/day, 14.6 times the recommended human dose based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus due to nizatidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nizatidine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nizatidine during labor and delivery.
### Nursing Mothers
- Studies conducted in lactating women have shown that 0.1% of the administered oral dose of nizatidine is secreted in human milk in proportion to plasma concentrations. Because of the growth depression in pups reared by lactating rats treated with nizatidine, 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
- Of the 955 patients in clinical studies who were treated with nizatidine, 337 (35.3%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. 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.
- 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 Nizatidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nizatidine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nizatidine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nizatidine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nizatidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nizatidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- 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
# IV Compatibility
There is limited information regarding IV Compatibility of Nizatidine in the drug label.
# Overdosage
- Overdoses of nizatidine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.
- There is little clinical experience with overdosage of nizatidine in humans. Test animals that received large doses of nizatidine have exhibited cholinergic-type effects, including lacrimation, salivation, emesis, miosis, and diarrhea. Single oral doses of 800 mg/kg in dogs and of 1,200 mg/kg in monkeys were not lethal. Intravenous median lethal doses in the rat and mouse were 301 mg/kg and 232 mg/kg respectively.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- If overdosage occurs, use of activated charcoal, emesis, or lavage should be considered along with clinical monitoring and supportive therapy. The ability of hemodialysis to remove nizatidine from the body has not been conclusively demonstrated; however, due to its large volume of distribution, nizatidine is not expected to be efficiently removed from the body by this method.
# Pharmacology
## Mechanism of Action
- Nizatidine is a competitive, reversible inhibitor of histamine at the histamine H2-receptors, particularly those in the gastric parietal cells.
- Effects on Acid Secretion: Nizatidine significantly inhibited nocturnal gastric acid secretion for up to 12 hours. Nizatidine also significantly inhibited gastric acid secretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1).
- Effects on Other Gastrointestinal Secretions – Pepsin: Oral administration of 75 to 300 mg of nizatidine did not affect pepsin activity in gastric secretions. Total pepsin output was reduced in proportion to the reduced volume of gastric secretions.
- Intrinsic Factor: Oral administration of 75 to 300 mg of nizatidine increased betazole-stimulated secretion of intrinsic factor.
- Serum Gastrin: Nizatidine had no effect on basal serum gastrin. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of nizatidine.
- Other Pharmacologic Actions
- Hormones: Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or estradiol.
Nizatidine had no demonstrable antiandrogenic action.
## Structure
- Nizatidine USP is a histamine H2-receptor antagonist. Chemically, it is N-2-2-[(Dimethylamino)methyl]-4-thiazolylmethylthioethyl]-N'-methyl-2-nitro-1,1-ethenediamine. The structural formula is represented below:
- It is an off-white to buff crystalline solid that is soluble in water. Nizatidine has a bitter taste and mild sulfur-like odor. Nizatidine Capsules USP, for oral administration, contain 150 mg or 300 mg nizatidine and the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, magnesium stearate and pregelatinized starch. The capsule shells contain: ammonium hydroxide, black iron oxide, gelatin, potassium hydroxide, propylene glycol, shellac, silicon dioxide, sodium lauryl sulfate and titanium dioxide.
- The 150 mg capsule shell also contains D&C Yellow No. 10 and FD&C Yellow No. 6.
- The 300 mg capsule shell also contains black iron oxide, red iron oxide and yellow iron oxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Nizatidine in the drug label.
## Pharmacokinetics
- The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800 mcg/L for a 150 mg dose and 1,400 to 3,600 mcg/L for a 300 mg dose) occur from 0.5 to 3 hours following the dose. A concentration of 1,000 mcg/L is equivalent to 3 mcmol/L; a dose of 300 mg is equivalent to 905 mcmoles. Plasma concentrations 12 hours after administration are less than 10 mcg/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distribution is 0.8 to 1.5 L/kg. Because of the short half-life and rapid clearance of nizatidine, accumulation of the drug would not be expected in individuals with normal renal function who take either 300 mg once daily at bedtime or 150 mg twice daily. Nizatidine exhibits dose proportionality over the recommended dose range.
- The oral bioavailability of nizatidine is unaffected by concomitant ingestion of propantheline. Antacids consisting of aluminum and magnesium hydroxides with simethicone decrease the absorption of nizatidine by about 10%. With food, the AUC and Cmax increase by approximately 10%.
- In humans, less than 7% of an oral dose is metabolized as N2-monodesmethylnizatidine, an H2-receptor antagonist, which is the principal metabolite excreted in the urine. Other likely metabolites are the N2-oxide (less than 5% of the dose) and the S-oxide (less than 6% of the dose).
- More than 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Renal clearance is about 500 mL/min, which indicates excretion by active tubular secretion. Less than 6% of an administered dose is eliminated in the feces.
- Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. In individuals who are functionally anephric, the half-life is 3.5 to 11 hours, and the plasma clearance is 7 to 14 L/h. To avoid accumulation of the drug in individuals with clinically significant renal impairment, the amount and/or frequency of doses of nizatidine should be reduced in proportion to the severity of dysfunction.
- Approximately 35% of nizatidine is bound to plasma protein, mainly to a1-acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro.
- In multicenter, double-blind, placebo-controlled studies in the United States, endoscopically diagnosed duodenal ulcers healed more rapidly following administration of nizatidine, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2). Lower doses, such as 100 mg h.s., had slightly lower effectiveness.
- Treatment with a reduced dose of nizatidine has been shown to be effective as maintenance therapy following healing of active duodenal ulcers. In multicenter, double-blind, placebo-controlled studies conducted in the United States, 150 mg of nizatidine taken at bedtime resulted in a significantly lower incidence of duodenal ulcer recurrence in patients treated for up to 1 year (Table 3).
- In 2 multicenter, double-blind, placebo-controlled clinical trials performed in the United States and Canada, nizatidine was more effective than placebo in improving endoscopically diagnosed esophagitis and in healing erosive and ulcerative esophagitis.
- In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of nizatidine given to 88 patients compared with placebo in 98 patients in Study 1 yielded a higher healing rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P<0.05). Of 99 patients on nizatidine and 94 patients on placebo, Study 2 at the same dosage yielded similar results at 6 weeks (21% vs 11%, P <0.05) and at 12 weeks (29% vs 13%, P<0.01).
- In addition, relief of associated heartburn was greater in patients treated with nizatidine. Patients treated with nizatidine consumed fewer antacids than did patients treated with placebo.
- In a multicenter, double-blind, placebo-controlled study conducted in the United States and Canada, endoscopically diagnosed benign gastric ulcers healed significantly more rapidly following administration of nizatidine than of placebo (Table 4).
- P-values are one-sided, obtained by Chi-square test, and not adjusted for multiple comparisons.
- In a multicenter, double-blind, comparator-controlled study in Europe, healing rates for patients receiving nizatidine (300 mg h.s. or 150 mg b.i.d.) were equivalent to rates for patients receiving a comparator drug, and statistically superior to historical placebo control rates.
## Nonclinical Toxicology
- A 2-year oral carcinogenicity study in rats with doses as high as 500 mg/kg/day (about 80 times the recommended daily therapeutic dose) showed no evidence of a carcinogenic effect. There was a dose-related increase in the density of enterochromaffin-like (ECL) cells in the gastric oxyntic mucosa. In a 2-year study in mice, there was no evidence of a carcinogenic effect in male mice; although hyperplastic nodules of the liver were increased in the high-dose males as compared with placebo. Female mice given the high dose of nizatidine (2,000 mg/kg/day, about 330 times the human dose) showed marginally statistically significant increases in hepatic carcinoma and hepatic nodular hyperplasia with no numerical increase seen in any of the other dose groups. The rate of hepatic carcinoma in the high-dose animals was within the historical control limits seen for the strain of mice used. The female mice were given a dose larger than the maximum tolerated dose, as indicated by excessive (30%) weight decrement as compared with concurrent controls and evidence of mild liver injury (transaminase elevations). The occurrence of a marginal finding at high dose only in animals given an excessive and somewhat hepatotoxic dose, with no evidence of a carcinogenic effect in rats, male mice, and female mice (given up to 360 mg/kg/day, about 60 times the human dose), and a negative mutagenicity battery are not considered evidence of a carcinogenic potential for nizatidine.
- Nizatidine was not mutagenic in a battery of tests performed to evaluate its potential genetic toxicity, including bacterial mutation tests, unscheduled DNA synthesis, sister chromatid exchange, the mouse lymphoma assay, chromosome aberration tests, and a micronucleus test.
- In a 2-generation, perinatal and postnatal fertility study in rats, doses of nizatidine up to 650 mg/kg/day produced no adverse effects on the reproductive performance of parental animals or their progeny.
# Clinical Studies
There is limited information regarding Clinical Studies of Nizatidine in the drug label.
# How Supplied
- Nizatidine Capsules USP, 150 mg are #2, buff opaque capsules imprinted WPI and 3137 supplied in bottles of 60.
- Nizatidine Capsules USP, 300 mg are #0, light brown opaque capsules imprinted WPI and 3138 supplied in bottles of 30.
## Storage
- Store at 20°-25°C (68°-77°F).
- Dispense in a tight, light-resistant container as defined in the USP.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL 150 MG
NDC 0591-3137-60
Nizatidine
Capsules USP
150 mg
Watson® 60 Capsules Rx only
Each capsule contains:
Nizatidine USP, 150 mg
Usual adult dosage. See package insert for
dosage and full prescribing information.
Dispense in a tight, light-resistant
container as defined in the USP.
Store at 20º-25ºC (68º-77ºF).
[See USP controlled room temperature.]
Manufactured By:
Watson Pharma Private Limited
Verna, Salcette Goa 403 722 INDIA
Code No. GO/DRUGS/741 190936
Distributed By: Watson Pharma, Inc.
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Nizatidine in the drug label.
# Precautions with Alcohol
- Alcohol-Nizatidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Axid®[3]
# Look-Alike Drug Names
There is limited information regarding Nizatidine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nizatidine | |
06b9f7ed4e70ed8f75c845c54b8591dcd58b5e87 | wikidoc | Nociceptin | Nociceptin
Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor (NOP, ORL-1), and initiates its function to act on numerous brain activities such as pain sensation and fear learning. It is derived from the prepronociceptin protein, as are a further 2 peptides, nocistatin & NocII, which inhibit the N/OFQ receptor function. Nociceptin itself acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers. The gene coding for prepronociceptin is located on Ch8p21 in humans. Nociceptin acts at the Nociceptin receptor (NOP receptor) formerly known as ORL1. Nociceptin is the first example of reverse pharmacology; the NOP receptor was discovered before the endogenous ligand which was discovered by two separate groups in 1995.
# Roles of Nociceptin
Since its discovery, nociceptin has been of great interest to researchers. Nociceptin is a peptide related to the opioid class of compounds (ex. morphine and codeine), but it does not act at the classic opioid receptors (namely, mu, kappa, and delta opioid receptors) which typically act as pain relievers. Nociceptin is widely distributed in the CNS; it is found in the hypothalamus, brainstem, and forebrain, as well as in the ventral and dorsal horns of the spinal cord. The NOP receptor is also widely distributed throughout areas of the brain, including the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, and spinal cord.
## Pain
The N/OFQ-NOP system is found in central and peripheral nervous tissue, where it is well placed to modulate nociception, or the body's sensation of pain. Unlike morphine and other opioids that are used to alleviate pain, nociceptin's role in nociception is not straightforward. Administration of N/OFQ in the brain causes increased sensations of pain (hyperalgesia). This makes it unique from classic opioid peptides, which typically act as analgesics (pain relievers), as it means that nociceptin can even counteract analgesia, thus acting as an antiopioid. Additionally, blocking the nociceptin receptor can lead to an increased pain threshold and a decreased tolerance development to analgesic opioids. As such, nociceptin has a lower risk of addiction than many pain relievers that are currently used. Recent studies have proposed that this anti-analgesic function of nociceptin stems from the inhibition of the periaqueductal grey, which controls pain modulation from the central nervous system. This effect of nociceptin may lead to its future use as a method to reduce morphine dosage and decrease the development of tolerance and dependence. When administered to the spinal cord, nociceptin produces similar analgesic effects to classical opioids.
## Mood Disorders
There are various studies on animals that suggest that the N/OFQ-NOP system has a part to play in both anxiety and depression. It appears that nociceptin is an anxiolytic (anxiety inhibitor) but also seems to perpetuate depression, since preventing N/OFQ from binding to NOP seems to improve depression.
## Drug Abuse Medications
The NOP receptor has shown potential as a target for medications designed to alleviate the effects of substance abuse disorders. Areas in the hypothalamus and amygdala that correlate to the reward process of drug abuse have been found to contain NOP receptors. Nociceptin has also been found to inhibit dopamine production related to the reward process. Specifically, nociceptin acts to inhibit neural rewards induced by drugs such as amphetamines, morphine, cocaine, and especially alcohol in animal models, though the exact mechanism of this has not yet been proven. Additionally, nociceptin may have lower tolerance development than drugs such as morphine. This was shown when nociceptin compounds were used as a pain medication substitution for morphine. Nociceptin also has therapeutic capabilities for addictions to multiple drugs, potentially playing a role in compounds that have decreased withdrawal tendencies (such as muscle aches, anxiety, and restlessness).
## Learning and Memory
In animal studies, the N/OFQ-NOP receptor pathway has also been found to play both positive and negative roles in both learning and memory. For example, malfunctions in this pathway are linked to altered fear learning in brain disorders such as post-traumatic stress disorder (PTSD). As such, the receptor pathway maintains homeostatic responses to fear and stressful situations. Nociceptin could also play an inhibitory role in memory function, as some studies show that it impairs spatial learning in vivo, while inhibiting long term potentiation and synaptic transmission in vitro.
## Cardiovascular System
The N/OFQ-NOP system has also been implicated in control of the cardiovascular system, as nociceptin administration has led to high blood pressure and bradycardia. Nociceptin has significant effects on cardiovascular parameters such as blood pressure and heart rate that vary by species, as it is excitatory for rodents yet inhibitory for sheep.
## Renal System
In the renal system, nociceptin plays a role in water balance, electrolyte balance, and arterial blood pressure regulation. It has also shown potential as a diuretic treatment for alleviating water-retaining diseases.
## Immune System
Additional research suggests that nociceptin may be involved in the immune system and sepsis. A study at the University of Leicester looked at patients who were critically ill with sepsis and found that blood N/OFQ levels were significantly higher in patients who died within thirty days in comparison to survivors.
## Digestive System
In the gut, nociceptin has been found to have varying effects on stomach and intestinal contractility while also stimulating the increased consumption of food. Additional studies have shown that nociceptin may have an effect as an anti-epileptic drug component. | Nociceptin
Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor (NOP, ORL-1), and initiates its function to act on numerous brain activities such as pain sensation and fear learning. It is derived from the prepronociceptin protein, as are a further 2 peptides, nocistatin & NocII, which inhibit the N/OFQ receptor function.[1] Nociceptin itself acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers. The gene coding for prepronociceptin is located on Ch8p21 in humans.[2] Nociceptin acts at the Nociceptin receptor (NOP receptor) formerly known as ORL1. Nociceptin is the first example of reverse pharmacology; the NOP receptor was discovered before the endogenous ligand which was discovered by two separate groups in 1995.[3]
# Roles of Nociceptin
Since its discovery, nociceptin has been of great interest to researchers. Nociceptin is a peptide related to the opioid class of compounds (ex. morphine and codeine), but it does not act at the classic opioid receptors (namely, mu, kappa, and delta opioid receptors) which typically act as pain relievers. Nociceptin is widely distributed in the CNS; it is found in the hypothalamus, brainstem, and forebrain, as well as in the ventral and dorsal horns of the spinal cord. The NOP receptor is also widely distributed throughout areas of the brain, including the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, and spinal cord.[4]
## Pain
The N/OFQ-NOP system is found in central and peripheral nervous tissue, where it is well placed to modulate nociception, or the body's sensation of pain.[2] Unlike morphine and other opioids that are used to alleviate pain, nociceptin's role in nociception is not straightforward. Administration of N/OFQ in the brain causes increased sensations of pain (hyperalgesia).[3] This makes it unique from classic opioid peptides, which typically act as analgesics (pain relievers), as it means that nociceptin can even counteract analgesia, thus acting as an antiopioid. Additionally, blocking the nociceptin receptor can lead to an increased pain threshold and a decreased tolerance development to analgesic opioids. As such, nociceptin has a lower risk of addiction than many pain relievers that are currently used.[5] Recent studies have proposed that this anti-analgesic function of nociceptin stems from the inhibition of the periaqueductal grey, which controls pain modulation from the central nervous system. This effect of nociceptin may lead to its future use as a method to reduce morphine dosage and decrease the development of tolerance and dependence.[4] When administered to the spinal cord, nociceptin produces similar analgesic effects to classical opioids.[6]
## Mood Disorders
There are various studies on animals that suggest that the N/OFQ-NOP system has a part to play in both anxiety and depression.[7] It appears that nociceptin is an anxiolytic (anxiety inhibitor) but also seems to perpetuate depression, since preventing N/OFQ from binding to NOP seems to improve depression.[8][9]
## Drug Abuse Medications
The NOP receptor has shown potential as a target for medications designed to alleviate the effects of substance abuse disorders. Areas in the hypothalamus and amygdala that correlate to the reward process of drug abuse have been found to contain NOP receptors. Nociceptin has also been found to inhibit dopamine production related to the reward process. Specifically, nociceptin acts to inhibit neural rewards induced by drugs such as amphetamines, morphine, cocaine, and especially alcohol in animal models, though the exact mechanism of this has not yet been proven. Additionally, nociceptin may have lower tolerance development than drugs such as morphine. This was shown when nociceptin compounds were used as a pain medication substitution for morphine. Nociceptin also has therapeutic capabilities for addictions to multiple drugs, potentially playing a role in compounds that have decreased withdrawal tendencies (such as muscle aches, anxiety, and restlessness).[5]
## Learning and Memory
In animal studies, the N/OFQ-NOP receptor pathway has also been found to play both positive and negative roles in both learning and memory. For example, malfunctions in this pathway are linked to altered fear learning in brain disorders such as post-traumatic stress disorder (PTSD). As such, the receptor pathway maintains homeostatic responses to fear and stressful situations.[10] Nociceptin could also play an inhibitory role in memory function, as some studies show that it impairs spatial learning in vivo, while inhibiting long term potentiation and synaptic transmission in vitro.[4]
## Cardiovascular System
The N/OFQ-NOP system has also been implicated in control of the cardiovascular system, as nociceptin administration has led to high blood pressure and bradycardia. Nociceptin has significant effects on cardiovascular parameters such as blood pressure and heart rate that vary by species, as it is excitatory for rodents yet inhibitory for sheep.[4]
## Renal System
In the renal system, nociceptin plays a role in water balance, electrolyte balance, and arterial blood pressure regulation. It has also shown potential as a diuretic treatment for alleviating water-retaining diseases.[4]
## Immune System
Additional research suggests that nociceptin may be involved in the immune system and sepsis.[11] A study at the University of Leicester looked at patients who were critically ill with sepsis and found that blood N/OFQ levels were significantly higher in patients who died within thirty days in comparison to survivors.[12]
## Digestive System
In the gut, nociceptin has been found to have varying effects on stomach and intestinal contractility while also stimulating the increased consumption of food. Additional studies have shown that nociceptin may have an effect as an anti-epileptic drug component.[4] | https://www.wikidoc.org/index.php/Nociceptin | |
46bf4a25da6d8df8ee4054ea54d82cff61cf1753 | wikidoc | Nociceptor | Nociceptor
# Overview
A nociceptor is a sensory receptor that sends signals that cause the perception of pain in response to potentially damaging stimulus. Nociceptors are the nerve endings responsible for nociception, one of the two types of persistent pain (the other, neuropathic pain, occurs when nerves in the central or peripheral nervous system are not functioning properly). When they are activated, nociceptors can trigger a reflex.
# Location
Nociceptors are sensory neurons that are found in external tissues such as skin, cornea and mucosa as well as in internal organs, such as the muscle, joint, bladder and gut. The cell bodies of these neurons are located in either the dorsal root ganglia or the trigeminal ganglia.
# Types and functions
There are several types of nociceptors and they are classified according to the stimulus modalities to which they respond: i.e. thermal, mechanical or chemical. Some nociceptors respond to more than one of these modalities and are consequently designated polymodal. Other nociceptors respond to none of these modalities (although they may respond to stimulation under conditions of inflammation) and have thereby earned the more poetic title of sleeping or silent nociceptors (Kandel et al, 2000). Thermal nociceptors are activated by noxious heat or cold, temperatures above 45°C and below 5°C (Kandel et al, 2000). Mechanical nociceptors respond to excess pressure or mechanical deformation. Polymodal nociceptors respond to damaging stimuli of a chemical, thermal, or mechanical nature (Kandel et al, 2000). Nociceptors may have either Aδ fiber axons or more slowly conducting C fiber axons. Thus, pain often comes in two phases, the first mediated by the fast-conducting Aδ fibers and the second part due to C fibers. Silent nociceptors do not usually fire action potentials, though they are much more likely to do so in the presence of inflammation or damaging chemicals (Kandel et al, 2000). Together these nociceptors allow the organism to feel pain in response to damaging pressure, excessive heat, excessive cold and a range of chemicals, the majority of which are damaging to the tissue surrounding the nociceptor.
# Pathway
Afferent nociceptive fibers (those that send information to, rather than from the brain) travel back to the spinal cord where they form synapses in its dorsal horn. The cells in the dorsal horn are divided into physiologically distinct layers called laminae. Different fiber types form synapses in different layers. Aδ fibers form synapses in laminae I and V, C fibers connect with neurons in lamina II, Aβ fibers connect with lamina I, III, & V. Information is then sent from the spinal cord to the thalamus and the cerebral cortex in the brain. | Nociceptor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A nociceptor is a sensory receptor that sends signals that cause the perception of pain in response to potentially damaging stimulus. Nociceptors are the nerve endings responsible for nociception, one of the two types of persistent pain (the other, neuropathic pain, occurs when nerves in the central or peripheral nervous system are not functioning properly). When they are activated, nociceptors can trigger a reflex.
# Location
Nociceptors are sensory neurons that are found in external tissues such as skin, cornea and mucosa as well as in internal organs, such as the muscle, joint, bladder and gut. The cell bodies of these neurons are located in either the dorsal root ganglia or the trigeminal ganglia.
# Types and functions
There are several types of nociceptors and they are classified according to the stimulus modalities to which they respond: i.e. thermal, mechanical or chemical. Some nociceptors respond to more than one of these modalities and are consequently designated polymodal. Other nociceptors respond to none of these modalities (although they may respond to stimulation under conditions of inflammation) and have thereby earned the more poetic title of sleeping or silent nociceptors (Kandel et al, 2000). Thermal nociceptors are activated by noxious heat or cold, temperatures above 45°C and below 5°C (Kandel et al, 2000). Mechanical nociceptors respond to excess pressure or mechanical deformation. Polymodal nociceptors respond to damaging stimuli of a chemical, thermal, or mechanical nature (Kandel et al, 2000). Nociceptors may have either Aδ fiber axons or more slowly conducting C fiber axons. Thus, pain often comes in two phases, the first mediated by the fast-conducting Aδ fibers and the second part due to C fibers. Silent nociceptors do not usually fire action potentials, though they are much more likely to do so in the presence of inflammation or damaging chemicals (Kandel et al, 2000). Together these nociceptors allow the organism to feel pain in response to damaging pressure, excessive heat, excessive cold and a range of chemicals, the majority of which are damaging to the tissue surrounding the nociceptor.
# Pathway
Afferent nociceptive fibers (those that send information to, rather than from the brain) travel back to the spinal cord where they form synapses in its dorsal horn. The cells in the dorsal horn are divided into physiologically distinct layers called laminae. Different fiber types form synapses in different layers. Aδ fibers form synapses in laminae I and V, C fibers connect with neurons in lamina II, Aβ fibers connect with lamina I, III, & V. Information is then sent from the spinal cord to the thalamus and the cerebral cortex in the brain. | https://www.wikidoc.org/index.php/Nociceptor | |
7819ebad5f4d0b1d37f20f5b4fa76e7f6485797e | wikidoc | Non-linear | Non-linear
In mathematics, a nonlinear system is a system which is not linear, i.e. a system which does not satisfy the superposition principle. Less technically, a nonlinear system is any problem where the variable(s) to be solved for cannot be written as a linear sum of independent components. A nonhomogenous system, which is linear apart from the presence of a function of the independent variables, is nonlinear according to a strict definition, but such systems are usually studied alongside linear systems, because they can be transformed to a linear system as long as a particular solution is known.
Generally, nonlinear problems are difficult (if possible) to solve and are much less understandable than linear problems. Even if not exactly solvable, the outcome of a linear problem is rather predictable, while the outcome of a nonlinear is inherently not.
Nonlinear problems are of interest to physicists and mathematicians because most physical systems are inherently nonlinear in nature. Physical examples of linear systems are not very common. Nonlinear equations are difficult to solve and give rise to interesting phenomena such as chaos. The weather is famously nonlinear, where simple changes in one part of the system produce complex effects throughout.
# Definition
In mathematics, a linear function (or map) f(x) is one which satisfies both of the following properties:
- Additivity: f(x + y) = f(x) + f(y)\,
- Homogeneity: f(\alpha x) = \alpha f(x)\,
An equation written as
is called linear if f(x) is linear (as defined above) and nonlinear otherwise. Note that x does not need to be a scalar (can be a vector, function, etc), and that C must not depend on x. The equation is called homogeneous if C = 0.
# Nonlinear algebraic equations
Generally, nonlinear algebraic problems are often exactly solvable, and if not they usually can be thoroughly understood through qualitative and numeric analysis. As an example, the equation
may be written as
and is nonlinear because f(x) satisfies neither additivity nor homogeneity (the nonlinearity is due to the x^2). Though nonlinear, this simple example may be solved exactly (via the quadratic formula) and is very well understood. On the other hand, the nonlinear equation
is not exactly solvable (see quintic equation), though it may be qualitatively analyzed and is well understood, for example through making a graph and examining the roots of f(x) - C = 0.
# Nonlinear recurrence relations
A nonlinear recurrence relation defines successive terms of a sequence as a nonlinear function of preceding terms. Examples of nonlinear recurrence relations are the logistic map and the relations that define the various Hofstadter sequences.
# Nonlinear differential equations
Problems involving nonlinear differential equations are extremely diverse, and methods of solution or analysis are very problem dependent.
One of the greatest difficulties of nonlinear problems is that it is not generally possible to combine known solutions into new solutions. In linear problems, for example, a family of linearly independent solutions can be used to construct general solutions through the superposition principle. A good example of this is one-dimensional heat transport with Dirichlet boundary conditions, the solution of which can be written as a time-dependent linear combination of sinusoids of differing frequencies, this makes solutions very flexible. It is often possible to find several very specific solutions to nonlinear equations, however the lack of a superposition principle prevents the construction of new solutions.
## Ordinary differential equations
First order ordinary differential equations are often exactly solvable by separation of variables, especially for autonomous equations. For example, the nonlinear equation
will easily yield u = (x + C)^{-1} as a general solution which happens to be simpler than the solution to the linear equation du/dx = -u. The equation is nonlinear because it may be written as
and the left-hand side of the equation is not a linear function of u and its derivatives. Note that if the u² term were replaced with u, the problem would be linear (the exponential decay problem).
Second and higher order ordinary differential equations (more generally, systems of nonlinear equations) rarely yield closed form solutions, though implicit solutions and solutions involving nonelementary integrals are encountered.
Common methods for the qualitative analysis of nonlinear ordinary differential equations include:
- Examination of any conserved quantities, especially in Hamiltonian systems.
- Examination of dissipative quantities (see Lyapunov function) analogous to conserved quantities.
- Linearization via Taylor expansion.
- Change of variables into something easier to study.
- Bifurcation theory.
- Perturbation methods (can be applied to algebraic equations too).
## Partial differential equations
The most common basic approach to studying nonlinear partial differential equations is to change the variables (or otherwise transform the problem) so that the resulting problem is simpler (possibly even linear). Sometimes, the equation may be transformed into one or more ordinary differential equations, as seen in the similarity transform or separation of variables, which is always useful whether or not the resulting ordinary differential equation(s) is solvable.
Another common (though less mathematic) tactic, often seen in fluid and heat mechanics, is to use scale analysis to simplify a general, natural equation in a certain specific boundary value problem. For example, the (very) nonlinear Navier-Stokes equations can be simplified into one linear partial differential equation in the case of transient, laminar, one dimensional flow in a circular pipe; the scale analysis provides conditions under which the flow is laminar and one dimensional and also yields the simplified equation.
Other methods include examining the characteristics and using the methods outlined above for ordinary differential equations.
## Example: pendulum
A classic, extensively studied nonlinear problem is the dynamics of a pendulum. Using Lagrangian mechanics, it may be shown that the motion of a pendulum can be described by the dimensionless nonlinear equation
where gravity is "down" and \theta is as shown in the figure at right. One approach to "solving" this equation is to use \scriptstyle \frac{d \theta}{d t} as an integrating factor, which would eventually yield
which is an implicit solution involving an elliptic integral. This "solution" generally does not have many uses because most of the nature of the solution is hidden in the nonelementary integral (nonelementary even if C_0 = 0).
Another way to approach the problem is to linearize any nonlinearities (the sine function term in this case) at the various points of interest through Taylor expansions. For example, the linearization at \theta = 0, called the small angle approximation, is
since \sin(\theta) \approx \theta for \theta \approx 0. This is a simple harmonic oscillator corresponding to oscillations of the pendulum near the bottom of its path. Another linearization would be at \theta = \pi, corresponding to the pendulum being straight up:
since \sin(\theta) \approx \pi - \theta for \theta \approx \pi. The solution to this problem involves hyperbolic sinusoids, and note that unlike the small angle approximation, this approximation is unstable, meaning that |\theta| will usually grow without limit, though bounded solutions are possible. This corresponds to the difficulty of balancing a pendulum upright, it is literally an unstable state.
One more interesting linearization is possible around \theta = \pi/2, around which \sin(\theta) \approx 1:
This corresponds to a free fall problem. A very useful qualitative picture of the pendulum's dynamics may be obtained by piecing together such linearizations, as seen in the figure at right. Other techniques may be used to find (exact) phase portraits and approximate periods.
# Metaphorical use
Engineers often use the term nonlinear to refer to irrational behavior, with the implication that the person who has become nonlinear is on the edge of losing control or even having a nervous breakdown.
# Types of nonlinear behaviors
- Indeterminism - the behavior of a system cannot be predicted.
- Multistability - alternating between two or more exclusive states.
- Aperiodic oscillations - functions that do not repeat values after some period (otherwise known as chaotic oscillations or chaos).
# Examples of nonlinear equations
- AC power flow model
- Bellman equation for optimal policy
- Boltzmann transport equation
- General relativity
- Ginzburg-Landau equation
- Navier-Stokes equations of fluid dynamics
- Korteweg–de Vries equation
- nonlinear optics
- nonlinear Schrödinger equation
- Richards equation for unsaturated water flow
- Robot unicycle balancing
- Sine-Gordon equation
- Landau-Lifshitz equation
- Ishimori equation
See also the list of non-linear partial differential equations | Non-linear
In mathematics, a nonlinear system is a system which is not linear, i.e. a system which does not satisfy the superposition principle. Less technically, a nonlinear system is any problem where the variable(s) to be solved for cannot be written as a linear sum of independent components. A nonhomogenous system, which is linear apart from the presence of a function of the independent variables, is nonlinear according to a strict definition, but such systems are usually studied alongside linear systems, because they can be transformed to a linear system as long as a particular solution is known.
Generally, nonlinear problems are difficult (if possible) to solve and are much less understandable than linear problems. Even if not exactly solvable, the outcome of a linear problem is rather predictable, while the outcome of a nonlinear is inherently not.
Nonlinear problems are of interest to physicists and mathematicians because most physical systems are inherently nonlinear in nature. Physical examples of linear systems are not very common. Nonlinear equations are difficult to solve and give rise to interesting phenomena such as chaos. The weather is famously nonlinear, where simple changes in one part of the system produce complex effects throughout.
# Definition
In mathematics, a linear function (or map) <math>f(x)</math> is one which satisfies both of the following properties:
- Additivity: <math>f(x + y) = f(x) + f(y)\,</math>
- Homogeneity: <math>f(\alpha x) = \alpha f(x)\,</math>
An equation written as
is called linear if <math>f(x)</math> is linear (as defined above) and nonlinear otherwise. Note that <math>x</math> does not need to be a scalar (can be a vector, function, etc), and that <math>C</math> must not depend on <math>x</math>. The equation is called homogeneous if <math>C = 0</math>.
# Nonlinear algebraic equations
Generally, nonlinear algebraic problems are often exactly solvable, and if not they usually can be thoroughly understood through qualitative and numeric analysis. As an example, the equation
may be written as
and is nonlinear because <math>f(x)</math> satisfies neither additivity nor homogeneity (the nonlinearity is due to the <math>x^2</math>). Though nonlinear, this simple example may be solved exactly (via the quadratic formula) and is very well understood. On the other hand, the nonlinear equation
is not exactly solvable (see quintic equation), though it may be qualitatively analyzed and is well understood, for example through making a graph and examining the roots of <math>f(x) - C = 0</math>.
# Nonlinear recurrence relations
A nonlinear recurrence relation defines successive terms of a sequence as a nonlinear function of preceding terms. Examples of nonlinear recurrence relations are the logistic map and the relations that define the various Hofstadter sequences.
# Nonlinear differential equations
Problems involving nonlinear differential equations are extremely diverse, and methods of solution or analysis are very problem dependent.
One of the greatest difficulties of nonlinear problems is that it is not generally possible to combine known solutions into new solutions. In linear problems, for example, a family of linearly independent solutions can be used to construct general solutions through the superposition principle. A good example of this is one-dimensional heat transport with Dirichlet boundary conditions, the solution of which can be written as a time-dependent linear combination of sinusoids of differing frequencies, this makes solutions very flexible. It is often possible to find several very specific solutions to nonlinear equations, however the lack of a superposition principle prevents the construction of new solutions.
## Ordinary differential equations
First order ordinary differential equations are often exactly solvable by separation of variables, especially for autonomous equations. For example, the nonlinear equation
will easily yield <math>u = (x + C)^{-1}</math> as a general solution which happens to be simpler than the solution to the linear equation <math>du/dx = -u</math>. The equation is nonlinear because it may be written as
and the left-hand side of the equation is not a linear function of u and its derivatives. Note that if the u² term were replaced with u, the problem would be linear (the exponential decay problem).
Second and higher order ordinary differential equations (more generally, systems of nonlinear equations) rarely yield closed form solutions, though implicit solutions and solutions involving nonelementary integrals are encountered.
Common methods for the qualitative analysis of nonlinear ordinary differential equations include:
- Examination of any conserved quantities, especially in Hamiltonian systems.
- Examination of dissipative quantities (see Lyapunov function) analogous to conserved quantities.
- Linearization via Taylor expansion.
- Change of variables into something easier to study.
- Bifurcation theory.
- Perturbation methods (can be applied to algebraic equations too).
## Partial differential equations
The most common basic approach to studying nonlinear partial differential equations is to change the variables (or otherwise transform the problem) so that the resulting problem is simpler (possibly even linear). Sometimes, the equation may be transformed into one or more ordinary differential equations, as seen in the similarity transform or separation of variables, which is always useful whether or not the resulting ordinary differential equation(s) is solvable.
Another common (though less mathematic) tactic, often seen in fluid and heat mechanics, is to use scale analysis to simplify a general, natural equation in a certain specific boundary value problem. For example, the (very) nonlinear Navier-Stokes equations can be simplified into one linear partial differential equation in the case of transient, laminar, one dimensional flow in a circular pipe; the scale analysis provides conditions under which the flow is laminar and one dimensional and also yields the simplified equation.
Other methods include examining the characteristics and using the methods outlined above for ordinary differential equations.
## Example: pendulum
A classic, extensively studied nonlinear problem is the dynamics of a pendulum. Using Lagrangian mechanics, it may be shown[1] that the motion of a pendulum can be described by the dimensionless nonlinear equation
where gravity is "down" and <math>\theta</math> is as shown in the figure at right. One approach to "solving" this equation is to use <math>\scriptstyle \frac{d \theta}{d t}</math> as an integrating factor, which would eventually yield
which is an implicit solution involving an elliptic integral. This "solution" generally does not have many uses because most of the nature of the solution is hidden in the nonelementary integral (nonelementary even if <math>C_0 = 0</math>).
Another way to approach the problem is to linearize any nonlinearities (the sine function term in this case) at the various points of interest through Taylor expansions. For example, the linearization at <math>\theta = 0</math>, called the small angle approximation, is
since <math>\sin(\theta) \approx \theta</math> for <math>\theta \approx 0</math>. This is a simple harmonic oscillator corresponding to oscillations of the pendulum near the bottom of its path. Another linearization would be at <math>\theta = \pi</math>, corresponding to the pendulum being straight up:
since <math>\sin(\theta) \approx \pi - \theta</math> for <math>\theta \approx \pi</math>. The solution to this problem involves hyperbolic sinusoids, and note that unlike the small angle approximation, this approximation is unstable, meaning that <math>|\theta|</math> will usually grow without limit, though bounded solutions are possible. This corresponds to the difficulty of balancing a pendulum upright, it is literally an unstable state.
One more interesting linearization is possible around <math>\theta = \pi/2</math>, around which <math>\sin(\theta) \approx 1</math>:
This corresponds to a free fall problem. A very useful qualitative picture of the pendulum's dynamics may be obtained by piecing together such linearizations, as seen in the figure at right. Other techniques may be used to find (exact) phase portraits and approximate periods.
# Metaphorical use
Engineers often use the term nonlinear to refer to irrational behavior, with the implication that the person who has become nonlinear is on the edge of losing control or even having a nervous breakdown.
# Types of nonlinear behaviors
- Indeterminism - the behavior of a system cannot be predicted.
- Multistability - alternating between two or more exclusive states.
- Aperiodic oscillations - functions that do not repeat values after some period (otherwise known as chaotic oscillations or chaos).
# Examples of nonlinear equations
- AC power flow model
- Bellman equation for optimal policy
- Boltzmann transport equation
- General relativity
- Ginzburg-Landau equation
- Navier-Stokes equations of fluid dynamics
- Korteweg–de Vries equation
- nonlinear optics
- nonlinear Schrödinger equation
- Richards equation for unsaturated water flow
- Robot unicycle balancing
- Sine-Gordon equation
- Landau-Lifshitz equation
- Ishimori equation
See also the list of non-linear partial differential equations | https://www.wikidoc.org/index.php/Non-linear | |
9ed2e56a349e4bbf5ff46ed955b44efe1e4c3b89 | wikidoc | Vecuronium | Vecuronium
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# Black Box Warning
# Overview
Vecuronium is a skeletal muscle relaxant, neuromuscular blocking drugs that is FDA approved for the prophylaxis of anesthesia, during surgery as an adjunct to general anesthesia to facilitate tracheal intubation or mechanical ventilation; adjunct.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include immunologic: anaphylaxis, hypersensitivity reaction, musculoskeletal: muscle weakness, Prolonged neuromuscular block,respiratory: bronchospasm.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage must be individualized
### Anesthesia, During surgery as an adjunct to general anesthesia to facilitate tracheal intubation or mechanical ventilation; Adjunct
- Initial
- 0.08-0.1 mg/kg IV bolus
- Maintenance
- 0.01-0.015 mg/kg IV 25-40 min after initial dose, repeat every 12-15 min as needed
- 1 mcg/kg/min continuous IV infusion 20-40 min after initial intubation dose, after early evidence of spontaneous recovery; then adjust to maintain 90% suppression of twitch response; range 0.8-1.2 mcg/kg/min
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vecuronium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vecuronium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness not established in pediatric patients 7 weeks of age or younger
### Anesthesia, During surgery as an adjunct to general anesthesia to facilitate tracheal intubation or mechanical ventilation; Adjunct
- (age 8 weeks-1 yr)
- More sensitive on a mg/kg basis than adults and recovery may take 1.5 times longer
- (age 1-10 yr)
- Dosage must be individualized; may require slightly higher initial dose and slightly more frequent supplemental doses than adults
- (age 10-16 yr)
- Initial, 0.08-0.1 mg/kg IV bolus
- Maintenance, 0.01-0.015 mg/kg IV 25-40 min after initial dose, repeat every 12-15 min as needed; may require more frequent supplementation than adults
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vecuronium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vecuronium in pediatric patients.
# Contraindications
- Vecuronium bromide is contraindicated in patients known to have a hypersensitivity to it.
# Warnings
- Vecuronium should be administered in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with its actions and the possible complications that might occur following its use. the drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available. the clinician must be prepared to assist or control respiration. to reduce the possibility of prolonged neuromuscular blockade and other possible complications that might occur following long-term use in the icu, vecuronium or any other neuromuscular blocking agent should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and who are familiar with appropriate peripheral nerve stimulator muscle monitoring techniques (see Precautions).
- In patients who are known to have myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of vecuronium may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.
### Anaphylaxis
- Severe anaphylactic reactions to neuromuscular blocking agents, including vecuronium bromide, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reaction to nondepolarizing blocking agents as a class consists of an extension of the drug's pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiration insufficiency or apnea.
- Inadequate reversal of the neuromuscular blockade is possible with vecuronium bromide as with all curariform drugs. These adverse reactions are managed by manual or mechanical ventilation until recovery is judged adequate. Little or no increase in intensity of blockade or duration of action with vecuronium bromide is noted from the use of thiobarbiturates, narcotic analgesics, nitrous oxide, or droperidol. See Overdosage for discussion of other drugs used in anesthetic practice which also cause respiratory depression.
- Prolonged to profound extensions of paralysis and/or muscle weakness as well as muscle atrophy have been reported after long-term use to support mechanical ventilation in the intensive care unit (see Precautions). The administration of vecuronium bromide has been associated with rare instances of hypersensitivity reactions (bronchospasm, hypotension and/or tachycardia, sometimes associated with acute urticaria or erythema); (see also Clinical pharmacology).
- There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including vecuronium bromide. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (See Warnings and Precautions).
## Postmarketing Experience
There is limited information regarding Vecuronium Postmarketing Experience in the drug label.
# Drug Interactions
- Prior administration of succinylcholine may enhance the neuromuscular blocking effect of vecuronium and its duration of action. If succinylcholine is used before vecuronium, the administration of vecuronium should be delayed until the succinylcholine effect shows signs of wearing off. With succinylcholine as the intubating agent, initial doses of 0.04 to 0.06 mg/kg of vecuronium may be administered to produce complete neuromuscular block with clinical duration of action of 25 to 30 minutes (see Clinical Pharmacology).
- The use of vecuronium before succinylcholine, in order to attenuate some of the side effects of succinylcholine, has not been sufficiently studied.
- Other nondepolarizing neuromuscular blocking agents (pancuronium, d-tubocurarine, metocurine, and gallamine) act in the same fashion as does vecuronium, therefore, these drugs and vecuronium, may manifest an additive effect when used together. There are insufficient data to support concomitant use of vecuronium and other competitive muscle relaxants in the same patient.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with vecuronium. It is also not known whether vecuronium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vecuronium should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vecuronium in women who are pregnant.
### Labor and Delivery
- The use of vecuronium in patients undergoing cesarean section has been reported in the literature. Following tracheal intubation with succinylcholine, vecuronium dosages of 0.04 mg/kg (n=11) and 0.06 to 0.08 mg/kg (n=20) were administered. The umbilical venous plasma concentrations were 11% of maternal concentrations at delivery and mean neonate APGAR scores at 5 minutes were ≥ 9 in both reports. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when vecuronium is administered to a nursing woman.
### Pediatric Use
- Infants under 1 year of age but older than 7 weeks also tested under halothane anesthesia, are moderately more sensitive to vecuronium on a mg/kg basis than adults and take about 1½ times as long to recover. See Dosage and Administration: Use in Pediatrics subsection for recommendations for use in pediatric patients 7 weeks to 16 years of age. The safety and effectiveness of vecuronium in pediatric patients less than 7 weeks of age have not been established.
### Geriatic Use
- Clinical studies of vecuronium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. There are some reports in the peer reviewed literature of increased effect and longer duration of action of vecuronium in the elderly compared to younger patients. However, other reports have found no significant differences between healthy elderly and younger adults. Advanced age or other conditions associated with slower circulation time, may be associated with a delay in onset time (see Precautions: Altered Circulation Time). Nevertheless, recommended doses of vecuronium should not be increased in these patients to reduce onset time, as higher doses produce a longer duration of action (see Clinical Pharmacology). Dose selections 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. Close monitoring of neuromuscular function is recommended.
- Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including vecuronium bromide have been reported.
### Gender
There is no FDA guidance on the use of Vecuronium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vecuronium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Vecuronium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Vecuronium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vecuronium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vecuronium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Vecuronium bromide for injection is for intravenous use only.
- This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium bromide by volatile anesthetics and by prior use of succinylcholine (see Precautions: Drug Interactions).
- To obtain maximum clinical benefits of vecuronium bromide and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.
- The recommended initial dose of vecuronium bromide is 0.08 to 0.1 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium bromide is enhanced. If vecuronium bromide is first administered more than 5 minutes after the start of inhalation agent or when steady-state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.06 to 0.085 mg/kg.
- Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium bromide. If intubation is performed using succinylcholine, a reduction of initial dose of vecuronium bromide to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required.
- During prolonged surgical procedures, maintenance doses of 0.01 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium bromide injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.
- Since vecuronium bromide lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)
- Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see Clinical Pharmacology: Pharmacokinetics).
### Use by Continuous Infusion
- After an intubating dose of 80 to 100 mcg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 minutes later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations (see Precautions: Long-term Use in ICU).
- The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.
- Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60 percent, 45 to 60 minutes after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.
- Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see Clinical Pharmacology).
- Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer's Injection.
- Unused portions of infusion solutions should be discarded.
- Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
- The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
- NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half.
### Use in Pediatrics
- Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.
- Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 1½ times as long to recover (see also PRECAUTIONS: Pediatric Use). Information presently available does not permit recommendation on usage in pediatric patients less than 7 weeks of age (see Precautions: Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.
### Monitoring
There is limited information regarding Vecuronium Monitoring in the drug label.
# IV Compatibility
- Vecuronium bromide is compatible in solution with:
- Use within 24 hours of mixing with the above solutions.
- Vecuronium bromide is also compatible in solution with:
- Bacteriostatic Water for Injection (NOT FOR USE IN NEWBORNS)
- Use within 5 days of mixing with the above solution.
- Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.
- See Dosage and Administration: Compatibility for diluents compatible with Vecuronium Bromide for Injection.
- When reconstituted with compatible IV solutions not containing an antimicrobial preservative (e.g., sterile water for injection), refrigerate and use within 24 hours. Discard unused portion.
- When reconstituted with bacteriostatic water for injection (NOT FOR USE IN NEWBORNS), use within 5 days. The reconstituted solution may be stored at room temperature or refrigerated.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
# Overdosage
- The possibility of iatrogenic overdosage can be minimized by carefully monitoring muscle twitch response to peripheral nerve stimulation.
- Excessive doses of vecuronium produce enhanced pharmacological effects. Residual neuromuscular blockade beyond the time period needed may occur with vecuronium as with other neuromuscular blockers. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade from other causes of decreased respiratory reserve.
- Respiratory depression may be due either wholly or in part to other drugs used during the conduct of general anesthesia such as narcotics, thiobarbiturates and other central nervous system depressants.
- Under such circumstances the primary treatment is maintenance of a patent airway and manual or mechanical ventilation until complete recovery of normal respiration is assured. Pyridostigmine, neostigmine, or edrophonium, in conjunction with atropine or glycopyrrolate will usually antagonize the skeletal muscle relaxant action of vecuronium. Satisfactory reversal can be judged by adequacy of skeletal muscle tone and by adequacy of respiration. A peripheral nerve stimulator may also be used to monitor restoration of twitch height. Failure of prompt reversal (within 30 minutes) may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression of their own. Under such circumstances the management is the same as that of prolonged neuromuscular blockade. Ventilation must be supported by artificial means until the patient has resumed control of his respiration. Prior to the use of reversal agents, reference should be made to the specific package insert of the reversal agent.
- The effects of hemodialysis and peritoneal dialysis on plasma levels of vecuronium and its metabolite are unknown.
# Pharmacology
## Mechanism of Action
- Vecuronium is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for cholinergic receptors at the motor end-plate.
## Structure
Vecuronium Bromide for Injection is a nondepolarizing neuromuscular blocking agent of intermediate duration, chemically designated as 1-(3α,17β-Dihydroxy-2β-piperidino-5α-androstan-16β,5α-yl)-1-methylpiperidinium bromide, diacetate. The structural formula is:
- Its chemical formula is C34H57BrN2O4 with molecular weight 637.73.
- Vecuronium Bromide for Injection is supplied as a sterile nonpyrogenic freeze-dried buffered cake of very fine microscopic crystalline particles for intravenous injection only. Each vial contains 10 mg or 20 mg of vecuronium bromide. In addition, each 10 mg vial contains 20.75 mg citric acid anhydrous, 16.25 mg sodium phosphate dibasic anhydrous, 97 mg mannitol (to adjust tonicity), sodium hydroxide and/or phosphoric acid to buffer and adjust to a pH range of 3.5 to 4.5. Each 20 mg vial contains 41.5 mg citric acid anhydrous, 32.5 mg sodium phosphate dibasic anhydrous, 194 mg mannitol (to adjust tonicity), sodium hydroxide and/or phosphoric acid to buffer and adjust to a pH range of 3.5 to 4.5.
## Pharmacodynamics
- The antagonism to acetylcholine is inhibited and neuromuscular block is reversed by acetylcholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine. Vecuronium is about 1/3 more potent than pancuronium; the duration of neuromuscular blockade produced by vecuronium is shorter than that of pancuronium at initially equipotent doses. The time to onset of paralysis decreases and the duration of maximum effect increases with increasing vecuronium doses. The use of a peripheral nerve stimulator is recommended in assessing the degree of muscular relaxation with all neuromuscular blocking drugs. The ED90 (dose required to produce 90% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.057 mg/kg (0.049 to 0.062 mg/kg in various studies). An initial vecuronium bromide dose of 0.08 to 0.1 mg/kg generally produces first depression of twitch in approximately 1 minute, good or excellent intubation conditions within 2.5 to 3 minutes, and maximum neuromuscular blockade within 3 to 5 minutes of injection in most patients.
- Under balanced anesthesia, the time to recovery to 25% of control (clinical duration) is approximately 25 to 40 minutes after injection and recovery is usually 95% complete approximately 45 to 65 minutes after injection of intubating dose. The neuromuscular blocking action of vecuronium is slightly enhanced in the presence of potent inhalation anesthetics. If vecuronium is first administered more than 5 minutes after the start of the inhalation of enflurane, isoflurane, or halothane, or when steady-state has been achieved, the intubating dose of vecuronium may be decreased by approximately 15% (see Dosage and Administration). Prior administration of succinylcholine may enhance the neuromuscular blocking effect of vecuronium and its duration of action. With succinylcholine as the intubating agent, initial doses of 0.04 to 0.06 mg/kg of vecuronium bromide will produce complete neuromuscular block with clinical duration of action of 25 to 30 minutes. If succinylcholine is used prior to vecuronium, the administration of vecuronium should be delayed until the patient starts recovering from succinylcholine-induced neuromuscular blockade. The effect of prior use of other nondepolarizing neuromuscular blocking agents on the activity of vecuronium has not been studied (see Precautions: Drug Interactions).
- Repeated administration of maintenance doses of vecuronium has little or no cumulative effect on the duration of neuromuscular blockade. Therefore, repeat doses can be administered at relatively regular intervals with predictable results. After an initial dose of 0.08 to 0.1 mg/kg under balanced anesthesia, the first maintenance dose (suggested maintenance dose is 0.01 to 0.015 mg/kg) is generally required within 25 to 40 minutes; subsequent maintenance doses, if required, may be administered at approximately 12 to 15 minute intervals. Halothane anesthesia increases the clinical duration of the maintenance dose only slightly. Under enflurane a maintenance dose of 0.01 mg/kg is approximately equal to 0.015 mg/kg dose under balanced anesthesia.
- The recovery index (time from 25% to 75% recovery) is approximately 15 to 25 minutes under balanced or halothane anesthesia. When recovery from vecuronium neuromuscular blocking effect begins, it proceeds more rapidly than recovery from pancuronium. Once spontaneous recovery has started, the neuromuscular block produced by vecuronium is readily reversed with various anticholinesterase agents, e.g., pyridostigmine, neostigmine, or edrophonium in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. Rapid recovery is a finding consistent with vecuronium short elimination half-life, although there have been occasional reports of prolonged neuromuscular blockade in patients in the intensive care unit (see Precautions).
- The administration of clinical doses of vecuronium is not characterized by laboratory or clinical signs of chemically mediated histamine release. This does not preclude the possibility of rare hypersensitivity reactions (see ADVERSE REACTIONS).
## Pharmacokinetics
- At clinical doses of 0.04 to 0.1 mg/kg, 60 to 80% of vecuronium bromide is usually bound to plasma protein. The distribution half-life following a single intravenous dose (range 0.025 to 0.28 mg/kg) is approximately 4 minutes. Elimination half-life over this sample dosage range is approximately 65 to 75 minutes in healthy surgical patients and in renal failure patients undergoing transplant surgery.
- In late pregnancy, elimination half-life may be shortened to approximately 35 to 40 minutes. The volume of distribution at steady-state is approximately 300 to 400 mL/kg; systemic rate of clearance is approximately 3 to 4.5 mL/kg/minute. In man, urine recovery of vecuronium varies from 3 to 35% within 24 hours. Data derived from patients requiring insertion of a T-tube in the common bile duct suggests that 25 to 50% of a total intravenous dose of vecuronium may be excreted in bile within 42 hours. Only unchanged vecuronium has been detected in human plasma following use during surgery. In addition, one metabolite, 3-desacetyl vecuronium, has been rarely detected in human plasma following prolonged clinical use in the ICU. (See PRECAUTIONS: Long-term Use in ICU). The 3-desacetyl vecuronium metabolite has been recovered in the urine of some patients in quantities that account for up to 10% of injected dose; 3-desacetyl vecuronium has also been recovered by T-tube in some patients accounting for up to 25% of the injected dose.
- This metabolite has been judged by animal screening (dogs and cats) to have 50% or more of the potency of vecuronium; equipotent doses are of approximately the same duration as vecuronium in dogs and cats. Biliary excretion accounts for about half the dose of vecuronium within 7 hours in the anesthetized rat. Circulatory bypass of the liver (cat preparation) prolongs recovery from vecuronium. Limited data derived from patients with cirrhosis or cholestasis suggests that some measurements of recovery may be doubled in such patients. In patients with renal failure, measurements of recovery do not differ significantly from similar measurements in healthy patients.
- Studies involving routine hemodynamic monitoring in good risk surgical patients reveal that the administration of vecuronium in doses up to three times that needed to produce clinical relaxation (0.15 mg/kg) did not produce clinically significant changes in systolic, diastolic or mean arterial pressure. The heart rate, under similar monitoring, remained unchanged in some studies and was lowered by a mean of up to 8% in other studies. A large dose of 0.28 mg/kg administered during a period of no stimulation, while patients were being prepared for coronary artery bypass grafting was not associated with alterations in rate-pressure-product or pulmonary capillary wedge pressure. Systemic vascular resistance was lowered slightly and cardiac output was increased insignificantly. (The drug has not been studied in patients with hemodynamic dysfunction secondary to cardiac valvular disease.) Limited clinical experience with use of vecuronium bromide during the surgery for pheochromocytoma has shown that administration of this drug is not associated with changes in blood pressure or heart rate.
- Unlike other nondepolarizing skeletal muscle relaxants, vecuronium has no clinically significant effects on hemodynamic parameters. Vecuronium will not counteract those hemodynamic changes or known side effects produced by or associated with anesthetic agents, other drugs or various other factors known to alter hemodynamics.
## Nonclinical Toxicology
There is limited information regarding Vecuronium Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Vecuronium Clinical Studies in the drug label.
# How Supplied
- Vecuronium Bromide for Injection is supplied as follows:
## Storage
- Store dry powder at 20° to 25°C (68° to 77°F). Protect from light. Retain in carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Vecuronium Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Vecuronium 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 Vecuronium Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Vecuronium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vecuronium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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# Black Box Warning
# Overview
Vecuronium is a skeletal muscle relaxant, neuromuscular blocking drugs that is FDA approved for the prophylaxis of anesthesia, during surgery as an adjunct to general anesthesia to facilitate tracheal intubation or mechanical ventilation; adjunct.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include immunologic: anaphylaxis, hypersensitivity reaction, musculoskeletal: muscle weakness, Prolonged neuromuscular block,respiratory: bronchospasm.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage must be individualized
### Anesthesia, During surgery as an adjunct to general anesthesia to facilitate tracheal intubation or mechanical ventilation; Adjunct
- Initial
- 0.08-0.1 mg/kg IV bolus
- Maintenance
- 0.01-0.015 mg/kg IV 25-40 min after initial dose, repeat every 12-15 min as needed
- 1 mcg/kg/min continuous IV infusion 20-40 min after initial intubation dose, after early evidence of spontaneous recovery; then adjust to maintain 90% suppression of twitch response; range 0.8-1.2 mcg/kg/min
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vecuronium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vecuronium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness not established in pediatric patients 7 weeks of age or younger
### Anesthesia, During surgery as an adjunct to general anesthesia to facilitate tracheal intubation or mechanical ventilation; Adjunct
- (age 8 weeks-1 yr)
- More sensitive on a mg/kg basis than adults and recovery may take 1.5 times longer
- (age 1-10 yr)
- Dosage must be individualized; may require slightly higher initial dose and slightly more frequent supplemental doses than adults
- (age 10-16 yr)
- Initial, 0.08-0.1 mg/kg IV bolus
- Maintenance, 0.01-0.015 mg/kg IV 25-40 min after initial dose, repeat every 12-15 min as needed; may require more frequent supplementation than adults
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vecuronium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vecuronium in pediatric patients.
# Contraindications
- Vecuronium bromide is contraindicated in patients known to have a hypersensitivity to it.
# Warnings
- Vecuronium should be administered in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with its actions and the possible complications that might occur following its use. the drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available. the clinician must be prepared to assist or control respiration. to reduce the possibility of prolonged neuromuscular blockade and other possible complications that might occur following long-term use in the icu, vecuronium or any other neuromuscular blocking agent should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and who are familiar with appropriate peripheral nerve stimulator muscle monitoring techniques (see Precautions).
- In patients who are known to have myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of vecuronium may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.
### Anaphylaxis
- Severe anaphylactic reactions to neuromuscular blocking agents, including vecuronium bromide, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reaction to nondepolarizing blocking agents as a class consists of an extension of the drug's pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiration insufficiency or apnea.
- Inadequate reversal of the neuromuscular blockade is possible with vecuronium bromide as with all curariform drugs. These adverse reactions are managed by manual or mechanical ventilation until recovery is judged adequate. Little or no increase in intensity of blockade or duration of action with vecuronium bromide is noted from the use of thiobarbiturates, narcotic analgesics, nitrous oxide, or droperidol. See Overdosage for discussion of other drugs used in anesthetic practice which also cause respiratory depression.
- Prolonged to profound extensions of paralysis and/or muscle weakness as well as muscle atrophy have been reported after long-term use to support mechanical ventilation in the intensive care unit (see Precautions). The administration of vecuronium bromide has been associated with rare instances of hypersensitivity reactions (bronchospasm, hypotension and/or tachycardia, sometimes associated with acute urticaria or erythema); (see also Clinical pharmacology).
- There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including vecuronium bromide. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (See Warnings and Precautions).
## Postmarketing Experience
There is limited information regarding Vecuronium Postmarketing Experience in the drug label.
# Drug Interactions
- Prior administration of succinylcholine may enhance the neuromuscular blocking effect of vecuronium and its duration of action. If succinylcholine is used before vecuronium, the administration of vecuronium should be delayed until the succinylcholine effect shows signs of wearing off. With succinylcholine as the intubating agent, initial doses of 0.04 to 0.06 mg/kg of vecuronium may be administered to produce complete neuromuscular block with clinical duration of action of 25 to 30 minutes (see Clinical Pharmacology).
- The use of vecuronium before succinylcholine, in order to attenuate some of the side effects of succinylcholine, has not been sufficiently studied.
- Other nondepolarizing neuromuscular blocking agents (pancuronium, d-tubocurarine, metocurine, and gallamine) act in the same fashion as does vecuronium, therefore, these drugs and vecuronium, may manifest an additive effect when used together. There are insufficient data to support concomitant use of vecuronium and other competitive muscle relaxants in the same patient.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with vecuronium. It is also not known whether vecuronium can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vecuronium should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vecuronium in women who are pregnant.
### Labor and Delivery
- The use of vecuronium in patients undergoing cesarean section has been reported in the literature. Following tracheal intubation with succinylcholine, vecuronium dosages of 0.04 mg/kg (n=11) and 0.06 to 0.08 mg/kg (n=20) were administered. The umbilical venous plasma concentrations were 11% of maternal concentrations at delivery and mean neonate APGAR scores at 5 minutes were ≥ 9 in both reports. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when vecuronium is administered to a nursing woman.
### Pediatric Use
- Infants under 1 year of age but older than 7 weeks also tested under halothane anesthesia, are moderately more sensitive to vecuronium on a mg/kg basis than adults and take about 1½ times as long to recover. See Dosage and Administration: Use in Pediatrics subsection for recommendations for use in pediatric patients 7 weeks to 16 years of age. The safety and effectiveness of vecuronium in pediatric patients less than 7 weeks of age have not been established.
### Geriatic Use
- Clinical studies of vecuronium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. There are some reports in the peer reviewed literature of increased effect and longer duration of action of vecuronium in the elderly compared to younger patients. However, other reports have found no significant differences between healthy elderly and younger adults. Advanced age or other conditions associated with slower circulation time, may be associated with a delay in onset time (see Precautions: Altered Circulation Time). Nevertheless, recommended doses of vecuronium should not be increased in these patients to reduce onset time, as higher doses produce a longer duration of action (see Clinical Pharmacology). Dose selections 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. Close monitoring of neuromuscular function is recommended.
- Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents. In addition, inform your patients that severe anaphylactic reactions to neuromuscular blocking agents, including vecuronium bromide have been reported.
### Gender
There is no FDA guidance on the use of Vecuronium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vecuronium with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Vecuronium in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Vecuronium in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vecuronium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vecuronium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Vecuronium bromide for injection is for intravenous use only.
- This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium bromide by volatile anesthetics and by prior use of succinylcholine (see Precautions: Drug Interactions).
- To obtain maximum clinical benefits of vecuronium bromide and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.
- The recommended initial dose of vecuronium bromide is 0.08 to 0.1 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium bromide is enhanced. If vecuronium bromide is first administered more than 5 minutes after the start of inhalation agent or when steady-state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.06 to 0.085 mg/kg.
- Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium bromide. If intubation is performed using succinylcholine, a reduction of initial dose of vecuronium bromide to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required.
- During prolonged surgical procedures, maintenance doses of 0.01 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium bromide injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.
- Since vecuronium bromide lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)
- Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see Clinical Pharmacology: Pharmacokinetics).
### Use by Continuous Infusion
- After an intubating dose of 80 to 100 mcg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 minutes later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations (see Precautions: Long-term Use in ICU).
- The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.
- Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60 percent, 45 to 60 minutes after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.
- Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see Clinical Pharmacology).
- Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer's Injection.
- Unused portions of infusion solutions should be discarded.
- Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
- The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
- NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half.
### Use in Pediatrics
- Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.
- Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 1½ times as long to recover (see also PRECAUTIONS: Pediatric Use). Information presently available does not permit recommendation on usage in pediatric patients less than 7 weeks of age (see Precautions: Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.
### Monitoring
There is limited information regarding Vecuronium Monitoring in the drug label.
# IV Compatibility
- Vecuronium bromide is compatible in solution with:
- Use within 24 hours of mixing with the above solutions.
- Vecuronium bromide is also compatible in solution with:
- Bacteriostatic Water for Injection (NOT FOR USE IN NEWBORNS)
- Use within 5 days of mixing with the above solution.
- Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.
- See Dosage and Administration: Compatibility for diluents compatible with Vecuronium Bromide for Injection.
- When reconstituted with compatible IV solutions not containing an antimicrobial preservative (e.g., sterile water for injection), refrigerate and use within 24 hours. Discard unused portion.
- When reconstituted with bacteriostatic water for injection (NOT FOR USE IN NEWBORNS), use within 5 days. The reconstituted solution may be stored at room temperature or refrigerated.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
# Overdosage
- The possibility of iatrogenic overdosage can be minimized by carefully monitoring muscle twitch response to peripheral nerve stimulation.
- Excessive doses of vecuronium produce enhanced pharmacological effects. Residual neuromuscular blockade beyond the time period needed may occur with vecuronium as with other neuromuscular blockers. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade from other causes of decreased respiratory reserve.
- Respiratory depression may be due either wholly or in part to other drugs used during the conduct of general anesthesia such as narcotics, thiobarbiturates and other central nervous system depressants.
- Under such circumstances the primary treatment is maintenance of a patent airway and manual or mechanical ventilation until complete recovery of normal respiration is assured. Pyridostigmine, neostigmine, or edrophonium, in conjunction with atropine or glycopyrrolate will usually antagonize the skeletal muscle relaxant action of vecuronium. Satisfactory reversal can be judged by adequacy of skeletal muscle tone and by adequacy of respiration. A peripheral nerve stimulator may also be used to monitor restoration of twitch height. Failure of prompt reversal (within 30 minutes) may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression of their own. Under such circumstances the management is the same as that of prolonged neuromuscular blockade. Ventilation must be supported by artificial means until the patient has resumed control of his respiration. Prior to the use of reversal agents, reference should be made to the specific package insert of the reversal agent.
- The effects of hemodialysis and peritoneal dialysis on plasma levels of vecuronium and its metabolite are unknown.
# Pharmacology
## Mechanism of Action
- Vecuronium is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for cholinergic receptors at the motor end-plate.
## Structure
Vecuronium Bromide for Injection is a nondepolarizing neuromuscular blocking agent of intermediate duration, chemically designated as 1-(3α,17β-Dihydroxy-2β-piperidino-5α-androstan-16β,5α-yl)-1-methylpiperidinium bromide, diacetate. The structural formula is:
- Its chemical formula is C34H57BrN2O4 with molecular weight 637.73.
- Vecuronium Bromide for Injection is supplied as a sterile nonpyrogenic freeze-dried buffered cake of very fine microscopic crystalline particles for intravenous injection only. Each vial contains 10 mg or 20 mg of vecuronium bromide. In addition, each 10 mg vial contains 20.75 mg citric acid anhydrous, 16.25 mg sodium phosphate dibasic anhydrous, 97 mg mannitol (to adjust tonicity), sodium hydroxide and/or phosphoric acid to buffer and adjust to a pH range of 3.5 to 4.5. Each 20 mg vial contains 41.5 mg citric acid anhydrous, 32.5 mg sodium phosphate dibasic anhydrous, 194 mg mannitol (to adjust tonicity), sodium hydroxide and/or phosphoric acid to buffer and adjust to a pH range of 3.5 to 4.5.
## Pharmacodynamics
- The antagonism to acetylcholine is inhibited and neuromuscular block is reversed by acetylcholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine. Vecuronium is about 1/3 more potent than pancuronium; the duration of neuromuscular blockade produced by vecuronium is shorter than that of pancuronium at initially equipotent doses. The time to onset of paralysis decreases and the duration of maximum effect increases with increasing vecuronium doses. The use of a peripheral nerve stimulator is recommended in assessing the degree of muscular relaxation with all neuromuscular blocking drugs. The ED90 (dose required to produce 90% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.057 mg/kg (0.049 to 0.062 mg/kg in various studies). An initial vecuronium bromide dose of 0.08 to 0.1 mg/kg generally produces first depression of twitch in approximately 1 minute, good or excellent intubation conditions within 2.5 to 3 minutes, and maximum neuromuscular blockade within 3 to 5 minutes of injection in most patients.
- Under balanced anesthesia, the time to recovery to 25% of control (clinical duration) is approximately 25 to 40 minutes after injection and recovery is usually 95% complete approximately 45 to 65 minutes after injection of intubating dose. The neuromuscular blocking action of vecuronium is slightly enhanced in the presence of potent inhalation anesthetics. If vecuronium is first administered more than 5 minutes after the start of the inhalation of enflurane, isoflurane, or halothane, or when steady-state has been achieved, the intubating dose of vecuronium may be decreased by approximately 15% (see Dosage and Administration). Prior administration of succinylcholine may enhance the neuromuscular blocking effect of vecuronium and its duration of action. With succinylcholine as the intubating agent, initial doses of 0.04 to 0.06 mg/kg of vecuronium bromide will produce complete neuromuscular block with clinical duration of action of 25 to 30 minutes. If succinylcholine is used prior to vecuronium, the administration of vecuronium should be delayed until the patient starts recovering from succinylcholine-induced neuromuscular blockade. The effect of prior use of other nondepolarizing neuromuscular blocking agents on the activity of vecuronium has not been studied (see Precautions: Drug Interactions).
- Repeated administration of maintenance doses of vecuronium has little or no cumulative effect on the duration of neuromuscular blockade. Therefore, repeat doses can be administered at relatively regular intervals with predictable results. After an initial dose of 0.08 to 0.1 mg/kg under balanced anesthesia, the first maintenance dose (suggested maintenance dose is 0.01 to 0.015 mg/kg) is generally required within 25 to 40 minutes; subsequent maintenance doses, if required, may be administered at approximately 12 to 15 minute intervals. Halothane anesthesia increases the clinical duration of the maintenance dose only slightly. Under enflurane a maintenance dose of 0.01 mg/kg is approximately equal to 0.015 mg/kg dose under balanced anesthesia.
- The recovery index (time from 25% to 75% recovery) is approximately 15 to 25 minutes under balanced or halothane anesthesia. When recovery from vecuronium neuromuscular blocking effect begins, it proceeds more rapidly than recovery from pancuronium. Once spontaneous recovery has started, the neuromuscular block produced by vecuronium is readily reversed with various anticholinesterase agents, e.g., pyridostigmine, neostigmine, or edrophonium in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. Rapid recovery is a finding consistent with vecuronium short elimination half-life, although there have been occasional reports of prolonged neuromuscular blockade in patients in the intensive care unit (see Precautions).
- The administration of clinical doses of vecuronium is not characterized by laboratory or clinical signs of chemically mediated histamine release. This does not preclude the possibility of rare hypersensitivity reactions (see ADVERSE REACTIONS).
## Pharmacokinetics
- At clinical doses of 0.04 to 0.1 mg/kg, 60 to 80% of vecuronium bromide is usually bound to plasma protein. The distribution half-life following a single intravenous dose (range 0.025 to 0.28 mg/kg) is approximately 4 minutes. Elimination half-life over this sample dosage range is approximately 65 to 75 minutes in healthy surgical patients and in renal failure patients undergoing transplant surgery.
- In late pregnancy, elimination half-life may be shortened to approximately 35 to 40 minutes. The volume of distribution at steady-state is approximately 300 to 400 mL/kg; systemic rate of clearance is approximately 3 to 4.5 mL/kg/minute. In man, urine recovery of vecuronium varies from 3 to 35% within 24 hours. Data derived from patients requiring insertion of a T-tube in the common bile duct suggests that 25 to 50% of a total intravenous dose of vecuronium may be excreted in bile within 42 hours. Only unchanged vecuronium has been detected in human plasma following use during surgery. In addition, one metabolite, 3-desacetyl vecuronium, has been rarely detected in human plasma following prolonged clinical use in the ICU. (See PRECAUTIONS: Long-term Use in ICU). The 3-desacetyl vecuronium metabolite has been recovered in the urine of some patients in quantities that account for up to 10% of injected dose; 3-desacetyl vecuronium has also been recovered by T-tube in some patients accounting for up to 25% of the injected dose.
- This metabolite has been judged by animal screening (dogs and cats) to have 50% or more of the potency of vecuronium; equipotent doses are of approximately the same duration as vecuronium in dogs and cats. Biliary excretion accounts for about half the dose of vecuronium within 7 hours in the anesthetized rat. Circulatory bypass of the liver (cat preparation) prolongs recovery from vecuronium. Limited data derived from patients with cirrhosis or cholestasis suggests that some measurements of recovery may be doubled in such patients. In patients with renal failure, measurements of recovery do not differ significantly from similar measurements in healthy patients.
- Studies involving routine hemodynamic monitoring in good risk surgical patients reveal that the administration of vecuronium in doses up to three times that needed to produce clinical relaxation (0.15 mg/kg) did not produce clinically significant changes in systolic, diastolic or mean arterial pressure. The heart rate, under similar monitoring, remained unchanged in some studies and was lowered by a mean of up to 8% in other studies. A large dose of 0.28 mg/kg administered during a period of no stimulation, while patients were being prepared for coronary artery bypass grafting was not associated with alterations in rate-pressure-product or pulmonary capillary wedge pressure. Systemic vascular resistance was lowered slightly and cardiac output was increased insignificantly. (The drug has not been studied in patients with hemodynamic dysfunction secondary to cardiac valvular disease.) Limited clinical experience with use of vecuronium bromide during the surgery for pheochromocytoma has shown that administration of this drug is not associated with changes in blood pressure or heart rate.
- Unlike other nondepolarizing skeletal muscle relaxants, vecuronium has no clinically significant effects on hemodynamic parameters. Vecuronium will not counteract those hemodynamic changes or known side effects produced by or associated with anesthetic agents, other drugs or various other factors known to alter hemodynamics.
## Nonclinical Toxicology
There is limited information regarding Vecuronium Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Vecuronium Clinical Studies in the drug label.
# How Supplied
- Vecuronium Bromide for Injection is supplied as follows:
## Storage
- Store dry powder at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Retain in carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Vecuronium Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Vecuronium 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 Vecuronium Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Vecuronium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Norcuron | |
cdbf4d2011f8793fa1b5b2985e5a8950ec376b42 | wikidoc | Novobiocin | Novobiocin
Synonyms and keywords: Novobiocin sodium; Streptonivicin
# Overview
Novobiocin is an aminocoumarin antibiotic that was produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym forS. spheroides, a member of the order Actinobacteria. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1. Novobiocin was first reported in the middle of 1950s (called then streptonivicin).
# Category
Aminocoumarin
# US Brand Names
ALBAMYCIN® (DISCONTINUED)
# Prescribing Information
### Contraindications
- Hypersensitivity to novobiocin
### Precautions
- Leukopenia or blood dyscrasias
- Liver dysfunction
### Adverse Reactions
- Myocarditis
- Skin eruption and fever are the most frequent hypersensitivity phenomena. The incidence of the RASH is in about 12% of treated patients with an onset between the 6th and 12th day of treatment. The rash may appear erythematous, maculopapular, scarlatiniform, or urticarial.
- YELLOW DISCOLORATION of the skin and plasma is the result of a circulating lipochrome pigment that is a degradation product of novobiocin.
- The hemorrhagic nature of cutaneous lesions may indicate that novobiocin has a coumarin-like effect.
- Hematology finding
- Jaundice
- Immune hypersensitivity reaction
- Eye / vision finding
- Respiratory finding
### Teratogenicity/Effects in Pregnancy
- Fetal risk cannot be ruled out.
- Clinical Management
### Breastfeeding
- Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.
- Clinical Management
### Dosage and Administration
Oral route
- The usual oral adult dose is 250 milligrams every 6 hours or 500 milligrams every 12 hours for treating serious infections due to susceptible S aureus or Proteus URINARY TRACT INFECTIONS when other less toxic antibiotics are contraindicated or ineffective.
- Up to 500 milligrams every 6 hours or 1 gram every 12 hours of novobiocin may be administered orally for resistant or severe infections.
- Dosage adjustment in renal failure is not indicated because less than 3% of a dose of novobiocin is eliminated in the urine.
- Dosage adjustment or discontinuation of novobiocin might be indicated if hepatic dysfunction develops.
Oral route
- The usual daily, oral pediatric dose of novobiocin is 15 milligrams of novobiocin/kilogram body weight for moderate to acute infections, administered in divided doses every 6 to 12 hours.
- Up to 30 to 45 milligrams of novobiocin/kilogram body weight may be administered orally in divided doses every 6 to 12 hours for resistant or severe infections.
- Use of novobiocin should be avoided in newborn and young infants because of the possibility of inducing hyperbilirubinemia.
### Therapeutic Uses
Excellent in-vitro activity against virtually all of the 103 strains of methicillin-resistant Staphylococcus aureus in one study.
Used in combination with rifampin in the treatment of methicillin-resistant Staphylococcus aureus.
- Adult:
- For treatment of susceptible urinary tract infections caused by Proteus species.
- Novobiocin plus acidification of the urine was more effective than novobiocin therapy alone in eradicating gram-negative bacilli in the urine of patients with chronic bacteriuria.
- Inadequate in treatment of gonococcal urethritis.
# Mechanism of Action
The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined. Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy tranduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.
# Structure
Novobiocin is an aromatic ether compound. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.. X-ray crytallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule. The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.
## Structure Activity Relationship
In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin.
# Clinical Use
Novobiocin was licenced for clinical use under the tradename Albamycin® (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in
preclinical and clinical trials. It has since been withdrawn from the market. Novobiocin is effective antistaphylococcal agent used in the treatment of MRSA. It is also active against Staphylococcus epidermidis and may be used to differentiate from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture. | Novobiocin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Novobiocin sodium; Streptonivicin
# Overview
Novobiocin is an aminocoumarin antibiotic that was produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym forS. spheroides,[1] a member of the order Actinobacteria. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.[2] Novobiocin was first reported in the middle of 1950s (called then streptonivicin).[3][4]
# Category
Aminocoumarin
# US Brand Names
ALBAMYCIN® (DISCONTINUED)
# Prescribing Information
### Contraindications
- Hypersensitivity to novobiocin
### Precautions
- Leukopenia or blood dyscrasias
- Liver dysfunction
### Adverse Reactions
- Myocarditis
- Skin eruption and fever are the most frequent hypersensitivity phenomena. The incidence of the RASH is in about 12% of treated patients with an onset between the 6th and 12th day of treatment. The rash may appear erythematous, maculopapular, scarlatiniform, or urticarial.
- YELLOW DISCOLORATION of the skin and plasma is the result of a circulating lipochrome pigment that is a degradation product of novobiocin.
- The hemorrhagic nature of cutaneous lesions may indicate that novobiocin has a coumarin-like effect.
- Hematology finding
- Jaundice
- Immune hypersensitivity reaction
- Eye / vision finding
- Respiratory finding
### Teratogenicity/Effects in Pregnancy
- Fetal risk cannot be ruled out.
- Clinical Management
### Breastfeeding
- Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.
- Clinical Management
### Dosage and Administration
Oral route
- The usual oral adult dose is 250 milligrams every 6 hours or 500 milligrams every 12 hours for treating serious infections due to susceptible S aureus or Proteus URINARY TRACT INFECTIONS when other less toxic antibiotics are contraindicated or ineffective.
- Up to 500 milligrams every 6 hours or 1 gram every 12 hours of novobiocin may be administered orally for resistant or severe infections.
- Dosage adjustment in renal failure is not indicated because less than 3% of a dose of novobiocin is eliminated in the urine.
- Dosage adjustment or discontinuation of novobiocin might be indicated if hepatic dysfunction develops.
Oral route
- The usual daily, oral pediatric dose of novobiocin is 15 milligrams of novobiocin/kilogram body weight for moderate to acute infections, administered in divided doses every 6 to 12 hours.
- Up to 30 to 45 milligrams of novobiocin/kilogram body weight may be administered orally in divided doses every 6 to 12 hours for resistant or severe infections.
- Use of novobiocin should be avoided in newborn and young infants because of the possibility of inducing hyperbilirubinemia.
### Therapeutic Uses
Excellent in-vitro activity against virtually all of the 103 strains of methicillin-resistant Staphylococcus aureus in one study.
Used in combination with rifampin in the treatment of methicillin-resistant Staphylococcus aureus.
- Adult:
- For treatment of susceptible urinary tract infections caused by Proteus species.
- Novobiocin plus acidification of the urine was more effective than novobiocin therapy alone in eradicating gram-negative bacilli in the urine of patients with chronic bacteriuria.
- Inadequate in treatment of gonococcal urethritis.
# Mechanism of Action
The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined.[2][5][6][7][8] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy tranduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.
# Structure
Novobiocin is an aromatic ether compound. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.[5]. X-ray crytallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule.[9] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.[10]
## Structure Activity Relationship
In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin. [10]
# Clinical Use
Novobiocin was licenced for clinical use under the tradename Albamycin® (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in
preclinical and clinical trials.[11][12] It has since been withdrawn from the market.[13] Novobiocin is effective antistaphylococcal agent used in the treatment of MRSA[14]. It is also active against Staphylococcus epidermidis and may be used to differentiate from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture. | https://www.wikidoc.org/index.php/Novobiocin | |
82874bc3ad9987dc382b37f1ee14f3c2c4b2e611 | wikidoc | Nucleation | Nucleation
Nucleation is the onset of a phase transition in a small region. The phase transition can be the formation of a bubble or of a crystal from a liquid. Creation of liquid droplets in saturated vapor or the creation of gaseous bubble in a saturated liquid is also characterized by nucleation (see Cloud condensation nuclei). Nucleation of crystalline, amorphous, and even vacancy clusters in solid materials is also important, for example to the semiconductor industry.
Nucleation normally occurs at nucleation sites on surfaces containing the liquid or vapor. Suspended particles or minute bubbles also provide nucleation sites. This is called heterogeneous nucleation. Nucleation without preferential nucleation sites is homogeneous nucleation. Homogeneous nucleation occurs spontaneously and randomly, but it requires superheating or supercooling of the medium. Nucleation is involved in such processes as cloud seeding and in instruments such as the bubble chamber and the cloud chamber.
# Examples of nucleation
- Pure water freezes at −42° C rather than at its freezing temperature of 0° C if no crystal nuclei, such as dust particles, are present to form an ice nucleus.
- Presence of cloud condensation nuclei is important in meteorology because they are often in short supply in the upper atmosphere (see cloud seeding).
- All natural and artificial crystallization process (of formation of solid crystals from a homogeneous solution) starts with a nucleation event.
- Bubbles of carbon dioxide nucleate shortly after the pressure is released from a container of carbonated liquid. Nucleation often occurs more easily at a pre-existing interface (heterogeneous nucleation), as happens on boiling chips and string used to make rock candy. So-called Diet Coke and Mentos eruptions are a dramatic example.
- Nucleation in boiling can occur in the bulk liquid if the pressure is reduced so that the liquid becomes superheated with respect to the pressure-dependent boiling point. More often nucleation occurs on the heating surface, at nucleation sites. Typically, nucleation sites are tiny crevices where free gas-liquid surface is maintained or spots on the heating surface with lower wetting properties. Substantial superheating of a liquid can be achieved after the liquid is de-gassed and if the heating surfaces are clean, smooth and made of materials well wetted by the liquid.
- Nucleation is a key concept in polymer, alloy, and ceramic systems.
- In chemistry and biophysics, nucleation can also refer to the phaseless formation of multimers which are intermediates in polymerization processes. This sort of process is believed to be the best model for processes such as crystallization and amyloidogenesis.
- In molecular biology, nucleation is used to term the critical stage in the assembly of a polymeric structure, such as a microtubule, at which a small cluster of monomers aggregates in the correct arrangement to initiate rapid polymerization. For instance, two actin molecules bind weakly, but addition of a third stabilizes the complex. This trimer then adds additional molecules and forms a nucleation site. The nucleation site serves the slow, or lag phase of the polymerization process.
# Mechanics of nucleation
## Homogeneous nucleation
Nucleation generally occurs with much more difficulty in the interior of a uniform substance, by a process called homogeneous nucleation. Liquids cooled below the maximum heterogeneous nucleation temperature (melting temperature), but which are above the homogeneous nucleation temperature (pure substance freezing temperature) are said to be supercooled. This is useful for making amorphous solids and other metastable structures, but can delay the progress of industrial chemical processes or produce undesirable effects in the context of casting.
The creation of a nucleus implies the formation of an interface at the boundaries of the new phase. Some energy is consumed to form this interface, based on the surface energy of each phase. If a hypothetical nucleus is too small, the energy that would be released by forming its volume is not enough to create its surface, and nucleation does not proceed. The critical nucleus size can be denoted by its radius, and it is when r=r- (or r critical) that the nucleation proceeds.
For example in the classic case of a spherical cluster that liberates -Gv Joules per cubic centimeter during formation (here Gv is a negative quantity), but which must pay the positive cost of σ Joules per square centimeter of surface interfacing with the world around, the free energy needed to form a cluster of radius r is...
Graphing this as a function of radius shows that it costs free energy to add molecules to this cluster, until the radius reaches
Addition of new molecules to clusters larger than this critical radius releases, rather than costs, available work. In other words at that point growth of the cluster is no longer limited by nucleation, but perhaps by diffusion (i.e. the supply of molecules) or by reaction kinetics instead.
As the phase transformation becomes more and more favorable, the formation of a given volume of nucleus frees enough energy to form an increasingly large surface, allowing progressively smaller nuclei to become viable. Eventually, thermal activation will provide enough energy to form stable nuclei. These can then grow until thermodynamic equilibrium is restored.
The spontaneous nucleation rate in, say, water changes very rapidly with temperature, so the spontaneous nucleation temperature can be quite well defined. 'Film boiling' on very hot surfaces and the Leidenfrost effect are both believed to be stabilized by spontaneous nucleation phenomena.
## Heterogeneous nucleation
In the case of heterogeneous nucleation, some energy is released by the partial destruction of the previous interface. For example, if a carbon dioxide bubble forms between water and the inside surface of a bottle, the energy inherent in the water-bottle interface is released wherever a layer of gas intervenes, and this energy goes toward the formation of bubble-water and bubble-bottle interfaces. The same effect can cause precipitate particles to form at the grain boundaries of a solid. This can interfere with precipitation strengthening, which relies on homogeneous nucleation to produce a uniform distribution of precipitate particles.
## Theory of the spinodal region nucleation
Nucleation processes can also be explained in terms of spinodal decomposition where phase separation is delayed until the system enters the unstable region where a small perturbation in composition leads to a decrease in energy and thus spontaneous growth of the perturbation. This region of a phase diagram is known as the spinodal region and the phase separation process is known as spinodal decomposition and may be governed by the Cahn–Hilliard equation.
# Footnotes
- ↑ R. J. Young (1981) Introduction to Polymers (CRC Press, NY) ISBN 0-412-22170-5
- ↑ F. F. Abraham (1974) Homogeneous nucleation theory (Academic Press, NY)
- ↑ Frank S. Ham (1959) Diffusion-limited growth of precipitate particles, J. Appl. Phys. 30:1518-1525 | Nucleation
Nucleation is the onset of a phase transition in a small region. The phase transition can be the formation of a bubble or of a crystal from a liquid. Creation of liquid droplets in saturated vapor or the creation of gaseous bubble in a saturated liquid is also characterized by nucleation (see Cloud condensation nuclei). Nucleation of crystalline, amorphous, and even vacancy clusters in solid materials is also important, for example to the semiconductor industry.
Nucleation normally occurs at nucleation sites on surfaces containing the liquid or vapor. Suspended particles or minute bubbles also provide nucleation sites. This is called heterogeneous nucleation. Nucleation without preferential nucleation sites is homogeneous nucleation. Homogeneous nucleation occurs spontaneously and randomly, but it requires superheating or supercooling of the medium. Nucleation is involved in such processes as cloud seeding and in instruments such as the bubble chamber and the cloud chamber.
# Examples of nucleation
- Pure water freezes at −42° C rather than at its freezing temperature of 0° C if no crystal nuclei, such as dust particles, are present to form an ice nucleus.
- Presence of cloud condensation nuclei is important in meteorology because they are often in short supply in the upper atmosphere (see cloud seeding).
- All natural and artificial crystallization process (of formation of solid crystals from a homogeneous solution) starts with a nucleation event.
- Bubbles of carbon dioxide nucleate shortly after the pressure is released from a container of carbonated liquid. Nucleation often occurs more easily at a pre-existing interface (heterogeneous nucleation), as happens on boiling chips and string used to make rock candy. So-called Diet Coke and Mentos eruptions are a dramatic example.
- Nucleation in boiling can occur in the bulk liquid if the pressure is reduced so that the liquid becomes superheated with respect to the pressure-dependent boiling point. More often nucleation occurs on the heating surface, at nucleation sites. Typically, nucleation sites are tiny crevices where free gas-liquid surface is maintained or spots on the heating surface with lower wetting properties. Substantial superheating of a liquid can be achieved after the liquid is de-gassed and if the heating surfaces are clean, smooth and made of materials well wetted by the liquid.
- Nucleation is a key concept in polymer[1], alloy, and ceramic systems.
- In chemistry and biophysics, nucleation can also refer to the phaseless formation of multimers which are intermediates in polymerization processes. This sort of process is believed to be the best model for processes such as crystallization and amyloidogenesis.
- In molecular biology, nucleation is used to term the critical stage in the assembly of a polymeric structure, such as a microtubule, at which a small cluster of monomers aggregates in the correct arrangement to initiate rapid polymerization. For instance, two actin molecules bind weakly, but addition of a third stabilizes the complex. This trimer then adds additional molecules and forms a nucleation site. The nucleation site serves the slow, or lag phase of the polymerization process.
# Mechanics of nucleation
## Homogeneous nucleation
Nucleation generally occurs with much more difficulty in the interior of a uniform substance, by a process called homogeneous nucleation. Liquids cooled below the maximum heterogeneous nucleation temperature (melting temperature), but which are above the homogeneous nucleation temperature (pure substance freezing temperature) are said to be supercooled. This is useful for making amorphous solids and other metastable structures, but can delay the progress of industrial chemical processes or produce undesirable effects in the context of casting.
The creation of a nucleus implies the formation of an interface at the boundaries of the new phase. Some energy is consumed to form this interface, based on the surface energy of each phase. If a hypothetical nucleus is too small, the energy that would be released by forming its volume is not enough to create its surface, and nucleation does not proceed. The critical nucleus size can be denoted by its radius, and it is when r=r* (or r critical) that the nucleation proceeds.
For example in the classic case[2] of a spherical cluster that liberates -Gv Joules per cubic centimeter during formation (here Gv is a negative quantity), but which must pay the positive cost of σ Joules per square centimeter of surface interfacing with the world around, the free energy needed to form a cluster of radius r is...
Graphing this as a function of radius shows that it costs free energy to add molecules to this cluster, until the radius reaches
Addition of new molecules to clusters larger than this critical radius releases, rather than costs, available work. In other words at that point growth of the cluster is no longer limited by nucleation, but perhaps by diffusion[3] (i.e. the supply of molecules) or by reaction kinetics instead.
As the phase transformation becomes more and more favorable, the formation of a given volume of nucleus frees enough energy to form an increasingly large surface, allowing progressively smaller nuclei to become viable. Eventually, thermal activation will provide enough energy to form stable nuclei. These can then grow until thermodynamic equilibrium is restored.
The spontaneous nucleation rate in, say, water changes very rapidly with temperature, so the spontaneous nucleation temperature can be quite well defined. 'Film boiling' on very hot surfaces and the Leidenfrost effect are both believed to be stabilized by spontaneous nucleation phenomena.
## Heterogeneous nucleation
In the case of heterogeneous nucleation, some energy is released by the partial destruction of the previous interface. For example, if a carbon dioxide bubble forms between water and the inside surface of a bottle, the energy inherent in the water-bottle interface is released wherever a layer of gas intervenes, and this energy goes toward the formation of bubble-water and bubble-bottle interfaces. The same effect can cause precipitate particles to form at the grain boundaries of a solid. This can interfere with precipitation strengthening, which relies on homogeneous nucleation to produce a uniform distribution of precipitate particles.
## Theory of the spinodal region nucleation
Nucleation processes can also be explained in terms of spinodal decomposition where phase separation is delayed until the system enters the unstable region where a small perturbation in composition leads to a decrease in energy and thus spontaneous growth of the perturbation. This region of a phase diagram is known as the spinodal region and the phase separation process is known as spinodal decomposition and may be governed by the Cahn–Hilliard equation.
# Footnotes
- ↑ R. J. Young (1981) Introduction to Polymers (CRC Press, NY) ISBN 0-412-22170-5
- ↑ F. F. Abraham (1974) Homogeneous nucleation theory (Academic Press, NY)
- ↑ Frank S. Ham (1959) Diffusion-limited growth of precipitate particles, J. Appl. Phys. 30:1518-1525
# External links
- The Extreme Diet Coke & Mentos Experiments - fun with nucleation
de:Nukleation
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nl:Nucleatie
fi:Nukleaatio
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nucleation | |
b5172c008915f1ffa0e5c7807fbe1f783a781315 | wikidoc | Nucleobase | Nucleobase
Nucleobases (or Nucleotide bases) are the parts of RNA and DNA that may be involved in pairing (see also base pairs). These include cytosine, guanine, adenine, thymine (DNA) and uracil (RNA). These are abbreviated as C, G, A, T, and U, respectively. They are usually simply called bases in genetics. Because A, G, C, and T appear in the DNA, these molecules are called DNA-bases; A, G, C, and U are called RNA-bases, respectively.
Uracil replaces thymine in RNA. These two bases are identical except that uracil lacks the 5' methyl group. Adenine and guanine belong to the double-ringed class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines (abbreviated as Y).
A base covalently bound to the 1' carbon of a ribose or deoxyribose is called a nucleoside, and a nucleoside with one or more phosphate groups attached at the 5' carbon is called a nucleotide.
Apart from adenosine (A), cytidine (C), guanosine (G), thymidine (T) and uridine (U), DNA and RNA also contain bases that have been modified after the nucleic acid chain has been formed. In DNA, the only modified base is 5-methylcytidine (m5C). In RNA, there are many modified bases, including pseudouridine (Ψ), dihydrouridine (D), inosine (I), ribothymidine (rT) and 7-methylguanosine (m7G).
Hypoxanthine and xanthine are two of the many bases created through mutagen presence, both of them through deamination (replacement of the amine-group with a hydroxyl-group). Hypoxanthine is produced from adenine, xanthine from guanine. Similarly, deamination of cytosine results in uracil.
# Structure
- The "skeleton" of adenine and guanin is purine, hence the name purine-bases.
- The "skeleton" of cytosine, uracil and thymine is pyrimidine, hence pyrimidine-bases.
## Main bases
These are incorporated into the growing chain during RNA and/or DNA synthesis.
## Modified purine bases
These are examples of modified adenosine or guanosine.
## Modified pyrimidine bases
These are examples of modified cytidine, thymidine or uridine.
# Novel Bases
A vast number of nucleobases analogues exist.
The most common application are used as fluorescent probes, either directly or indirectly, such as Aminoallyl nucleotide which are used to label cRNA or cDNA in microarrays.
Several groups are working on alternative "extra" base pairs to extend the genetic code, such as isoguanine and isocytosine or the fluorescent 2-amino-6-(2-thienyl)purine and pyrrole-2-carbaldehyde.
In medicine, several nucleoside analogues are used as anticancer and antiviral agents. The viral polymerase incorporates these compounds with non-canon bases. These compounds are activated in the cells by being converted into nucleotides, they are adminisered as nuclosides as charged nucleotides cannot easily cross cell membranes. | Nucleobase
Nucleobases (or Nucleotide bases) are the parts of RNA and DNA that may be involved in pairing (see also base pairs). These include cytosine, guanine, adenine, thymine (DNA) and uracil (RNA). These are abbreviated as C, G, A, T, and U, respectively. They are usually simply called bases in genetics. Because A, G, C, and T appear in the DNA, these molecules are called DNA-bases; A, G, C, and U are called RNA-bases, respectively.
Uracil replaces thymine in RNA. These two bases are identical except that uracil lacks the 5' methyl group. Adenine and guanine belong to the double-ringed class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines (abbreviated as Y).
A base covalently bound to the 1' carbon of a ribose or deoxyribose is called a nucleoside, and a nucleoside with one or more phosphate groups attached at the 5' carbon is called a nucleotide.
Apart from adenosine (A), cytidine (C), guanosine (G), thymidine (T) and uridine (U), DNA and RNA also contain bases that have been modified after the nucleic acid chain has been formed. In DNA, the only modified base is 5-methylcytidine (m5C). In RNA, there are many modified bases, including pseudouridine (Ψ), dihydrouridine (D), inosine (I), ribothymidine (rT) and 7-methylguanosine (m7G).[1][2]
Hypoxanthine and xanthine are two of the many bases created through mutagen presence, both of them through deamination (replacement of the amine-group with a hydroxyl-group). Hypoxanthine is produced from adenine, xanthine from guanine.[3] Similarly, deamination of cytosine results in uracil.
# Structure
- The "skeleton" of adenine and guanin is purine, hence the name purine-bases.
- The "skeleton" of cytosine, uracil and thymine is pyrimidine, hence pyrimidine-bases.
## Main bases
These are incorporated into the growing chain during RNA and/or DNA synthesis.
## Modified purine bases
These are examples of modified adenosine or guanosine.
## Modified pyrimidine bases
These are examples of modified cytidine, thymidine or uridine.
# Novel Bases
A vast number of nucleobases analogues exist.
The most common application are used as fluorescent probes, either directly or indirectly, such as Aminoallyl nucleotide which are used to label cRNA or cDNA in microarrays.
Several groups are working on alternative "extra" base pairs to extend the genetic code, such as isoguanine and isocytosine or the fluorescent 2-amino-6-(2-thienyl)purine and pyrrole-2-carbaldehyde.
In medicine, several nucleoside analogues are used as anticancer and antiviral agents. The viral polymerase incorporates these compounds with non-canon bases. These compounds are activated in the cells by being converted into nucleotides, they are adminisered as nuclosides as charged nucleotides cannot easily cross cell membranes. | https://www.wikidoc.org/index.php/Nucleobase | |
7ae36cc4e2cce424412a084fea846b939bbec814 | wikidoc | Nucleoside | Nucleoside
# Overview
Nucleosides are glycosylamines made by attaching a nucleobase (often referred to simply as base) to a ribose or deoxyribose ring. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine. In short, a nucleoside is a base linked to sugar.
Nucleosides can be phosphorylated by specific kinases in the cell, producing nucleotides, which are the molecular building blocks of DNA and RNA.
Nucleosides are produced as the second step in nucleic acid digestion, whereby nucleotidases break down nucleotides (such as the thymine nucleotide) into nucleosides (such as thymidine) and phosphate. The nucleosides, in turn, are subsequently broken down
- in the lumen of the digestive system by nucleosidases into nitrogenous bases and ribose (or deoxyribose), and
- inside the cell by nucleoside phosphorylases into nitrogenous bases, and ribose-1-phosphate (or deoxyribose-1-phosphate).
Nucleosides can be produced by combining nucleobases with deoxyribose rings as well.
Nucleosides differ from nucleotides by having a hydroxyl group attached to carbon number 5 (the one that isn't in the ring) of the ribose, rather than one or more phosphate groups.
In medicine several nucleoside analogues are used as antiviral or anticancer agents. The viral polymerase incorporates these compounds with non-canon bases. These compounds are activated in the cells by being converted into nucleotides, they are administered as nuclosides since charged nucleotides cannot easily cross cell membranes.
In molecular biology several analogues of the sugar back bone exist. Due to the low stability of RNA, which is prone to hydrolysis, several more stable alternative nucleoside/nucleotide analogues are used which correctly bind to RNA. This is achieved by using a different backbone sugar. These analogues includ LNA, morpholino, PNA.
In sequencing dideoxynucleotides are used. These nucleotides posses a non-canon sugar, dideoxyribose which lacks 3' hydroxyl group (which accepts the phosphate) and therefore cannot bond with the next base, terminating the chain as DNA polymerases mistake it for a regular deoxyribonucleotide. | Nucleoside
# Overview
Nucleosides are glycosylamines made by attaching a nucleobase (often referred to simply as base) to a ribose or deoxyribose ring. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine. In short, a nucleoside is a base linked to sugar.
Nucleosides can be phosphorylated by specific kinases in the cell, producing nucleotides, which are the molecular building blocks of DNA and RNA.
Nucleosides are produced as the second step in nucleic acid digestion, whereby nucleotidases break down nucleotides (such as the thymine nucleotide) into nucleosides (such as thymidine) and phosphate. The nucleosides, in turn, are subsequently broken down
- in the lumen of the digestive system by nucleosidases into nitrogenous bases and ribose (or deoxyribose), and
- inside the cell by nucleoside phosphorylases into nitrogenous bases, and ribose-1-phosphate (or deoxyribose-1-phosphate).
Nucleosides can be produced by combining nucleobases with deoxyribose rings as well.
Nucleosides differ from nucleotides by having a hydroxyl group attached to carbon number 5 (the one that isn't in the ring) of the ribose, rather than one or more phosphate groups.
In medicine several nucleoside analogues are used as antiviral or anticancer agents. The viral polymerase incorporates these compounds with non-canon bases. These compounds are activated in the cells by being converted into nucleotides, they are administered as nuclosides since charged nucleotides cannot easily cross cell membranes.
In molecular biology several analogues of the sugar back bone exist. Due to the low stability of RNA, which is prone to hydrolysis, several more stable alternative nucleoside/nucleotide analogues are used which correctly bind to RNA. This is achieved by using a different backbone sugar. These analogues includ LNA, morpholino, PNA.
In sequencing dideoxynucleotides are used. These nucleotides posses a non-canon sugar, dideoxyribose which lacks 3' hydroxyl group (which accepts the phosphate) and therefore cannot bond with the next base, terminating the chain as DNA polymerases mistake it for a regular deoxyribonucleotide. | https://www.wikidoc.org/index.php/Nucleoside | |
2734e1e613420312566af0a5cfa46e54f5a80238 | wikidoc | Nucleosome | Nucleosome
Nucleosomes form the fundamental repeating units of eukaryotic chromatin, which is used to pack the large eukaryotic genomes into the nucleus while still ensuring appropriate access to it (in mammalian cells approximately 2 m of linear DNA have to be packed into a nucleus of roughly 10 µm diameter). Nucleosomes are folded through a series of successively higher order structures to eventually form a chromosome; this both compacts DNA and creates an added layer of regulatory control which ensures correct gene expression. Nucleosomes are thought to carry epigenetically inherited information in the form of covalent modifications of their core histones.
The nucleosome hypothesis proposed by Don and Ada Olins and Roger Kornberg
in 1974, was a paradigm shift for understanding eukaryotic gene expression.
The nucleosome core particle consists of approximately 147 base pairs of DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer consisting of 2 copies each of the core histones H2A, H2B, H3, and H4. Linker histones such as H1 and its isoforms are involved in chromatin compaction and sit at the base of the nucleosome near the DNA entry and exit binding to the linker region of the DNA. Non-condensed nucleosomes without the linker histone resemble "beads on a string of DNA" under an electron microscope.
In contrast to most eukaryotic cells mature sperm cells largely use protamines to package their genomic DNA, most likely to achieve an even higher packaging ratio. Histone equivalents and a simplified chromatin structure have also been found in Archea, proving that eukaryotes are not the only organisms that use nucleosomes.
# Structure
## Structure of the core particle
### Overview
Early structural studies provided evidence that an octamer of histone proteins wraps DNA around itself in about two turns of a left-handed superhelix. In 1997 the first near atomic resolution crystal structure of the nucleosome was solved by the Richmond group showing some of the most important details of the particle. The structure of over 20 different nucleosome core particles have been solved to date, including those containing histone variants and histones from different species. The structure of the nucleosome core particle is remarkably conserved, and even a change of over 100 residues between frog and yeast histones results in electron density maps with an overall root mean square deviation (r.m.s.d) of only 1.6Å.
### The nucleosome core particle
The nucleosome core particle (shown in the figure) consists of about 146 bp of DNA wrapped in 1.67 left-handed superhelical turns around the histone octamer, consisting of 2 copies each of the core histones H2A, H2B, H3, and H4. Adjacent nucleosomes are joined by a stretch of free DNA termed "linker DNA" which varies from 10 - 80 bp in length depending on species and tissue type).
The core histone proteins contain a characteristic structural motif termed the "histone fold" which consists of three alpha-helices (α1-3) separated by two loops (L1-2). In solution the histones form H2A-H2B heterodimers and H3-H4 heterotetramers. Histones dimerise about their long α2 helices in an anti-parallel orientation, and in the case of H3 and H4, two such dimers form a 4-helix bundle stabilised by extensive H3-H3’ interaction. The H2A/H2B dimer binds onto the H3/H4 tetramer due to interactions between H4 and H2B which include the formation of a hydrophobic cluster.
The histone octamer is formed by a central H3/H4 tetramer sandwiched between two H2A/H2B dimers. Due to the highly basic charge of all four core histones, the histone octamer is only stable in the presence of DNA or very high salt concentrations.
The nucleosome contains over 120 direct protein-DNA interactions and several hundred water mediated ones. Direct protein - DNA interactions are not spread evenly about the octamer surface but rather located at discrete sites. These are due to the formation of two types of DNA binding sites within the octamer; the α1α1 site which uses the α1 helix from two adjacent histones and the L1L2 site formed by the L1 and L2 loops. Salt links and hydrogen bonding between both side chain basic and hydroxyl groups and main chain amides with the DNA backbone phosphates form the bulk of interactions with the DNA. This is important given that the ubiquitous distribution of nucleosomes along genomes requires it to be a non-sequence-specific DNA-binding factor. Although nucleosomes tend to prefer some DNA sequences over others, they are capable of binding practically to any sequence, which is thought to be due to the flexibility in the formation of these water-mediated interactions. In addition, non-polar interactions are made between protein side chains and the deoxyribose groups, and an arginine side chain intercalates into the DNA minor groove at all 14 sites it faces the octamer surface.
The distribution and strength of DNA binding sites about the octamer surface distorts the DNA within the nucleosome core. The DNA is non-uniformly bent and also contains twist defects. The twist of free B-form DNA in solution is 10.5 bp per turn, however, the overall twist of nucleosomal DNA is only 10.2 bp per turn, varying from a value of 9.4 to 10.9 bp per turn.
### Histone tail domains
The histone tail extensions constitute up to 30% by mass of histones, but are not visible in the crystal structures of nucleosomes due to their high intrinsic flexibility and have been thought to be largely unstructured. The N-terminal tails of histones H3 and H2B pass through a channel formed by the minor grooves of the two DNA strands, protruding from the DNA every 20 bp. The N-terminal tail of histone H4 on the other hand has a region of highly basic amino acids (16-25) which, in the crystal structure, forms an interaction with the highly acidic surface region of a H2A-H2B dimer of another nucleosome, being potentially relevant for the higher-order structure of nucleosomes. This interaction is thought to occur also under physiological conditions and suggests that acetylation of the H4 tail distorts the higher order structure of chromatin.
## Higher order structure
The organization of the DNA that is achieved by the nucleosome can not fully explain the packaging of DNA observed in the cell nucleus. Further compaction of chromatin into the cell nucleus is necessary, but is not yet well understood. The current understanding is that repeating nucleosomes with intervening "linker" DNA form a 10-nm-fiber, known descriptively as "beads on a string", and have a packing ratio of about five to ten. A chain of nucleosomes can be arranged in a 30 nm fiber, a compacted structure with a packing ratio of ~50 and whose formation is dependent on the presence of the H1 histone.
A crystal structure of a tetranucleosome has been presented and used to build up a proposed structure of the 30 nm fiber as a two-start helix.
There is still a certain amount of contention regarding this model as it is incompatible with recent electron microscopy data. Beyond this, the structure of chromatin is poorly understood, but it is classically suggested that the 30 nm fiber is arranged into loops along a central protein scaffold to form transcriptionally active euchromatin. Further compaction leads to transcriptionally inactive heterochromatin.
# Nucleosome dynamics
Although the nucleosome is a very stable protein-DNA complex, it is not static and has been shown to undergo a number of different structural re-arrangements including nucleosome sliding and DNA site exposure.
## Nucleosome sliding
Work performed in the Bradbury laboratory showed that nucleosomes reconstituted onto the 5S DNA positioning sequence were able to reposition themselves translationally onto adjacent sequences when incubated thermally. Later work showed that this repositioning did not require disruption of the histone octamer but was consistent with nucleosomes being able to “slide” along the DNA in cis. In 2008, It was further revealed that CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified. Although nucleosomes are intrinsically mobile, eukaryotes have evolved a large family of ATP-dependent chromatin remodelling enzymes to alter chromatin structure, many of which do so via nucleosome sliding.
## DNA site exposure
Work from the Widom laboratory has shown that nucleosomal DNA is in equilibrium between a wrapped and unwrapped state. Measurements of these rates using time resolved FRET revealed that DNA within the nucleosome remains fully wrapped for only 250ms before it is unwrapped for 10-50ms and then rapidly rewrapped . This implies that DNA does not need to be actively dissociated from the nucleosome but that there is a significant fraction of time during which it is fully accessible. Indeed, this can be extended to the observation that introducing a DNA binding sequence within the nucleosome increases the accessibility of adjacent regions of DNA when bound . This propensity for DNA within the nucleosome to “breathe” is predicted to have important functional consequences for all DNA binding proteins that operate in a chromatin environment.
# Modulating nucleosome structure
Eukaryotic genomes are ubiquitously associated into chromatin; however, cells need to spatially and temporally regulate specific loci independently of bulk chromatin. In order to achieve the high level of control required to co-ordinate nuclear processes such as DNA replication, repair and transcription, cells have developed a variety of means to locally and specifically modulate chromatin structure and function. This can involve covalent modification of histones, the incorporation of histone variants and non-covalent remodelling by ATP-dependent remodelling enzymes.
## Histone post-translational modifications
Since they were discovered in the mid 1960’s histone modifications have been predicted to affect transcription. The fact that most of the early post-translational modifications found were concentrated within the tail extensions that protrude from the nucleosome core lead to two main theories regarding the mechanism of histone modification. The first of the theories suggested that they may affect electrostatic interactions between the histone tails and DNA to “loosen” chromatin structure. Later it was proposed that combinations of these modifications may create binding epitopes with which to recruit other proteins. Recently, given that more modifications have been found in the structured regions of histones it has been put forward that these modifications may affect histone-DNA and histone-histone interactions within the nucleosome core.
Some modifications have been shown to be correlated with gene silencing, others seem to be correlated with gene activation. Common modifications include acetylation, methylation or ubiquitination of lysine; methylation of arginine and phosphorylation of serine. The information stored in this way is considered epigenetic since it is not encoded in the DNA but is still inherited to daughter cells. The maintenance of a repressed or activated status of a gene is often necessary for cellular differentiation.
## Histone variants
Whilst histones are remarkably conserved throughout evolution, several variant forms have been identified. Interestingly, this diversification of histone function is restricted to H2A and H3, with H2B and H4 being mostly invariant. H2A can be replaced by H2AZ (which leads to reduced nucleosome stability) or H2AX (which is associated with DNA repair and T cell differentiation) whereas the inactive X chromosomes in mammals are enriched in macroH2A. H3 can be replaced by H3.3 (which correlates with activate genes) and in centromeres H3 is replaced by CENPA.
## ATP-dependent nucleosome remodelling
A number of distinct reactions are associated with the term ATP-dependent chromatin remodelling. Remodelling enzymes have been shown to slide nucleosomes along DNA,disrupt histone-DNA contacts to the extent of destabilising the H2A/H2B dimer and to generate negative superhelical torsion in DNA and chromatin. Recently, the Swr1 remodelling enzyme has been shown to introduce the variant histone H2A.Z into nucleosomes. At present, it is not clear if all of these represent distinct reactions or merely alternative outcomes of a common mechanism. What is shared between all, and indeed the hallmark of ATP-dependent chromatin remodelling, is that they all result in altered DNA accessibility.
Studies looking at gene activation in vivo and, more astonishingly, remodelling in vitro has revealed that chromatin remodelling events and transcription-factor binding are cyclical and periodic in nature. While the consequences of this for the reaction mechanism of chromatin remodelling are not known, the dynamic nature of the system may allow it to respond faster to external stimuli.
## Dynamic nucleosome remodelling across the Yeast genome
Studies in 2007 have catalogued nucleosome positions in yeast and shown that nucleosomes are enriched in promoter regions .
About 80% of the yeast genome appears to be covered by nucleosomes and the pattern of nucleosome positioning clearly relates to DNA regions that regulate transcription and regions that are transcribed. Most recently, a new study examined ‘’dynamic changes’’ in nucleosome repositioning during a global transcriptional reprogramming event to elucidate the effects on nucleosome displacement during genome-wide transcriptional changes in yeast (Saccharomyces cerevisiae) . The results suggested that nucleosomes that were localized to promoter regions are displaced in response to stress (like heat shock). In addition, the removal of nucleosomes usually corresponded to transcriptional activation and the replacement of nucleosomes usually corresponded to transcriptional repression, presumably because transcription factor binding sites became more or less accessible, respectively. In general, only one or two nucleosomes were repositioned at the promoter to effect these transcriptional changes. However, even in chromosomal regions that were not associated with transcriptional changes, nucleosome repositioning was observed, suggesting that the covering and uncovering of transcriptional DNA does not necessarily produce a transcriptional event.
# Nucleosome assembly in vitro
Nucleosomes can be assembled in vitro by either using purified native or recombinant histones. One standard technique of loading the DNA around the histones involves the use of salt dialysis. A reaction consisting of the histone octamers and a naked DNA template can be incubated together at a salt concentration of 2 M. By steadily decreasing the salt concentration, the DNA will equilibrate to a position where it is wrapped around the histone octamers, forming nucleosomes. In appropriate conditions, this reconstitution process allows for the nucleosome positioning affinity of a given sequence to be mapped experimentally. | Nucleosome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Nucleosomes form the fundamental repeating units of eukaryotic chromatin[1], which is used to pack the large eukaryotic genomes into the nucleus while still ensuring appropriate access to it (in mammalian cells approximately 2 m of linear DNA have to be packed into a nucleus of roughly 10 µm diameter). Nucleosomes are folded through a series of successively higher order structures to eventually form a chromosome; this both compacts DNA and creates an added layer of regulatory control which ensures correct gene expression. Nucleosomes are thought to carry epigenetically inherited information in the form of covalent modifications of their core histones.
The nucleosome hypothesis proposed by Don and Ada Olins[2] and Roger Kornberg[3][4]
in 1974, was a paradigm shift for understanding eukaryotic gene expression.
The nucleosome core particle consists of approximately 147[5] base pairs of DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer consisting of 2 copies each of the core histones H2A, H2B, H3, and H4.[6] Linker histones such as H1 and its isoforms are involved in chromatin compaction and sit at the base of the nucleosome near the DNA entry and exit binding to the linker region of the DNA.[7] Non-condensed nucleosomes without the linker histone resemble "beads on a string of DNA" under an electron microscope.[8]
In contrast to most eukaryotic cells mature sperm cells largely use protamines to package their genomic DNA, most likely to achieve an even higher packaging ratio.[9] Histone equivalents and a simplified chromatin structure have also been found in Archea[10], proving that eukaryotes are not the only organisms that use nucleosomes.
# Structure
## Structure of the core particle
### Overview
Early structural studies provided evidence that an octamer of histone proteins wraps DNA around itself in about two turns of a left-handed superhelix. In 1997 the first near atomic resolution crystal structure of the nucleosome was solved by the Richmond group showing some of the most important details of the particle. The structure of over 20 different nucleosome core particles have been solved to date[11], including those containing histone variants and histones from different species. The structure of the nucleosome core particle is remarkably conserved, and even a change of over 100 residues between frog and yeast histones results in electron density maps with an overall root mean square deviation (r.m.s.d) of only 1.6Å[12].
### The nucleosome core particle
The nucleosome core particle (shown in the figure) consists of about 146[5] bp of DNA wrapped in 1.67 left-handed superhelical turns around the histone octamer, consisting of 2 copies each of the core histones H2A, H2B, H3, and H4. Adjacent nucleosomes are joined by a stretch of free DNA termed "linker DNA" which varies from 10 - 80 bp in length depending on species and tissue type[10]).
The core histone proteins contain a characteristic structural motif termed the "histone fold" which consists of three alpha-helices (α1-3) separated by two loops (L1-2). In solution the histones form H2A-H2B heterodimers and H3-H4 heterotetramers. Histones dimerise about their long α2 helices in an anti-parallel orientation, and in the case of H3 and H4, two such dimers form a 4-helix bundle stabilised by extensive H3-H3’ interaction. The H2A/H2B dimer binds onto the H3/H4 tetramer due to interactions between H4 and H2B which include the formation of a hydrophobic cluster[6].
The histone octamer is formed by a central H3/H4 tetramer sandwiched between two H2A/H2B dimers. Due to the highly basic charge of all four core histones, the histone octamer is only stable in the presence of DNA or very high salt concentrations.
The nucleosome contains over 120 direct protein-DNA interactions and several hundred water mediated ones[13]. Direct protein - DNA interactions are not spread evenly about the octamer surface but rather located at discrete sites. These are due to the formation of two types of DNA binding sites within the octamer; the α1α1 site which uses the α1 helix from two adjacent histones and the L1L2 site formed by the L1 and L2 loops. Salt links and hydrogen bonding between both side chain basic and hydroxyl groups and main chain amides with the DNA backbone phosphates form the bulk of interactions with the DNA. This is important given that the ubiquitous distribution of nucleosomes along genomes requires it to be a non-sequence-specific DNA-binding factor. Although nucleosomes tend to prefer some DNA sequences over others[14], they are capable of binding practically to any sequence, which is thought to be due to the flexibility in the formation of these water-mediated interactions. In addition, non-polar interactions are made between protein side chains and the deoxyribose groups, and an arginine side chain intercalates into the DNA minor groove at all 14 sites it faces the octamer surface.
The distribution and strength of DNA binding sites about the octamer surface distorts the DNA within the nucleosome core. The DNA is non-uniformly bent and also contains twist defects. The twist of free B-form DNA in solution is 10.5 bp per turn, however, the overall twist of nucleosomal DNA is only 10.2 bp per turn, varying from a value of 9.4 to 10.9 bp per turn.
### Histone tail domains
The histone tail extensions constitute up to 30% by mass of histones, but are not visible in the crystal structures of nucleosomes due to their high intrinsic flexibility and have been thought to be largely unstructured[15]. The N-terminal tails of histones H3 and H2B pass through a channel formed by the minor grooves of the two DNA strands, protruding from the DNA every 20 bp. The N-terminal tail of histone H4 on the other hand has a region of highly basic amino acids (16-25) which, in the crystal structure, forms an interaction with the highly acidic surface region of a H2A-H2B dimer of another nucleosome, being potentially relevant for the higher-order structure of nucleosomes. This interaction is thought to occur also under physiological conditions and suggests that acetylation of the H4 tail distorts the higher order structure of chromatin.
## Higher order structure
The organization of the DNA that is achieved by the nucleosome can not fully explain the packaging of DNA observed in the cell nucleus. Further compaction of chromatin into the cell nucleus is necessary, but is not yet well understood. The current understanding[16] is that repeating nucleosomes with intervening "linker" DNA form a 10-nm-fiber, known descriptively as "beads on a string", and have a packing ratio of about five to ten[10]. A chain of nucleosomes can be arranged in a 30 nm fiber, a compacted structure with a packing ratio of ~50[10] and whose formation is dependent on the presence of the H1 histone.
A crystal structure of a tetranucleosome has been presented and used to build up a proposed structure of the 30 nm fiber as a two-start helix.[17]
There is still a certain amount of contention regarding this model as it is incompatible with recent electron microscopy data[18]. Beyond this, the structure of chromatin is poorly understood, but it is classically suggested that the 30 nm fiber is arranged into loops along a central protein scaffold to form transcriptionally active euchromatin. Further compaction leads to transcriptionally inactive heterochromatin.
# Nucleosome dynamics
Although the nucleosome is a very stable protein-DNA complex, it is not static and has been shown to undergo a number of different structural re-arrangements including nucleosome sliding and DNA site exposure.
## Nucleosome sliding
Work performed in the Bradbury laboratory showed that nucleosomes reconstituted onto the 5S DNA positioning sequence were able to reposition themselves translationally onto adjacent sequences when incubated thermally[19]. Later work showed that this repositioning did not require disruption of the histone octamer but was consistent with nucleosomes being able to “slide” along the DNA in cis. In 2008, It was further revealed that CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified[20]. Although nucleosomes are intrinsically mobile, eukaryotes have evolved a large family of ATP-dependent chromatin remodelling enzymes to alter chromatin structure, many of which do so via nucleosome sliding.
## DNA site exposure
Work from the Widom laboratory has shown that nucleosomal DNA is in equilibrium between a wrapped and unwrapped state. Measurements of these rates using time resolved FRET revealed that DNA within the nucleosome remains fully wrapped for only 250ms before it is unwrapped for 10-50ms and then rapidly rewrapped [21]. This implies that DNA does not need to be actively dissociated from the nucleosome but that there is a significant fraction of time during which it is fully accessible. Indeed, this can be extended to the observation that introducing a DNA binding sequence within the nucleosome increases the accessibility of adjacent regions of DNA when bound [22]. This propensity for DNA within the nucleosome to “breathe” is predicted to have important functional consequences for all DNA binding proteins that operate in a chromatin environment.
# Modulating nucleosome structure
Eukaryotic genomes are ubiquitously associated into chromatin; however, cells need to spatially and temporally regulate specific loci independently of bulk chromatin. In order to achieve the high level of control required to co-ordinate nuclear processes such as DNA replication, repair and transcription, cells have developed a variety of means to locally and specifically modulate chromatin structure and function. This can involve covalent modification of histones, the incorporation of histone variants and non-covalent remodelling by ATP-dependent remodelling enzymes.
## Histone post-translational modifications
Since they were discovered in the mid 1960’s histone modifications have been predicted to affect transcription[23]. The fact that most of the early post-translational modifications found were concentrated within the tail extensions that protrude from the nucleosome core lead to two main theories regarding the mechanism of histone modification. The first of the theories suggested that they may affect electrostatic interactions between the histone tails and DNA to “loosen” chromatin structure. Later it was proposed that combinations of these modifications may create binding epitopes with which to recruit other proteins[24]. Recently, given that more modifications have been found in the structured regions of histones it has been put forward that these modifications may affect histone-DNA[25] and histone-histone[26] interactions within the nucleosome core.
Some modifications have been shown to be correlated with gene silencing, others seem to be correlated with gene activation. Common modifications include acetylation, methylation or ubiquitination of lysine; methylation of arginine and phosphorylation of serine. The information stored in this way is considered epigenetic since it is not encoded in the DNA but is still inherited to daughter cells. The maintenance of a repressed or activated status of a gene is often necessary for cellular differentiation.[10]
## Histone variants
Whilst histones are remarkably conserved throughout evolution, several variant forms have been identified. Interestingly, this diversification of histone function is restricted to H2A and H3, with H2B and H4 being mostly invariant. H2A can be replaced by H2AZ (which leads to reduced nucleosome stability) or H2AX (which is associated with DNA repair and T cell differentiation) whereas the inactive X chromosomes in mammals are enriched in macroH2A. H3 can be replaced by H3.3 (which correlates with activate genes) and in centromeres H3 is replaced by CENPA.[10]
## ATP-dependent nucleosome remodelling
A number of distinct reactions are associated with the term ATP-dependent chromatin remodelling. Remodelling enzymes have been shown to slide nucleosomes along DNA[27],disrupt histone-DNA contacts to the extent of destabilising the H2A/H2B dimer[28][29] and to generate negative superhelical torsion in DNA and chromatin[30]. Recently, the Swr1 remodelling enzyme has been shown to introduce the variant histone H2A.Z into nucleosomes[31]. At present, it is not clear if all of these represent distinct reactions or merely alternative outcomes of a common mechanism. What is shared between all, and indeed the hallmark of ATP-dependent chromatin remodelling, is that they all result in altered DNA accessibility.
Studies looking at gene activation in vivo[32] and, more astonishingly, remodelling in vitro[33] has revealed that chromatin remodelling events and transcription-factor binding are cyclical and periodic in nature. While the consequences of this for the reaction mechanism of chromatin remodelling are not known, the dynamic nature of the system may allow it to respond faster to external stimuli.
## Dynamic nucleosome remodelling across the Yeast genome
Studies in 2007 have catalogued nucleosome positions in yeast and shown that nucleosomes are enriched in promoter regions [34][35][36].
About 80% of the yeast genome appears to be covered by nucleosomes and the pattern of nucleosome positioning clearly relates to DNA regions that regulate transcription and regions that are transcribed. Most recently, a new study examined ‘’dynamic changes’’ in nucleosome repositioning during a global transcriptional reprogramming event to elucidate the effects on nucleosome displacement during genome-wide transcriptional changes in yeast (Saccharomyces cerevisiae) [37]. The results suggested that nucleosomes that were localized to promoter regions are displaced in response to stress (like heat shock). In addition, the removal of nucleosomes usually corresponded to transcriptional activation and the replacement of nucleosomes usually corresponded to transcriptional repression, presumably because transcription factor binding sites became more or less accessible, respectively. In general, only one or two nucleosomes were repositioned at the promoter to effect these transcriptional changes. However, even in chromosomal regions that were not associated with transcriptional changes, nucleosome repositioning was observed, suggesting that the covering and uncovering of transcriptional DNA does not necessarily produce a transcriptional event.
# Nucleosome assembly in vitro
Nucleosomes can be assembled in vitro by either using purified native or recombinant histones.[38][39] One standard technique of loading the DNA around the histones involves the use of salt dialysis. A reaction consisting of the histone octamers and a naked DNA template can be incubated together at a salt concentration of 2 M. By steadily decreasing the salt concentration, the DNA will equilibrate to a position where it is wrapped around the histone octamers, forming nucleosomes. In appropriate conditions, this reconstitution process allows for the nucleosome positioning affinity of a given sequence to be mapped experimentally. [40] | https://www.wikidoc.org/index.php/Nucleosome | |
1ae7a03b7df2be202ada5d1eb31cdea103f26513 | wikidoc | Nudibranch | Nudibranch
A nudibranch (Template:PronEng) is a member of one suborder of soft-bodied, shell-less marine opisthobranch gastropod mollusks, which are noted for their often extraordinary colors and striking forms. The suborder Nudibranchia is the largest suborder of heterobranchs, with more than 3,000 described species.
The word "nudibranch" comes from the Latin nudus, naked, and the Greek brankhia, gills.
Nudibranchs are often casually called "sea slugs", a non-scientific term which has led some people to assume that every sea slug is a nudibranch. However, while it is true that nudibranchs are very numerous in terms of species, and are often very attractive, there are numerous other kinds of sea slugs belonging to several taxonomic groups that are not very closely related to nudibranchs. A fair number of these other sea slugs are colorful and thus are even more easily confused with nudibranchs.
(Other marine shell-less gastropods or "sea slug" groups include additional heterobranch shell-less gastropod groups such as the Cephalaspidea sea slugs including the colorful Aglajidae, and other heterobranchs such as the Sacoglossa, the sea butterflies, the sea angels, and the often rather large sea hares. The term sea slug is also sometimes loosely applied to the only very distantly related, pelagic, caenogastropods within the superfamily Carinarioidea, and may also be casually used for the even more distantly related pulmonate sea slugs, the Onchidiidae.)
# Distribution
Nudibranchs occur worldwide.
# Habitat
Nudibranchs live at virtually all depths of salt water, but reach their greatest size and variation in warm, shallow waters.
# Description
The body forms of nudibranchs vary enormously, but because they are opisthobranchs, unlike most other gastropods they are bilaterally symmetrical because they have undergone secondary detorsion.
They lack a mantle cavity.
They vary in adult size from 20 to 600 mm.
The adult form is without a shell or operculum (a bony or horny plate covering the opening of the shell, when the body is withdrawn).
The name nudibranch is appropriate, since the dorids (infraclass Anthobranchia) breathe through a branchial plume of bushy extremities on their back, rather than using gills. By contrast, on the back of the aeolids in infraclass Cladobranchia there are brightly colored sets of tentacles called cerata.
Nudibranchs have cephalic (head) tentacles, which are sensitive to touch, taste, and smell. Club-shaped rhinophores detect odors.
# Life habits
## Reproduction
Nudibranchs are hermaphroditic, and thus have a set of reproductive organs for both genders, but they can rarely fertilize themselves.
Nudibranchs typically deposit their eggs within a gelatinous spiral.
## Feeding
Nudibranchs are carnivorous. Some feed on sponges, others on hydroids, others on bryozoans, and some are cannibals, eating other sea slugs, or, on some occasions, members of their own species. There is also a group that feeds on tunicates and barnacles.
They even sometimes feed on anemones.
# Colors and camouflage
Among this group can be found the most colorful creatures on earth. In the course of evolution, sea slugs have lost their shell because they have developed other defense mechanisms. Their anatomy may resemble the texture and color of the surrounding plants, allowing them to camouflage (cryptic behavior). Others, as seen especially well on Chromodorids, have an intense and bright coloring, which warns that they are distasteful or poisonous (aposematic coloration).
Nudibranchs that feed on hydroids can store the hydroid's nematocysts (stinging cells) in the dorsal body wall, the cerata. The nematocysts wander through the alimentary tract without harming the nudibranch. Once further into the organ, the cells are brought to the specific placements on the creatures hind body via intestinal protuberances. Nudibranches can protect themselves from the hydroids and their nematocysts. It is not yet clear how, but special cells with large vacuoles probably play an important role. They can also take in plants' chloroplasts (plant cell organelles used for photosynthesis) and use them to make food for themselves.
Another way of protection is the release of a sour liquid from the skin. Once the specimen is physically irritated or touched by another creature, it will release the slime automatically.
# Taxonomy
The taxonomy of the Nudibranchia is still under investigation. Many taxonomists in the past treated the Nudibranchia as an order, based on the authoritative work of Johannes Thiele (1931), who built on the concepts of Henri Milne-Edwards (1848). Newer insights derived from morphological data and gene-sequence research, have confirmed these ideas. On the basis of investigation of 18S rDNA sequence data, there is strong evidence for support of the monophyly of the Nudibranchia and its two major groups, the Anthobranchia/Doridoidea and Cladobranchia.
- Infraorder Anthobranchia Férussac, 1819 (dorids)
Superfamily Doridoidea Rafinesque, 1815
Superfamily Doridoxoidea Bergh, 1900
Superfamily Onchidoridoidea Alder & Hancock, 1845
Superfamily Polyceroidea Alder & Hancock, 1845
- Superfamily Doridoidea Rafinesque, 1815
- Superfamily Doridoxoidea Bergh, 1900
- Superfamily Onchidoridoidea Alder & Hancock, 1845
- Superfamily Polyceroidea Alder & Hancock, 1845
- Infraorder Cladobranchia Willan & Morton, 1984 (aeolids)
Superfamily Aeolidioidea J. E. Gray, 1827
Superfamily Arminoidea Rafinesque, 1814
Superfamily Dendronotoidea Allman, 1845
Superfamily Metarminoidea Odhner in Franc, 1968
- Superfamily Aeolidioidea J. E. Gray, 1827
- Superfamily Arminoidea Rafinesque, 1814
- Superfamily Dendronotoidea Allman, 1845
- Superfamily Metarminoidea Odhner in Franc, 1968
A study published in May 2001, has again revised the taxonomy of the Nudibranchia . They are thus divided into two major clades:
- Anthobranchia (= Bathydoridoidea + Doridoidea)
- Dexiarchia nom. nov. (= Doridoxoidea + Dendronotoidea + Aeolidoidea + “Arminoidea”).
The dorids (infraorder Anthobranchia) have the following characteristics: the branchial plume forms a cluster on the posterior part of the neck, around the eyes. Fringes on the mantle do not contain any intestines.
The aeolids (infraorder Cladobranchia) have the following characteristics: Instead of the branchial plume, they have cerata. They lack a mantle. Only species of the Cladobranchia are reported to house zooxanthellae.
# Where to view nudibranchs
The Birch Aquarium at La Jolla, California, has the largest collection of nudibranchs on display in the United States.
# Footnotes
- ↑ Klussmann-Kolb A (2001). "The Reproductive Systems of the Nudibranchia (Gastropoda, Opisthobranchia): Comparative Histology and Ultrastructure of the Nidamental Glands with Aspects of Functional Morphology". Zoologischer Anzeiger. 240 (2): 119-136..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}
- ↑ Schrödl M.; Wägele H.2 Willan R.C. (2001). "Taxonomic Redescription of the Doridoxidae(Gastropoda: Opisthobranchia), an Enigmatic Family of Deep Water Nudibranchs, with Discussion of Basal Nudibranch Phylogeny". Zoologischer Anzeiger,. 240 (1): 83-97. doi:10.1078/0044-5231-00008. More than one of |pages= and |page= specified (help) | Nudibranch
A nudibranch (Template:PronEng) is a member of one suborder of soft-bodied, shell-less marine opisthobranch gastropod mollusks, which are noted for their often extraordinary colors and striking forms. The suborder Nudibranchia is the largest suborder of heterobranchs, with more than 3,000 described species.
The word "nudibranch" comes from the Latin nudus, naked, and the Greek brankhia, gills.
Nudibranchs are often casually called "sea slugs", a non-scientific term which has led some people to assume that every sea slug is a nudibranch. However, while it is true that nudibranchs are very numerous in terms of species, and are often very attractive, there are numerous other kinds of sea slugs belonging to several taxonomic groups that are not very closely related to nudibranchs. A fair number of these other sea slugs are colorful and thus are even more easily confused with nudibranchs.
(Other marine shell-less gastropods or "sea slug" groups include additional heterobranch shell-less gastropod groups such as the Cephalaspidea sea slugs including the colorful Aglajidae, and other heterobranchs such as the Sacoglossa, the sea butterflies, the sea angels, and the often rather large sea hares. The term sea slug is also sometimes loosely applied to the only very distantly related, pelagic, caenogastropods within the superfamily Carinarioidea, and may also be casually used for the even more distantly related pulmonate sea slugs, the Onchidiidae.)
# Distribution
Nudibranchs occur worldwide.
# Habitat
Nudibranchs live at virtually all depths of salt water, but reach their greatest size and variation in warm, shallow waters.
# Description
The body forms of nudibranchs vary enormously, but because they are opisthobranchs, unlike most other gastropods they are bilaterally symmetrical because they have undergone secondary detorsion.
They lack a mantle cavity.
They vary in adult size from 20 to 600 mm.
The adult form is without a shell or operculum (a bony or horny plate covering the opening of the shell, when the body is withdrawn).
The name nudibranch is appropriate, since the dorids (infraclass Anthobranchia) breathe through a branchial plume of bushy extremities on their back, rather than using gills. By contrast, on the back of the aeolids in infraclass Cladobranchia there are brightly colored sets of tentacles called cerata.
Nudibranchs have cephalic (head) tentacles, which are sensitive to touch, taste, and smell. Club-shaped rhinophores detect odors.
# Life habits
## Reproduction
Nudibranchs are hermaphroditic, and thus have a set of reproductive organs for both genders, but they can rarely fertilize themselves.
Nudibranchs typically deposit their eggs within a gelatinous spiral. [1]
## Feeding
Nudibranchs are carnivorous. Some feed on sponges, others on hydroids, others on bryozoans, and some are cannibals, eating other sea slugs, or, on some occasions, members of their own species. There is also a group that feeds on tunicates and barnacles.
They even sometimes feed on anemones.
# Colors and camouflage
Among this group can be found the most colorful creatures on earth. In the course of evolution, sea slugs have lost their shell because they have developed other defense mechanisms. Their anatomy may resemble the texture and color of the surrounding plants, allowing them to camouflage (cryptic behavior). Others, as seen especially well on Chromodorids, have an intense and bright coloring, which warns that they are distasteful or poisonous (aposematic coloration).
Nudibranchs that feed on hydroids can store the hydroid's nematocysts (stinging cells) in the dorsal body wall, the cerata. The nematocysts wander through the alimentary tract without harming the nudibranch. Once further into the organ, the cells are brought to the specific placements on the creatures hind body via intestinal protuberances. Nudibranches can protect themselves from the hydroids and their nematocysts. It is not yet clear how, but special cells with large vacuoles probably play an important role. They can also take in plants' chloroplasts (plant cell organelles used for photosynthesis) and use them to make food for themselves.
Another way of protection is the release of a sour liquid from the skin. Once the specimen is physically irritated or touched by another creature, it will release the slime automatically.
# Taxonomy
The taxonomy of the Nudibranchia is still under investigation. Many taxonomists in the past treated the Nudibranchia as an order, based on the authoritative work of Johannes Thiele (1931), who built on the concepts of Henri Milne-Edwards (1848). Newer insights derived from morphological data and gene-sequence research, have confirmed these ideas. On the basis of investigation of 18S rDNA sequence data, there is strong evidence for support of the monophyly of the Nudibranchia and its two major groups, the Anthobranchia/Doridoidea and Cladobranchia.
- Infraorder Anthobranchia Férussac, 1819 (dorids)
Superfamily Doridoidea Rafinesque, 1815
Superfamily Doridoxoidea Bergh, 1900
Superfamily Onchidoridoidea Alder & Hancock, 1845
Superfamily Polyceroidea Alder & Hancock, 1845
- Superfamily Doridoidea Rafinesque, 1815
- Superfamily Doridoxoidea Bergh, 1900
- Superfamily Onchidoridoidea Alder & Hancock, 1845
- Superfamily Polyceroidea Alder & Hancock, 1845
- Infraorder Cladobranchia Willan & Morton, 1984 (aeolids)
Superfamily Aeolidioidea J. E. Gray, 1827
Superfamily Arminoidea Rafinesque, 1814
Superfamily Dendronotoidea Allman, 1845
Superfamily Metarminoidea Odhner in Franc, 1968
- Superfamily Aeolidioidea J. E. Gray, 1827
- Superfamily Arminoidea Rafinesque, 1814
- Superfamily Dendronotoidea Allman, 1845
- Superfamily Metarminoidea Odhner in Franc, 1968
A study published in May 2001, has again revised the taxonomy of the Nudibranchia [2]. They are thus divided into two major clades:
- Anthobranchia (= Bathydoridoidea + Doridoidea)
- Dexiarchia nom. nov. (= Doridoxoidea + Dendronotoidea + Aeolidoidea + “Arminoidea”).
The dorids (infraorder Anthobranchia) have the following characteristics: the branchial plume forms a cluster on the posterior part of the neck, around the eyes. Fringes on the mantle do not contain any intestines.
The aeolids (infraorder Cladobranchia) have the following characteristics: Instead of the branchial plume, they have cerata. They lack a mantle. Only species of the Cladobranchia are reported to house zooxanthellae.
# Where to view nudibranchs
The Birch Aquarium at La Jolla, California, has the largest collection of nudibranchs on display in the United States.
# Footnotes
- ↑ Klussmann-Kolb A (2001). "The Reproductive Systems of the Nudibranchia (Gastropoda, Opisthobranchia): Comparative Histology and Ultrastructure of the Nidamental Glands with Aspects of Functional Morphology". Zoologischer Anzeiger. 240 (2): 119-136..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}
- ↑ Schrödl M.; Wägele H.2 Willan R.C. (2001). "Taxonomic Redescription of the Doridoxidae(Gastropoda: Opisthobranchia), an Enigmatic Family of Deep Water Nudibranchs, with Discussion of Basal Nudibranch Phylogeny". Zoologischer Anzeiger,. 240 (1): 83-97. doi:10.1078/0044-5231-00008. More than one of |pages= and |page= specified (help) | https://www.wikidoc.org/index.php/Nudibranch | |
8032f26c219d4a751b806124598bf92820e83b32 | wikidoc | Nutmeg oil | Nutmeg oil
Nutmeg oil is a volatile oil containing borneol and eugenol.
# General uses
The essential oil is obtained by the steam distillation of ground nutmeg and is used heavily in the perfumery and pharmaceutical industries.
The oil is colorless or light yellow and smells and tastes of nutmeg. It contains numerous components of interest to the oleochemical industry, and is used as a natural food flavouring in baked goods, syrups (e.g. Coca Cola), beverages, sweets etc. It replaces ground nutmeg as it leaves no particles in the food. The essential oil is also used in the cosmetic and pharmaceutical industries for instance in tooth paste and as a major ingredient in some cough syrups. In traditional medicine nutmeg and nutmeg oil were used for illnesses related to the nervous and digestive systems. Myristicin in the essential oil is probably the agent responsible for the hallucinogenic properties of nutmeg oil.
# External uses
Externally, the oil is used for rheumatic pain and, like clove oil, can be applied as an emergency treatment to dull toothache. In France, it is given in drop doses in honey for digestive upsets and used for bad breath.
Put 1-2 drops on a cotton swab, and apply to the gums around an aching tooth until dental treatment can be obtained. Use 3-5 drops on a sugar lump or in a teaspoon of honey for nausea, gastroenteritis, chronic diarrhea, and indigestion.
Alternatively a massage oil can be created by diluting 10 drops in 10 ml almond oil. This can be used for muscular pains associated with rheumatism or overexertion. It can also be combined with thyme or rosemary essential oils. To prepare for childbirth, massage the abdomen daily in the three weeks before the baby is due with a mixture of 5 drops nutmeg oil and no more than 5 drops sage oil in 25 ml almond oil. | Nutmeg oil
Nutmeg oil is a volatile oil containing borneol and eugenol.
# General uses
The essential oil is obtained by the steam distillation of ground nutmeg and is used heavily in the perfumery and pharmaceutical industries.
The oil is colorless or light yellow and smells and tastes of nutmeg. It contains numerous components of interest to the oleochemical industry, and is used as a natural food flavouring in baked goods, syrups (e.g. Coca Cola), beverages, sweets etc. It replaces ground nutmeg as it leaves no particles in the food. The essential oil is also used in the cosmetic and pharmaceutical industries for instance in tooth paste and as a major ingredient in some cough syrups. In traditional medicine nutmeg and nutmeg oil were used for illnesses related to the nervous and digestive systems[citation needed]. Myristicin in the essential oil is probably the agent responsible for the hallucinogenic properties of nutmeg oil.
# External uses
Externally, the oil is used for rheumatic pain and, like clove oil, can be applied as an emergency treatment to dull toothache. In France, it is given in drop doses in honey for digestive upsets and used for bad breath.
Put 1-2 drops on a cotton swab, and apply to the gums around an aching tooth until dental treatment can be obtained. Use 3-5 drops on a sugar lump or in a teaspoon of honey for nausea, gastroenteritis, chronic diarrhea, and indigestion.
Alternatively a massage oil can be created by diluting 10 drops in 10 ml almond oil. This can be used for muscular pains associated with rheumatism or overexertion. It can also be combined with thyme or rosemary essential oils. To prepare for childbirth, massage the abdomen daily in the three weeks before the baby is due with a mixture of 5 drops nutmeg oil and no more than 5 drops sage oil in 25 ml almond oil. | https://www.wikidoc.org/index.php/Nutmeg_oil | |
36d413e71e5de83dd2aefbdfda420cdfea9534e3 | wikidoc | Nyctalopin | Nyctalopin
Nyctalopin is a protein located on the surface of photoreceptor-to-ON bipolar cell synapse in the retina. It is composed of 481 amino acids. and is encoded in human by the NYX gene. This gene is found on the chromosome X and has two exons. This protein is a leucine-rich proteoglycan which is expressed in the eye, spleen and brain in mice. Mutations in this gene cause congenital stationary night blindness in humans (CSNB). which is a stable retinal disorder. The consequence of this mutation results in an abnormal night vision. Nyctalopin is critical due to the fact that it generates a depolarizing bipolar cell response due to the mutation on the NYX gene. Most of the time, CSNB are associated to hygh myopia which is the result of a mutation on the same gene. Several mutations can occur on the NYX gene resulting on many form of night blindness in humans. Some studies show that these mutations are more present in Asian population than in Caucasian population. A mouse strain called nob (no b-wave) carries a spontaneous mutation leading to a frameshift in this gene. These mice are used as an animal model for congenital stationary night blindness.
# Discovery
The first evidence of the existence of mutation in NYX gene, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness was provided by Richard G. Weleber at the University of Alberta in 2000.
# Gene location
The NYX gene is located on the short arm (p) of chromosome X, from base pair 41,447,434 to base pair 41,475,710.
# Protein structure
Nyctalopin contains a N-terminal signal peptide and a C-terminal glycosylphosphatidylinositol (GPI) anchor. Predicted signal sequence is likely to be processed by a co-translational mechanism. Nyctalopin does not have two transmembrane domains and the only transmembrane domain is found to be between the amino acid 452 ad 472. In the endoplasmic reticulum, the protein is oriented with the N-terminus in the lumen of the endoplasmic reticulum and the C-terminus is located in the cytoplasm. The central part of the polypeptide encodes 11 consecutive leucines-rich repeats (LRRs). These LRR are flanked by N-terminal and C-terminal rich LRRs Tandem LRRs domains are folded into ß-sheets and α-helices, all joined by loops. According to the cysteine pattern, nyctalopin is part of the class II small leucine-rich proteoglycans. These proteins, are involved in several functions such as cell signalling, growth control, and formation of the extracellular matrix. LRR domains are involved in the protein–protein interaction in small leucine rich repeat proteoglycan family members. Also, LRR domains have a critical role in nyctalopin function. Congenital stationary night blindness in humans appears when a mutation in the LRR domains of nyctalopin occurs.
# Mutations
The complete form of congenital stationary night blindness is due to the absence of nyctalopin. This absence is due to a mutation involving an 85 base pair deletion. In humans, more than 30 mutations are found in the NYX gene and most of them have an impact either on the tertiary structure of the LRR domains of nyctalopin or to truncate the protein. | Nyctalopin
Nyctalopin is a protein located on the surface of photoreceptor-to-ON bipolar cell synapse in the retina. It is composed of 481 amino acids.[1] and is encoded in human by the NYX gene.[2][3][4] This gene is found on the chromosome X[5] and has two exons.[1] This protein is a leucine-rich proteoglycan[6] which is expressed in the eye, spleen and brain in mice.[7] Mutations in this gene cause congenital stationary night blindness in humans (CSNB).[8] which is a stable retinal disorder.[2] The consequence of this mutation results in an abnormal night vision. Nyctalopin is critical due to the fact that it generates a depolarizing bipolar cell response due to the mutation on the NYX gene.[6] Most of the time, CSNB are associated to hygh myopia which is the result of a mutation on the same gene.[1] Several mutations can occur on the NYX gene resulting on many form of night blindness in humans.[1] Some studies show that these mutations are more present in Asian population than in Caucasian population.[1] A mouse strain called nob (no b-wave) carries a spontaneous mutation leading to a frameshift in this gene. These mice are used as an animal model for congenital stationary night blindness.[9]
# Discovery
The first evidence of the existence of mutation in NYX gene, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness was provided by Richard G. Weleber at the University of Alberta in 2000.[2]
# Gene location
The NYX gene is located on the short arm (p) of chromosome X, from base pair 41,447,434 to base pair 41,475,710.[10]
# Protein structure
Nyctalopin contains a N-terminal signal peptide and a C-terminal glycosylphosphatidylinositol (GPI) anchor.[11] Predicted signal sequence is likely to be processed by a co-translational mechanism.[12] Nyctalopin does not have two transmembrane domains and the only transmembrane domain is found to be between the amino acid 452 ad 472.[12] In the endoplasmic reticulum, the protein is oriented with the N-terminus in the lumen of the endoplasmic reticulum and the C-terminus is located in the cytoplasm.[12] The central part of the polypeptide encodes 11 consecutive leucines-rich repeats (LRRs).[3] These LRR are flanked by N-terminal and C-terminal rich LRRs[3] Tandem LRRs domains are folded into ß-sheets and α-helices, all joined by loops.[12] According to the cysteine pattern, nyctalopin is part of the class II small leucine-rich proteoglycans.[3] These proteins, are involved in several functions such as cell signalling, growth control, and formation of the extracellular matrix.[3] LRR domains are involved in the protein–protein interaction in small leucine rich repeat proteoglycan family members.[11] Also, LRR domains have a critical role in nyctalopin function. Congenital stationary night blindness in humans appears when a mutation in the LRR domains of nyctalopin occurs.
# Mutations
The complete form of congenital stationary night blindness is due to the absence of nyctalopin.[12] This absence is due to a mutation involving an 85 base pair deletion.[13] In humans, more than 30 mutations are found in the NYX gene and most of them have an impact either on the tertiary structure of the LRR domains of nyctalopin or to truncate the protein.[11] | https://www.wikidoc.org/index.php/Nyctalopin | |
f1ea37cb880396b9ade62986254540c4c5a480aa | wikidoc | OGN (gene) | OGN (gene)
Osteoglycin (also called mimecan), encoded by the OGN gene, is a human protein.
This gene encodes a protein which induces ectopic bone formation in conjunction with transforming growth factor beta. This protein is a small proteoglycan which contains tandem leucine-rich repeats (LRR). The gene expresses three transcript variants.
The level of expression of this gene has been correlated with enlarged hearts and more specifically left ventricular hypertrophy. | OGN (gene)
Osteoglycin (also called mimecan), encoded by the OGN gene, is a human protein.[1]
This gene encodes a protein which induces ectopic bone formation in conjunction with transforming growth factor beta. This protein is a small proteoglycan which contains tandem leucine-rich repeats (LRR). The gene expresses three transcript variants.[1]
The level of expression of this gene has been correlated with enlarged hearts and more specifically left ventricular hypertrophy.[2][3] | https://www.wikidoc.org/index.php/OGN_(gene) | |
b9de1d7500ae9b60a7dbe0ba84d739b7c0d38383 | wikidoc | OGT (gene) | OGT (gene)
UDP-N-acetylglucosamine—peptide N-acetylglucosaminyltransferase (EC 2.4.1.255), also known as O-linked β-N-acetylglucosamine transferase and O-GlcNAc transferase, OGT is an enzyme that in humans is encoded by the OGT gene.
# Function
O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) catalyzes the addition of a single N-acetylglucosamine in O-glycosidic linkage to serine or threonine residues of intracellular proteins. Since both phosphorylation and O-GlcNAcylation compete for similar serine or threonine residues, the two processes may compete for sites, or they may alter the substrate specificity of nearby sites by steric or electrostatic effects. The protein contains 9 or 14 tetratricopeptide repeats, depending on the splice variant, and a putative bipartite nuclear localization signal. Two alternatively spliced transcript variants encoding distinct isoforms (nucleocytoplasmic and mitochondrial) have been found for this gene. OGT glycosylates many proteins including: Histone H2B, AKT1, PFKL, KMT2E/MLL5, MAPT/TAU, Host cell factor C1, and SIN3A.
O-GlcNAc transferase is a part of a host of biological functions within the human body. OGT is involved in the resistance of insulin in muscle cells and adipocytes by inhibiting the Threonine 308 phosphorylation of AKT1, increasing the rate of IRS1 phosphorylation (at Serine 307 and Serine 632/635), reducing insulin signaling, and glycosylating components of insulin signals. Additionally, O-GlcNAc transferase catalyzes intracellular glycosylation of serine and threonine residues with the addition of N-acetylglucosamine. Studies show that OGT alleles are vital for embryogenesis, and that OGT is necessary for intracellular glycosylation and embryonic stem cell vitality. O-GlcNAc transferase also catalyzes the posttranslational modification that modifies transcription factors and RNA polymerase II, however the specific function of this modification is mostly unknown.
OGT cleaves Host Cell Factor C1, at one of the 6 repeat sequences. The TPR repeat domain of OGT binds to the carboxyl terminal portion of an HCF1 proteolytic repeat so that the cleavage region is in the glycosyltransferase active site above uridine-diphosphate-GlcNAc The large proportion of OGT complexed with HCF1 is necessary for HCF1 cleavage, and HCFC1 is required for OGT stabilization in the nucleus. HCF1 regulates OGT stability using a post-transcriptional mechanism, however the mechanism of the interaction with HCFC1 is still unknown.
# Structure
The human OGT gene has 1046 amino acid residues, and is a heterotrimer consisting of two 110 kDa subunits and one 78 kDa subunit. The 110 kDa subunit contains 13 tetratricopeptide (TPR) repeats; the 13th repeat is truncated. These subunits are dimerized by TPR repeats 6 and 7. OGT is highly expressed in the pancreas and also expressed in the heart, brain, skeletal muscle, and the placenta. There have been trace amounts found in the lung and the liver. The binding sites have been determined for the 110 kDa subunit. It has 3 binding sites at amino acid residues 849, 852, and 935. The probable active site is residue 508.
The crystal structure of O-GlcNAc transferase has not been well studied, but the structure of a binary complex with UDP and a ternary complex with UDP and a peptide substrate has been researched. The OGT-UDP complex contains three domains in its catalytic region, the amino (N)-terminal domain, the carboxy (C)-terminal domain, and the intervening domain (Int-D). The catalytic region is linked to TPR repeats by a translational helix (H3), which loops from the C-cat domain to the N-Cat domain along the upper surface of the catalytic region. The OGT-UDP-peptide complex has a larger space between the TPR domain and the catalytic region than the OGT-UDP complex. The CKII peptide, which contains three serine residues and a threonine residue, binds in this space. This structure supports an ordered sequential bi-bi mechanism that matches the fact that “at saturating peptide concentrations, a competitive inhibition pattern was obtained for UDP with respect to UDP-GlcNAc.”
# Mechanism of catalysis
The molecular mechanism of O-linked N-acetylglucosamine transferase has not been extensively studied either, since there is not a confirmed crystal structure of the enzyme. A proposed mechanism supported by product inhibition patterns by UDP at saturating peptide conditions proceeds with starting materials Uridine diphosphate N-acetylglucosamine, and a peptide chain with a reactive serine or threonine hydroxyl group. The proposed reaction is an ordered sequential bi-bi mechanism.
The chemical reaction can be written as:
(1) UDP-N-acetyl-D-glucosamine + -L-serine → UDP + -3-O-(N-acetyl-D-glucosaminyl)-L-serine
(2) UDP-N-acetyl-D-glucosamine + -L-threonine → UDP + -3-O-(N-acetyl-D-glucosaminyl)-L-threonine
First, the hydroxyl group of serine is deprotonated by Histidine 498, a catalytic base in this proposed reaction. Lysine 842 is also present to stabilize the UDP moiety. The oxygen ion then attacks the sugar-phosphate bond between the glucosamine and UDP. This results in the splitting of UDP-N-acetylglucosamine into N-acetylglucosamine – Peptide and UDP. Proton transfers take place at the phosphate and Histidine 498. This mechanism is spurred by OGT gene containing O-linked N-acetylglucosamine transferase. Aside from proton transfers the reaction proceeds in one step, as shown in Figure 2. Figure 2 uses a lone serine residue as a representative of the peptide with a reactive hydroxyl group. Threonine could have also been used in the mechanism.
# Regulation
O-GlcNAc transferase is part of a dynamic competition for a serine or threonine hydroxyl functional group in a peptide unit. Figure 3 shows an example of both reciprocal same-site occupancy and adjacent-site occupancy. For the same-site occupancy, OGT competes with kinase to catalyze the glycosylation of the protein instead of phosphorylation. The adjacent-site occupancy example shows the naked protein catalyzed by OGT converted to a glycoprotein, which can increase the turnover of proteins such as the tumor repressor p53.
The post-translational modification of proteins by O-GlcNAc is spurred by glucose flux through the hexosamine biosynthetic pathway. OGT catalyzes attachment of the O-GlcNAc group to serine and threonine, while O-GlcNAcase spurs sugar removal.
This regulation is important for multiple cellular processes including transcription, signal transduction, and proteasomal degradation. Also, there is competitive regulation between OGT and kinase for the protein to attach to a phosphate group or O-GlcNAc, which can alter the function of proteins in the body through downstream effects.
OGT inhibits the activity of 6-phosophofructosekinase PFKL by mediating the glycosylation process. This then acts as a part of glycolysis regulation. O-GlcNAc has been defined as a negative transcription regulator in response to steroid hormone signaling.
Studies show that O-GlcNAc transferase interacts directly with the Ten eleven translocation 2 (TET2) enzyme, which converts 5-methylcytosine to 5-hydroxymethylcytosine and regulates gene transcription. Additionally, increasing levels of OGT for O-GlcNAcylation may have therapeutic effects for Alzheimer's disease patients. Brain glucose metabolism is impaired in Alzheimer's disease, and a study suggests that this leads to hyperphosphorylation of tau and degerenation of tau O-GlcNCAcylation. Replenishing tau O-GlcNacylation in the brain along with protein phosphatase could deter this process and improve brain glucose metabolism. | OGT (gene)
UDP-N-acetylglucosamine—peptide N-acetylglucosaminyltransferase (EC 2.4.1.255), also known as O-linked β-N-acetylglucosamine transferase and O-GlcNAc transferase, OGT is an enzyme that in humans is encoded by the OGT gene.[1][2]
# Function
O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) catalyzes the addition of a single N-acetylglucosamine in O-glycosidic linkage to serine or threonine residues of intracellular proteins. Since both phosphorylation and O-GlcNAcylation compete for similar serine or threonine residues, the two processes may compete for sites, or they may alter the substrate specificity of nearby sites by steric or electrostatic effects. The protein contains 9 or 14 tetratricopeptide repeats, depending on the splice variant, and a putative bipartite nuclear localization signal. Two alternatively spliced transcript variants encoding distinct isoforms (nucleocytoplasmic and mitochondrial) have been found for this gene.[2] OGT glycosylates many proteins including: Histone H2B,[3] AKT1,[4] PFKL,[5] KMT2E/MLL5,[5] MAPT/TAU,[6] Host cell factor C1,[7] and SIN3A.[8]
O-GlcNAc transferase is a part of a host of biological functions within the human body. OGT is involved in the resistance of insulin in muscle cells and adipocytes by inhibiting the Threonine 308 phosphorylation of AKT1, increasing the rate of IRS1 phosphorylation (at Serine 307 and Serine 632/635), reducing insulin signaling, and glycosylating components of insulin signals.[9] Additionally, O-GlcNAc transferase catalyzes intracellular glycosylation of serine and threonine residues with the addition of N-acetylglucosamine. Studies show that OGT alleles are vital for embryogenesis, and that OGT is necessary for intracellular glycosylation and embryonic stem cell vitality.[10] O-GlcNAc transferase also catalyzes the posttranslational modification that modifies transcription factors and RNA polymerase II, however the specific function of this modification is mostly unknown.[11]
OGT cleaves Host Cell Factor C1, at one of the 6 repeat sequences. The TPR repeat domain of OGT binds to the carboxyl terminal portion of an HCF1 proteolytic repeat so that the cleavage region is in the glycosyltransferase active site above uridine-diphosphate-GlcNAc [12] The large proportion of OGT complexed with HCF1 is necessary for HCF1 cleavage, and HCFC1 is required for OGT stabilization in the nucleus. HCF1 regulates OGT stability using a post-transcriptional mechanism, however the mechanism of the interaction with HCFC1 is still unknown.[13]
# Structure
The human OGT gene has 1046 amino acid residues, and is a heterotrimer consisting of two 110 kDa subunits and one 78 kDa subunit.[14] The 110 kDa subunit contains 13 tetratricopeptide (TPR) repeats; the 13th repeat is truncated. These subunits are dimerized by TPR repeats 6 and 7. OGT is highly expressed in the pancreas and also expressed in the heart, brain, skeletal muscle, and the placenta. There have been trace amounts found in the lung and the liver.[1] The binding sites have been determined for the 110 kDa subunit. It has 3 binding sites at amino acid residues 849, 852, and 935. The probable active site is residue 508.[5]
The crystal structure of O-GlcNAc transferase has not been well studied, but the structure of a binary complex with UDP and a ternary complex with UDP and a peptide substrate has been researched.[12] The OGT-UDP complex contains three domains in its catalytic region, the amino (N)-terminal domain, the carboxy (C)-terminal domain, and the intervening domain (Int-D). The catalytic region is linked to TPR repeats by a translational helix (H3), which loops from the C-cat domain to the N-Cat domain along the upper surface of the catalytic region.[12] The OGT-UDP-peptide complex has a larger space between the TPR domain and the catalytic region than the OGT-UDP complex. The CKII peptide, which contains three serine residues and a threonine residue, binds in this space. This structure supports an ordered sequential bi-bi mechanism that matches the fact that “at saturating peptide concentrations, a competitive inhibition pattern was obtained for UDP with respect to UDP-GlcNAc.”[12]
# Mechanism of catalysis
The molecular mechanism of O-linked N-acetylglucosamine transferase has not been extensively studied either, since there is not a confirmed crystal structure of the enzyme. A proposed mechanism supported by product inhibition patterns by UDP at saturating peptide conditions proceeds with starting materials Uridine diphosphate N-acetylglucosamine, and a peptide chain with a reactive serine or threonine hydroxyl group. The proposed reaction is an ordered sequential bi-bi mechanism.[12]
The chemical reaction can be written as:
(1) UDP-N-acetyl-D-glucosamine + [protein]-L-serine → UDP + [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-serine
(2) UDP-N-acetyl-D-glucosamine + [protein]-L-threonine → UDP + [protein]-3-O-(N-acetyl-D-glucosaminyl)-L-threonine
First, the hydroxyl group of serine is deprotonated by Histidine 498, a catalytic base in this proposed reaction. Lysine 842 is also present to stabilize the UDP moiety. The oxygen ion then attacks the sugar-phosphate bond between the glucosamine and UDP. This results in the splitting of UDP-N-acetylglucosamine into N-acetylglucosamine – Peptide and UDP. Proton transfers take place at the phosphate and Histidine 498. This mechanism is spurred by OGT gene containing O-linked N-acetylglucosamine transferase. Aside from proton transfers the reaction proceeds in one step, as shown in Figure 2.[12] Figure 2 uses a lone serine residue as a representative of the peptide with a reactive hydroxyl group. Threonine could have also been used in the mechanism.
# Regulation
O-GlcNAc transferase is part of a dynamic competition for a serine or threonine hydroxyl functional group in a peptide unit. Figure 3 shows an example of both reciprocal same-site occupancy and adjacent-site occupancy. For the same-site occupancy, OGT competes with kinase to catalyze the glycosylation of the protein instead of phosphorylation. The adjacent-site occupancy example shows the naked protein catalyzed by OGT converted to a glycoprotein, which can increase the turnover of proteins such as the tumor repressor p53.[15]
The post-translational modification of proteins by O-GlcNAc is spurred by glucose flux through the hexosamine biosynthetic pathway. OGT catalyzes attachment of the O-GlcNAc group to serine and threonine, while O-GlcNAcase spurs sugar removal.[16][17]
This regulation is important for multiple cellular processes including transcription, signal transduction, and proteasomal degradation. Also, there is competitive regulation between OGT and kinase for the protein to attach to a phosphate group or O-GlcNAc, which can alter the function of proteins in the body through downstream effects.[5][16]
OGT inhibits the activity of 6-phosophofructosekinase PFKL by mediating the glycosylation process. This then acts as a part of glycolysis regulation. O-GlcNAc has been defined as a negative transcription regulator in response to steroid hormone signaling.[9]
Studies show that O-GlcNAc transferase interacts directly with the Ten eleven translocation 2 (TET2) enzyme, which converts 5-methylcytosine to 5-hydroxymethylcytosine and regulates gene transcription.[18] Additionally, increasing levels of OGT for O-GlcNAcylation may have therapeutic effects for Alzheimer's disease patients. Brain glucose metabolism is impaired in Alzheimer's disease, and a study suggests that this leads to hyperphosphorylation of tau and degerenation of tau O-GlcNCAcylation. Replenishing tau O-GlcNacylation in the brain along with protein phosphatase could deter this process and improve brain glucose metabolism.[6] | https://www.wikidoc.org/index.php/OGT_(gene) | |
4edeb43059d645b36b931cce7e56f80463714393 | wikidoc | OS9 (gene) | OS9 (gene)
Protein OS-9 is a protein that in humans is encoded by the OS9 gene.
# Function
This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
# Model organisms
Model organisms have been used in the study of OS9 function. A conditional knockout mouse line called Os9tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | OS9 (gene)
Protein OS-9 is a protein that in humans is encoded by the OS9 gene.[1][2][3][4][5]
# Function
This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[5]
# Model organisms
Model organisms have been used in the study of OS9 function. A conditional knockout mouse line called Os9tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[6] Male and female animals underwent a standardized phenotypic screen[7] to determine the effects of deletion.[8][9][10][11] Additional screens performed: - In-depth immunological phenotyping[12] | https://www.wikidoc.org/index.php/OS9_(gene) | |
fa6d03949a11b11e7fdc1b412150162f9acd0d68 | wikidoc | Obstetrics | Obstetrics
# Overview
Obstetrics (from the Latin obstare, "to stand by") is the surgical specialty dealing with the care of a woman and her offspring during pregnancy, childbirth and the puerperium (the period shortly after birth). Midwifery is the equivalent non-surgical specialty. Most obstetricians are also gynaecologists. See Obstetrics and gynaecology.
The average gestational period for humans is 40 weeks by gestational age and 38 weeks by fertilization age. This is divided into three trimesters.
# Antenatal care
In obstetric practice, an obstetrician or midwife sees a pregnant woman on a regular basis to check the progress of the pregnancy, to verify the absence of ex-novo disease, to monitor the state of preexisting disease and its possible effect on the ongoing pregnancy. A woman's schedule of antenatal appointment varies according to the presence of risk factors, such as diabetes, and local resources.
Some of the clinically and statistically more important risk factors that must be systematically excluded, especially in advancing pregnancy, are pre-eclampsia, abnormal placentation, abnormal fetal presentation and Intrauterine Growth Retardation.
For example, to identify pre-eclampsia, blood-pressure and albuminuria (level of urine protein) are checked at every opportunity.
Placenta praevia must be excluded (PP = low lying placenta that, at least partially, obstructs the birth canal and therefore warrants elective caesarean delivery); this can only be achieved with the use of an ultrasound scan.
In late pregnancy fetal presentation must be established: cepfalic presentation (head first) is the norm but the fetus may present feet-first or buttocks-first (breech), side-on (transverse), or at an angle (oblique presentation).
Intrauterine Growth Retardation is a general designation, where the fetus is smaller than expected when compared to its gestational age (in this case fetal growth parameters show a tendency to drop off from the 50th percentile eventually falling below the 10th percentile, when plotted on a fetal growth chart). Causes can be intrinsic (to the fetus) or extrinsic (maternal or placental problems).
# Signs
## Trimesters
First trimester: elevated β-hCG (human chorionic gonadotrophin) of up to 100,000 mIU/mL by 10 weeks GA is thought to contribute to morning sickness, fatigue, mood swings and food cravings. The symptoms can last through 12 to 16 weeks of gestation.
Second trimester: The abdomen shows an obvious swelling arising from the pelvis, starting the "obvious phase" of pregnancy. Hyperpigmentation, including linea nigra, may appear.
Third trimester: The mother may experience backaches due to increased strain. Typically, the curvature of the spine is changed as pregnancy evolves in order to counteract the change in weight distribution. The mother may also suffer mild urinary incontinence due to pressure on the bladder by the pregnant uterus, as well as heartburn(due to compression of the stomach).
## Overall
- Bluish discoloration of vagina and cervix (Chadwick's sign)
- Softening and cyanosis of cervix after 4 weeks (Goodell's sign)
- Softening of uterus after 6 weeks (Hegar's or Ladin's sign)
- Breast swelling and tenderness
- Linea nigra from umbilicus to pubis
- Telangiectasias
- Palmar erythema
- Amenorrhea
- Nausea and vomiting
- Breast pain
- Fetal movement
- Sciatica (Pain caused by compression of the sciatic nerve)
# Maternal physiology
During pregnancy, the woman undergoes many physiological changes, which are entirely normal, including cardiovascular, hematologic, metabolic, renal and respiratory changes that become very important in the event of complications.
## Cardiovascular
The woman is the sole provider of nourishment for the embryo and later, the fetus, and so her plasma and blood volume slowly increase by 40-50% over the course of the pregnancy to accommodate the changes. This results in overall vasodilation, an increase in heart rate (15 beats/min more than usual), stroke volume, and cardiac output. Cardiac output increases by about 50%, mostly during the first trimester. The systemic vascular resistance also drops due to the smooth muscle relaxation caused by elevated progesterone, leading to a fall in blood pressure. Diastolic blood pressure consequently decreases between 12-26 weeks, and increases again to prepregnancy levels by 36 weeks. If the blood pressure remains abnormal beyond 36 weeks, the woman should be investigated for pre-eclampsia, a condition that precedes eclampsia.
## Hematology
- The plasma volume increases by 50% and the red blood cell volume increases only by 20-30%.
- Consequently, the hematocrit decreases.
- White blood cell count increases and may peak at over 20 mil/mL in stressful conditions.
- Decrease in platelet concentration to a minimal normal values of 100-150 mil/mL
- The pregnant woman also becomes hypercoagulable due to increased liver production of coagulation factors, mainly fibrinogen and factor VIII.
## Metabolism
During pregnancy, both protein metabolism and carbohydrate metabolism are affected. One kilogram of extra protein is deposited, with half going to the fetus and placenta, and another half going to uterine contractile proteins, breast glandular tissue, plasma protein, and hemoglobin.
## Nutrition
- Increased caloric requirement by 300 kcal/day
- Gain of 20 to 30 lb (10 to 15 kg)
- Increased protein requirement to 70 or 75 g/day
- Increased folate requirement from 0.4 to 0.8 mg/day (important in preventing neural tube defects)
All patients are advised to take prenatal vitamins to compensate for the increased nutritional requirements. The use of Omega 3 fatty acids supports mental and visual development of infants. Choline supplementation of research mammals supports mental development that lasts throughout life.
## Gastrointestinal
- nausea and vomiting ("morning sickness") may be due to elevated Beta-hCG, which should resolve by 14 to 16 weeks
- prolonged gastric empty time
- decreased gastroesophageal sphincter tone, which can lead to acid reflux
- decreased colonic motility, which leads to increased water absorption and constipation
## Renal
- Increase in kidney and ureter size
- Increased glomerular filtration rate (GFR) by 50%, which subsides around 20 weeks postpartum
Decreased BUN (blood urea nitrogen) and creatinine, and glucosuria (due to saturated tubular reabsorption)
Persistent glucosuria can suggest gestational diabetes
- Decreased BUN (blood urea nitrogen) and creatinine, and glucosuria (due to saturated tubular reabsorption)
Persistent glucosuria can suggest gestational diabetes
- Persistent glucosuria can suggest gestational diabetes
- Increased renin-angiotensin system, causing increased aldosterone levels
Plasma sodium does not change because this is offset by the increase in GFR
- Plasma sodium does not change because this is offset by the increase in GFR
## Pulmonary
- Increased tidal volume (30-40%)
- Decreased total lung capacity (TLC) by 5% due to elevation of diaphragm from uteral compression
- Decreased expiratory reserve volume
- Increased minute ventilation (30-40%) which causes a decrease in PaCO2 and a compensated respiratory alkalosis
All of these changes can contribute to the dyspnea (shortness of breath) that a pregnant woman may experience.
## Endocrine
- Increased estrogen, which is mainly produced in the placenta
Fetal well being is associated with maternal estrogen levels
Causes an increase in thyroxine-binding globulin (TBG)
- Fetal well being is associated with maternal estrogen levels
- Causes an increase in thyroxine-binding globulin (TBG)
- Increased human chorionic gonadotropin (β-hCG), which is produced by the placenta. This maintains progesterone production by the corpus luteum
- Human placental lactogen (hPL) is produced by the placenta and ensures nutrient supply to the fetus. It also causes lipolysis and is an insulin antagonist, which is a diabetogenic effect.
- Increased progesterone production, first by corpus luteum and later by the placenta. Its main course of action is to relax smooth muscle.
- Increased prolactin
- Increased alkaline phosphatase
## Musculoskeleton and dermatology
- Lower back pain due to a shift in gravity
- Increased estrogen can cause spider angiomata and palmar erythema
- Increase melanocyte stimulating hormone (MSH) can cause hyperpigmentation of nipples, umbilicus, abdominal midline (linea nigra), perineum, and face (melasma or chloasma)
## Others
- Edema, or swelling, of the feet is common during pregnancy, partly because the enlarging uterus compresses veins and lymphatic drainage from the legs.
# Prenatal care
Prenatal care is important in screening for various complications of pregnancy. This includes routine office visits with physical exams and routine lab tests:
## First trimester
- complete blood count (CBC)
- blood type (blood transfusion may be needed in an emergency)
- general antibody screen (indirect Coombs test) for HDN
Rh D negative antenatal patients should receive RhoGam at 28 weeks to prevent Rh disease.
- Rh D negative antenatal patients should receive RhoGam at 28 weeks to prevent Rh disease.
- Rapid plasma reagent (RPR) which screens for syphilis
- Rubella antibody screen
- Hepatitis B surface antigen
- Gonorrhea and Chlamydia culture
- PPD for tuberculosis
- Pap smear
- Urinalysis and culture
- HIV screen
- Group B Streptococcus screen -- will receive IV penicillin if positive (if mother is allergic, alternative therapies include IV clindamycin or IV vancomycin)
## Second trimester
- MSAFP/triple screen (maternal serum alpha-fetoprotein) - elevation correlated with neural tube defects and decrease correlated with Down's syndrome
- ultrasound
- amniocentesis in older patients
## Third trimester
- hematocrit (if low, mother will receive iron supplementation)
- Glucose loading test (OGTT, GLT, GTT) - screens for gestational diabetes; if > 140 mg/dL, a glucose tolerance test (GTT) is administered; a fasting glucose > 105 mg/dL suggests gestational diabetes.
# Complications
See Complications of pregnancy
## Fetal assessments
- ultrasound is used for many functions:
Dating the gestational age of a pregnancy, most accurate in first trimester
Detecting fetal anomalies in the second trimester
biophysical profiles (BPP)
Blood flow velocity in umbilical cord -- decrease/absence/reversal or diastolic blood flow in the umbilical artery is worrisome.
Congenital anomalies can be diagnosed with second trimester ultrasound
- Dating the gestational age of a pregnancy, most accurate in first trimester
- Detecting fetal anomalies in the second trimester
- biophysical profiles (BPP)
- Blood flow velocity in umbilical cord -- decrease/absence/reversal or diastolic blood flow in the umbilical artery is worrisome.
- Congenital anomalies can be diagnosed with second trimester ultrasound
- Fetal karyotype for the screening of genetic diseases can be obtained via amniocentesis or chorionic villus sampling (CVS)
- Fetal hematocrit for the assessment of fetal anemia, Rh isoimmunization, or hydrops can be determined by percutaneous umbilical blood sampling (PUBS) which is done by placing a needle through the abdomen into the uterus and taking a portion of the umbilical cord.
- Fetal lung maturity is associated with how much surfactant the fetus is producing. Reduced production of surfactant indicates decreased lung maturity and is a high risk factor for neonatal respiratory distress syndrome (NRDS). Typically a lecithin:sphingomyelin ratio greater than 1.5 is associated with increased lung maturity.
- Nonstress test (NST) for fetal heart rate
- Oxytocin challenge test
# Induction
Reasons to induce include:
- pre-eclampsia
- IUGR
- diabetes
- other general medical condition, such as renal disease
- "postdates" - the pregnancy has lasted longer than 41 weeks after the last menstrual period
Induction may occur any time after 34 weeks of gestation if the risk to the fetus or mother is greater than the risk of delivering a premature fetus regardless of lung maturity.
If a woman does not eventually labour by 41-42 weeks, induction may be performed, as the placenta may become unstable after this date.
Induction may be achieved via several methods:
- pessary of Prostin cream, prostaglandin E2
- iv. or oral administration of misoprostol
- cervical insertion of a 30-mL Foley catheter
- rupturing the amniotic membranes
- intravenous infusion of synthetic oxytocin (Pitocin or Syntocinon)
# Labor
During labor itself, the obstetrician may be called on to do a number of things:
- monitor the progress of labor, by reviewing the nursing chart, performing vaginal examination, and assessing the trace produced by a fetal monitoring device (the cardiotocograph)
- accelerate the progress of labor by infusion of the hormone oxytocin
- provide pain relief, either by nitrous oxide (nowadays uncommon, at least in the U.S.), opiates, or by epidural anesthesia done by anaethestists, an anesthesiologist, or a nurse anesthetist.
- surgically assisting labor, by forceps or the Ventouse (a suction cap applied to the fetus' head)
- Caesarean section, if vaginal delivery is decided against or appears too difficult. Caesarean section can either be elective, that is, arranged before labor, or decided during labor as an alternative to hours of waiting. True "emergency" Cesarean sections (where minutes count) are a rarity.
# Antenatal
During the time immediately after birth both baby as well as mother are hormonally cued to bond, the mother through the release of oxytocin a hormone also released with breastfeeding.
# Emergencies in obstetrics
Two main emergencies are ectopic pregnancy and (pre)eclampsia.
- Ectopic pregnancy is when an embryo implants in the Fallopian tube or (rarely) on the ovary or inside the peritoneal cavity. This may cause massive internal bleeding.
- Pre-eclampsia is a disease which is defined by a combination of signs and symptoms that are related to maternal hypertension. The cause is unknown, and markers are being sought to predict its development from the earlist stages of pregnancy.
Some unknown factors cause vascular damage in the , causing hypertension and proteinuria. If severe, it progresses to fulminant pre-eclampsia, with headaches and visual disturbances. This is a prelude to eclampsia, where a convulsion occurs, which can be fatal.
# Imaging, monitoring and care
In present society, medical science has developed a number of procedures to monitor pregnancy.
## Antenatal record
On the first visit to her obstetrician or midwife, the pregnant woman is asked to carry out the antenatal record, which constitutes a medical history and physical examination.
On subsequent visits, the gestational age (GA) is rechecked with each visit.
Symphysis-fundal height (SFH; in cm) should equal gestational age after 20 weeks of gestation, and the fetal growth should be plotted on a curve during the antenatal visits.
The fetus is palpated by the midwife or obstetrician using Leopold maneuver to determine the position of the baby.
Blood pressure should also be monitored, and may be up to 140/90 in normal pregnancies. High blood pressure indicates hypertension and possibly pre-eclampsia, if severe swelling (edema) and spilled protein in the urine are also present.
Fetal screening is also used to help assess the viability of the fetus, as well as congenital problems. Genetic counseling is often offered for families who may be at an increased risk to have a child with a genetic condition.
Amniocentesis at around the 20th week is sometimes done for women 35 or older to check for Down's Syndrome and other chromosome abnormalities in the fetus.
Even earlier than amniocentesis is performed, the mother may undergo the triple test, nuchal screening, nasal bone, alpha-fetoprotein screening and Chorionic villus sampling, also to check for disorders such as Down Syndrome. Amniocentesis is a prenatal genetic screening of the fetus, which involves inserting a needle through the mother's abdominal wall and uterine wall, to extract fetal DNA from the amniotic fluid. There is a risk of miscarriage and fetal injury with amniocentesis because it involves penetrating the uterus with the baby still in utero.
## Imaging
Imaging is another important way to monitor a pregnancy. The mother and fetus are also usually imaged in the first trimester of pregnancy. This is done to predict problems with the mother; confirm that a pregnancy is present inside the uterus; guess the gestational age; determine the number of fetuses and placentae; evaluate for an ectopic pregnancy and first trimester bleeding; and assess for early signs of anomalies.
X-rays and computerized tomography (CT) are not used, especially in the first trimester, due to the ionizing radiation, which has teratogenic effects on the fetus. Instead, ultrasound is the imaging method of choice in the first trimester and throughout the pregnancy, because it emits no radiation, is portable, and allows for realtime imaging.
Ultrasound imaging may be done at any time throughout the pregnancy, but usually happens at the 12th week (dating scan) and the 20th week (detailed scan).
A normal gestation would reveal a gestational sac, yolk sac, and fetal pole.
The gestational age can be assessed by evaluating the mean gestation sac diameter (MGD) before week 6, and the crown-rump length after week 6.
Multiple gestation is evaluated by the number of placentae and amniotic sacs present.
Pregnancy has different cultural aspects related to the perception of the body, the relationship with partner and to the meaning of the event.
# Terms and definitions
- embryo - conceptus between time of fertilization to 10 weeks of gestation
- fetus - from 10 weeks of gestation to time of birth
- infant - time of birth to 1 year of age
- gestational age - time from last menstrual period (LMP) up to present
- first trimester - up to 14 weeks of gestation
- second trimester - 14 to 28 weeks of gestation
- third trimester - 28 weeks to delivery
- viability - minimum age for fetus survival, ca. third trimester
- previable infant - delivered prior to 24 weeks
- preterm infant - delivered between 24-37 weeks
- term infant - delivered between 37-42 weeks
- gravidity (G) - number of times a woman has been pregnant
- parity (P) - number of pregnancies with a birth beyond 20 weeks GA or an infant weighing more than 500 g
- Ga Pw-x-y-z - a = number of pregnancies, w = number of term births, x = number of preterm births, y = number of abortions (spontaneous or therapeutic), z = number of living children; for example, G4P1-2-1-3 means the woman had a total of 4 pregnancies, of which 1 is of term, 2 are preterm, 1 miscarriage or therapeutic abortion, and 3 total living children (1 term + 2 preterm). | Obstetrics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Obstetrics (from the Latin obstare, "to stand by") is the surgical specialty dealing with the care of a woman and her offspring during pregnancy, childbirth and the puerperium (the period shortly after birth). Midwifery is the equivalent non-surgical specialty. Most obstetricians are also gynaecologists. See Obstetrics and gynaecology.
The average gestational period for humans is 40 weeks by gestational age and 38 weeks by fertilization age. This is divided into three trimesters.
# Antenatal care
In obstetric practice, an obstetrician or midwife sees a pregnant woman on a regular basis to check the progress of the pregnancy, to verify the absence of ex-novo disease, to monitor the state of preexisting disease and its possible effect on the ongoing pregnancy. A woman's schedule of antenatal appointment varies according to the presence of risk factors, such as diabetes, and local resources.
Some of the clinically and statistically more important risk factors that must be systematically excluded, especially in advancing pregnancy, are pre-eclampsia, abnormal placentation, abnormal fetal presentation and Intrauterine Growth Retardation.
For example, to identify pre-eclampsia, blood-pressure and albuminuria (level of urine protein) are checked at every opportunity.
Placenta praevia must be excluded (PP = low lying placenta that, at least partially, obstructs the birth canal and therefore warrants elective caesarean delivery); this can only be achieved with the use of an ultrasound scan.
In late pregnancy fetal presentation must be established: cepfalic presentation (head first) is the norm but the fetus may present feet-first or buttocks-first (breech), side-on (transverse), or at an angle (oblique presentation).
Intrauterine Growth Retardation is a general designation, where the fetus is smaller than expected when compared to its gestational age (in this case fetal growth parameters show a tendency to drop off from the 50th percentile eventually falling below the 10th percentile, when plotted on a fetal growth chart). Causes can be intrinsic (to the fetus) or extrinsic (maternal or placental problems).
# Signs
## Trimesters
First trimester: elevated β-hCG (human chorionic gonadotrophin) of up to 100,000 mIU/mL by 10 weeks GA is thought to contribute to morning sickness, fatigue, mood swings and food cravings. The symptoms can last through 12 to 16 weeks of gestation.
Second trimester: The abdomen shows an obvious swelling arising from the pelvis, starting the "obvious phase" of pregnancy. Hyperpigmentation, including linea nigra, may appear.
Third trimester: The mother may experience backaches due to increased strain. Typically, the curvature of the spine is changed as pregnancy evolves in order to counteract the change in weight distribution. The mother may also suffer mild urinary incontinence due to pressure on the bladder by the pregnant uterus, as well as heartburn(due to compression of the stomach).
## Overall
- Bluish discoloration of vagina and cervix (Chadwick's sign)
- Softening and cyanosis of cervix after 4 weeks (Goodell's sign)
- Softening of uterus after 6 weeks (Hegar's or Ladin's sign)
- Breast swelling and tenderness
- Linea nigra from umbilicus to pubis
- Telangiectasias
- Palmar erythema
- Amenorrhea
- Nausea and vomiting
- Breast pain
- Fetal movement
- Sciatica (Pain caused by compression of the sciatic nerve)
# Maternal physiology
During pregnancy, the woman undergoes many physiological changes, which are entirely normal, including cardiovascular, hematologic, metabolic, renal and respiratory changes that become very important in the event of complications.
## Cardiovascular
The woman is the sole provider of nourishment for the embryo and later, the fetus, and so her plasma and blood volume slowly increase by 40-50% over the course of the pregnancy to accommodate the changes. This results in overall vasodilation, an increase in heart rate (15 beats/min more than usual), stroke volume, and cardiac output. Cardiac output increases by about 50%, mostly during the first trimester. The systemic vascular resistance also drops due to the smooth muscle relaxation caused by elevated progesterone, leading to a fall in blood pressure. Diastolic blood pressure consequently decreases between 12-26 weeks, and increases again to prepregnancy levels by 36 weeks. If the blood pressure remains abnormal beyond 36 weeks, the woman should be investigated for pre-eclampsia, a condition that precedes eclampsia.
## Hematology
- The plasma volume increases by 50% and the red blood cell volume increases only by 20-30%.
- Consequently, the hematocrit decreases.
- White blood cell count increases and may peak at over 20 mil/mL in stressful conditions.
- Decrease in platelet concentration to a minimal normal values of 100-150 mil/mL
- The pregnant woman also becomes hypercoagulable due to increased liver production of coagulation factors, mainly fibrinogen and factor VIII.
## Metabolism
During pregnancy, both protein metabolism and carbohydrate metabolism are affected. One kilogram of extra protein is deposited, with half going to the fetus and placenta, and another half going to uterine contractile proteins, breast glandular tissue, plasma protein, and hemoglobin.
## Nutrition
- Increased caloric requirement by 300 kcal/day
- Gain of 20 to 30 lb (10 to 15 kg)
- Increased protein requirement to 70 or 75 g/day
- Increased folate requirement from 0.4 to 0.8 mg/day (important in preventing neural tube defects)
All patients are advised to take prenatal vitamins to compensate for the increased nutritional requirements. The use of Omega 3 fatty acids supports mental and visual development of infants.[1] Choline supplementation of research mammals supports mental development that lasts throughout life.[2]
## Gastrointestinal
- nausea and vomiting ("morning sickness") may be due to elevated Beta-hCG, which should resolve by 14 to 16 weeks
- prolonged gastric empty time
- decreased gastroesophageal sphincter tone, which can lead to acid reflux
- decreased colonic motility, which leads to increased water absorption and constipation
## Renal
- Increase in kidney and ureter size
- Increased glomerular filtration rate (GFR) by 50%, which subsides around 20 weeks postpartum
Decreased BUN (blood urea nitrogen) and creatinine, and glucosuria (due to saturated tubular reabsorption)
Persistent glucosuria can suggest gestational diabetes
- Decreased BUN (blood urea nitrogen) and creatinine, and glucosuria (due to saturated tubular reabsorption)
Persistent glucosuria can suggest gestational diabetes
- Persistent glucosuria can suggest gestational diabetes
- Increased renin-angiotensin system, causing increased aldosterone levels
Plasma sodium does not change because this is offset by the increase in GFR
- Plasma sodium does not change because this is offset by the increase in GFR
## Pulmonary
- Increased tidal volume (30-40%)
- Decreased total lung capacity (TLC) by 5% due to elevation of diaphragm from uteral compression
- Decreased expiratory reserve volume
- Increased minute ventilation (30-40%) which causes a decrease in PaCO2 and a compensated respiratory alkalosis
All of these changes can contribute to the dyspnea (shortness of breath) that a pregnant woman may experience.
## Endocrine
- Increased estrogen, which is mainly produced in the placenta
Fetal well being is associated with maternal estrogen levels
Causes an increase in thyroxine-binding globulin (TBG)
- Fetal well being is associated with maternal estrogen levels
- Causes an increase in thyroxine-binding globulin (TBG)
- Increased human chorionic gonadotropin (β-hCG), which is produced by the placenta. This maintains progesterone production by the corpus luteum
- Human placental lactogen (hPL) is produced by the placenta and ensures nutrient supply to the fetus. It also causes lipolysis and is an insulin antagonist, which is a diabetogenic effect.
- Increased progesterone production, first by corpus luteum and later by the placenta. Its main course of action is to relax smooth muscle.
- Increased prolactin
- Increased alkaline phosphatase
## Musculoskeleton and dermatology
- Lower back pain due to a shift in gravity
- Increased estrogen can cause spider angiomata and palmar erythema
- Increase melanocyte stimulating hormone (MSH) can cause hyperpigmentation of nipples, umbilicus, abdominal midline (linea nigra), perineum, and face (melasma or chloasma)
## Others
- Edema, or swelling, of the feet is common during pregnancy, partly because the enlarging uterus compresses veins and lymphatic drainage from the legs.
# Prenatal care
Prenatal care is important in screening for various complications of pregnancy. This includes routine office visits with physical exams and routine lab tests:
## First trimester
- complete blood count (CBC)
- blood type (blood transfusion may be needed in an emergency)
- general antibody screen (indirect Coombs test) for HDN
Rh D negative antenatal patients should receive RhoGam at 28 weeks to prevent Rh disease.
- Rh D negative antenatal patients should receive RhoGam at 28 weeks to prevent Rh disease.
- Rapid plasma reagent (RPR) which screens for syphilis
- Rubella antibody screen
- Hepatitis B surface antigen
- Gonorrhea and Chlamydia culture
- PPD for tuberculosis
- Pap smear
- Urinalysis and culture
- HIV screen
- Group B Streptococcus screen -- will receive IV penicillin if positive (if mother is allergic, alternative therapies include IV clindamycin or IV vancomycin)
## Second trimester
- MSAFP/triple screen (maternal serum alpha-fetoprotein) - elevation correlated with neural tube defects and decrease correlated with Down's syndrome
- ultrasound
- amniocentesis in older patients
## Third trimester
- hematocrit (if low, mother will receive iron supplementation)
- Glucose loading test (OGTT, GLT, GTT) - screens for gestational diabetes; if > 140 mg/dL, a glucose tolerance test (GTT) is administered; a fasting glucose > 105 mg/dL suggests gestational diabetes.
# Complications
See Complications of pregnancy
## Fetal assessments
- ultrasound is used for many functions:
Dating the gestational age of a pregnancy, most accurate in first trimester
Detecting fetal anomalies in the second trimester
biophysical profiles (BPP)
Blood flow velocity in umbilical cord -- decrease/absence/reversal or diastolic blood flow in the umbilical artery is worrisome.
Congenital anomalies can be diagnosed with second trimester ultrasound
- Dating the gestational age of a pregnancy, most accurate in first trimester
- Detecting fetal anomalies in the second trimester
- biophysical profiles (BPP)
- Blood flow velocity in umbilical cord -- decrease/absence/reversal or diastolic blood flow in the umbilical artery is worrisome.
- Congenital anomalies can be diagnosed with second trimester ultrasound
- Fetal karyotype for the screening of genetic diseases can be obtained via amniocentesis or chorionic villus sampling (CVS)
- Fetal hematocrit for the assessment of fetal anemia, Rh isoimmunization, or hydrops can be determined by percutaneous umbilical blood sampling (PUBS) which is done by placing a needle through the abdomen into the uterus and taking a portion of the umbilical cord.
- Fetal lung maturity is associated with how much surfactant the fetus is producing. Reduced production of surfactant indicates decreased lung maturity and is a high risk factor for neonatal respiratory distress syndrome (NRDS). Typically a lecithin:sphingomyelin ratio greater than 1.5 is associated with increased lung maturity.
- Nonstress test (NST) for fetal heart rate
- Oxytocin challenge test
# Induction
Reasons to induce include:
- pre-eclampsia
- IUGR
- diabetes
- other general medical condition, such as renal disease
- "postdates" - the pregnancy has lasted longer than 41 weeks after the last menstrual period
Induction may occur any time after 34 weeks of gestation if the risk to the fetus or mother is greater than the risk of delivering a premature fetus regardless of lung maturity.
If a woman does not eventually labour by 41-42 weeks, induction may be performed, as the placenta may become unstable after this date.
Induction may be achieved via several methods:
- pessary of Prostin cream, prostaglandin E2
- iv. or oral administration of misoprostol
- cervical insertion of a 30-mL Foley catheter
- rupturing the amniotic membranes
- intravenous infusion of synthetic oxytocin (Pitocin or Syntocinon)
# Labor
During labor itself, the obstetrician may be called on to do a number of things:
- monitor the progress of labor, by reviewing the nursing chart, performing vaginal examination, and assessing the trace produced by a fetal monitoring device (the cardiotocograph)
- accelerate the progress of labor by infusion of the hormone oxytocin
- provide pain relief, either by nitrous oxide (nowadays uncommon, at least in the U.S.), opiates, or by epidural anesthesia done by anaethestists, an anesthesiologist, or a nurse anesthetist.
- surgically assisting labor, by forceps or the Ventouse (a suction cap applied to the fetus' head)
- Caesarean section, if vaginal delivery is decided against or appears too difficult. Caesarean section can either be elective, that is, arranged before labor, or decided during labor as an alternative to hours of waiting. True "emergency" Cesarean sections (where minutes count) are a rarity.
# Antenatal
During the time immediately after birth both baby as well as mother are hormonally cued to bond, the mother through the release of oxytocin a hormone also released with breastfeeding.
# Emergencies in obstetrics
Two main emergencies are ectopic pregnancy and (pre)eclampsia.
- Ectopic pregnancy is when an embryo implants in the Fallopian tube or (rarely) on the ovary or inside the peritoneal cavity. This may cause massive internal bleeding.
- Pre-eclampsia is a disease which is defined by a combination of signs and symptoms that are related to maternal hypertension. The cause is unknown, and markers are being sought to predict its development from the earlist stages of pregnancy.
Some unknown factors cause vascular damage in the [endothelium], causing hypertension and proteinuria. If severe, it progresses to fulminant pre-eclampsia, with headaches and visual disturbances. This is a prelude to eclampsia, where a convulsion occurs, which can be fatal.
# Imaging, monitoring and care
In present society, medical science has developed a number of procedures to monitor pregnancy.
## Antenatal record
On the first visit to her obstetrician or midwife, the pregnant woman is asked to carry out the antenatal record, which constitutes a medical history and physical examination.
On subsequent visits, the gestational age (GA) is rechecked with each visit.
Symphysis-fundal height (SFH; in cm) should equal gestational age after 20 weeks of gestation, and the fetal growth should be plotted on a curve during the antenatal visits.
The fetus is palpated by the midwife or obstetrician using Leopold maneuver to determine the position of the baby.
Blood pressure should also be monitored, and may be up to 140/90 in normal pregnancies. High blood pressure indicates hypertension and possibly pre-eclampsia, if severe swelling (edema) and spilled protein in the urine are also present.
Fetal screening is also used to help assess the viability of the fetus, as well as congenital problems. Genetic counseling is often offered for families who may be at an increased risk to have a child with a genetic condition.
Amniocentesis at around the 20th week is sometimes done for women 35 or older to check for Down's Syndrome and other chromosome abnormalities in the fetus.
Even earlier than amniocentesis is performed, the mother may undergo the triple test, nuchal screening, nasal bone, alpha-fetoprotein screening and Chorionic villus sampling, also to check for disorders such as Down Syndrome. Amniocentesis is a prenatal genetic screening of the fetus, which involves inserting a needle through the mother's abdominal wall and uterine wall, to extract fetal DNA from the amniotic fluid. There is a risk of miscarriage and fetal injury with amniocentesis because it involves penetrating the uterus with the baby still in utero.
## Imaging
Imaging is another important way to monitor a pregnancy. The mother and fetus are also usually imaged in the first trimester of pregnancy. This is done to predict problems with the mother; confirm that a pregnancy is present inside the uterus; guess the gestational age; determine the number of fetuses and placentae; evaluate for an ectopic pregnancy and first trimester bleeding; and assess for early signs of anomalies.
X-rays and computerized tomography (CT) are not used, especially in the first trimester, due to the ionizing radiation, which has teratogenic effects on the fetus. Instead, ultrasound is the imaging method of choice in the first trimester and throughout the pregnancy, because it emits no radiation, is portable, and allows for realtime imaging.
Ultrasound imaging may be done at any time throughout the pregnancy, but usually happens at the 12th week (dating scan) and the 20th week (detailed scan).
A normal gestation would reveal a gestational sac, yolk sac, and fetal pole.
The gestational age can be assessed by evaluating the mean gestation sac diameter (MGD) before week 6, and the crown-rump length after week 6.
Multiple gestation is evaluated by the number of placentae and amniotic sacs present.
Pregnancy has different cultural aspects related to the perception of the body, the relationship with partner and to the meaning of the event.
# Terms and definitions
- embryo - conceptus between time of fertilization to 10 weeks of gestation
- fetus - from 10 weeks of gestation to time of birth
- infant - time of birth to 1 year of age
- gestational age - time from last menstrual period (LMP) up to present
- first trimester - up to 14 weeks of gestation
- second trimester - 14 to 28 weeks of gestation
- third trimester - 28 weeks to delivery
- viability - minimum age for fetus survival, ca. third trimester
- previable infant - delivered prior to 24 weeks
- preterm infant - delivered between 24-37 weeks
- term infant - delivered between 37-42 weeks
- gravidity (G) - number of times a woman has been pregnant
- parity (P) - number of pregnancies with a birth beyond 20 weeks GA or an infant weighing more than 500 g
- Ga Pw-x-y-z - a = number of pregnancies, w = number of term births, x = number of preterm births, y = number of abortions (spontaneous or therapeutic), z = number of living children; for example, G4P1-2-1-3 means the woman had a total of 4 pregnancies, of which 1 is of term, 2 are preterm, 1 miscarriage or therapeutic abortion, and 3 total living children (1 term + 2 preterm). | https://www.wikidoc.org/index.php/Obstetric | |
4bbb8f2ded04df2decd141af8f43d8f24eae71a2 | wikidoc | Ochronosis | Ochronosis
# Overview
Ochronosis is a dermatological disorder that results in the adverse pigmentation of cartilage from a long term buildup of phenylalanine or tyrosine.
In this disorder, a pigment substance resulting from incomplete catabolism of tyrosine and phenylalanine is deposited, over the years, in cartilage, the eye, and to a lesser degree in the skin.
# Symptoms
Pigmented cartilage may appear blue due to scattering phenomenon, and to a lesser degree this may be true for skin with dermal deposition of this pigment. The skin of the axilla is very likely to be pigmented due to deposits of homogentisic acid in sudoriferous glands in these areas. The clinical features of this metabolic disorder are dark urine, pigmentation of the skin and arthritis. Particularly helpful is the almost constant presence of a patch of pigmentation (gray to brown in color) in the sclera, between the margin of the cornea and the outer or inner canthus. Because of the bluish color produced by the deep pigmentation, this condition may be confused with argyria. | Ochronosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ochronosis is a dermatological disorder that results in the adverse pigmentation of cartilage from a long term buildup of phenylalanine or tyrosine.
In this disorder, a pigment substance resulting from incomplete catabolism of tyrosine and phenylalanine is deposited, over the years, in cartilage, the eye, and to a lesser degree in the skin.
# Symptoms
Pigmented cartilage may appear blue due to scattering phenomenon, and to a lesser degree this may be true for skin with dermal deposition of this pigment. The skin of the axilla is very likely to be pigmented due to deposits of homogentisic acid in sudoriferous glands in these areas. The clinical features of this metabolic disorder are dark urine, pigmentation of the skin and arthritis. Particularly helpful is the almost constant presence of a patch of pigmentation (gray to brown in color) in the sclera, between the margin of the cornea and the outer or inner canthus. Because of the bluish color produced by the deep pigmentation, this condition may be confused with argyria. | https://www.wikidoc.org/index.php/Ochronosis | |
81e9d4947034b5907146d29d27bc5b67169c3a66 | wikidoc | Octahedron | Octahedron
An octahedron (plural: octahedra) is a polyhedron with eight faces. A regular octahedron is a Platonic solid composed of eight equilateral triangles, four of which meet at each vertex.
The octahedron's symmetry group is Oh, of order 48. This group's subgroups include D3d (order 12), the symmetry group of a triangular antiprism; D4h (order 16), the symmetry group of a square bipyramid; and Td (order 24), the symmetry group of a rectified tetrahedron. These symmetries can be emphasized by different decorations of the faces.
It is a three-dimensional cross polytope.
# Cartesian coordinates
An octahedron can be placed with its center at the origin and its vertices on the coordinate axes; the Cartesian coordinates of the vertices are then
# Area and volume
The area A and the volume V of a regular octahedron of edge length a are:
Thus the volume is four times that of a regular tetrahedron with the same edge length, while the surface area is twice (because we have 8 vs. 4 triangles).
# Geometric relations
The interior of the compound of two dual tetrahedra is an octahedron, and this compound, called the stella octangula, is its first and only stellation. Correspondingly, a regular octahedron is the result of cutting off from a regular tetrahedron, four regular tetrahedra of half the linear size (i.e. rectifying the tetrahedron). The vertices of the octahedron lie at the midpoints of the edges of the tetrahedron, and in this sense it relates to the tetrahedron in the same way that the cuboctahedron and icosidodecahedron relate to the other Platonic solids. One can also divide the edges of an octahedron in the ratio of the golden mean to define the vertices of an icosahedron. This is done by first placing vectors along the octahedron's edges such that each face is bounded by a cycle, then similarly partitioning each edge into the golden mean along the direction of its vector. There are five octahedra that define any given icosahedron in this fashion, and together they define a regular compound.
Octahedra and tetrahedra can be alternated to form a vertex, edge, and face-uniform tessellation of space, called the octet truss by Buckminster Fuller. This is the only such tiling save the regular tessellation of cubes, and is one of the 28 convex uniform honeycombs. Another is a tessellation of octahedra and cuboctahedra.
The octahedron is unique among the Platonic solids in having an even number of faces meeting at each vertex. Consequently, it is the only member of that group to possess mirror planes that do not pass through any of the faces.
Using the standard nomenclature for Johnson solids, an octahedron would be called a square bipyramid.
# Related polyhedra
The octahedron can also be considered a rectified tetrahedron. This can be shown by a 2-color face model. With this coloring, the octahedron has tetrahedral symmetry.
Compare this truncation sequence between a tetrahedron and its dual:
# Octahedra in the physical world
- Especially in roleplaying games, this solid is known as a d8, one of the more common Polyhedral dice.
- If each edge of an octahedron is replaced by a one ohm resistor, the resistance between opposite vertices is 1/2 ohms, and that between adjacent vertices 5/12 ohms.
- Natural crystals of diamond, alum or fluorite are commonly octahedral.
# Other octahedra
The regular octahedron has 6 vertices and 12 edges, the minimum for an octahedron; nonregular octahedra may have as many as 12 vertices and 18 edges.
- Hexagonal prism: 6 squares, 2 hexagons
- Heptagonal pyramid: 7 triangles, 1 heptagon
- Tetragonal bipyramid: 8 triangles, usually isosceles)
The regular octahedron is a special case with equilateral triangles
- The regular octahedron is a special case with equilateral triangles
- Truncated tetrahedron: 4 triangles, 4 hexagons
- Tetragonal trapezohedron - 8 kites | Octahedron
Template:Reg polyhedra db
An octahedron (plural: octahedra) is a polyhedron with eight faces. A regular octahedron is a Platonic solid composed of eight equilateral triangles, four of which meet at each vertex.
The octahedron's symmetry group is Oh, of order 48. This group's subgroups include D3d (order 12), the symmetry group of a triangular antiprism; D4h (order 16), the symmetry group of a square bipyramid; and Td (order 24), the symmetry group of a rectified tetrahedron. These symmetries can be emphasized by different decorations of the faces.
It is a three-dimensional cross polytope.
# Cartesian coordinates
An octahedron can be placed with its center at the origin and its vertices on the coordinate axes; the Cartesian coordinates of the vertices are then
# Area and volume
The area A and the volume V of a regular octahedron of edge length a are:
Thus the volume is four times that of a regular tetrahedron with the same edge length, while the surface area is twice (because we have 8 vs. 4 triangles).
# Geometric relations
The interior of the compound of two dual tetrahedra is an octahedron, and this compound, called the stella octangula, is its first and only stellation. Correspondingly, a regular octahedron is the result of cutting off from a regular tetrahedron, four regular tetrahedra of half the linear size (i.e. rectifying the tetrahedron). The vertices of the octahedron lie at the midpoints of the edges of the tetrahedron, and in this sense it relates to the tetrahedron in the same way that the cuboctahedron and icosidodecahedron relate to the other Platonic solids. One can also divide the edges of an octahedron in the ratio of the golden mean to define the vertices of an icosahedron. This is done by first placing vectors along the octahedron's edges such that each face is bounded by a cycle, then similarly partitioning each edge into the golden mean along the direction of its vector. There are five octahedra that define any given icosahedron in this fashion, and together they define a regular compound.
Octahedra and tetrahedra can be alternated to form a vertex, edge, and face-uniform tessellation of space, called the octet truss by Buckminster Fuller. This is the only such tiling save the regular tessellation of cubes, and is one of the 28 convex uniform honeycombs. Another is a tessellation of octahedra and cuboctahedra.
The octahedron is unique among the Platonic solids in having an even number of faces meeting at each vertex. Consequently, it is the only member of that group to possess mirror planes that do not pass through any of the faces.
Using the standard nomenclature for Johnson solids, an octahedron would be called a square bipyramid.
# Related polyhedra
The octahedron can also be considered a rectified tetrahedron. This can be shown by a 2-color face model. With this coloring, the octahedron has tetrahedral symmetry.
Compare this truncation sequence between a tetrahedron and its dual:
# Octahedra in the physical world
- Especially in roleplaying games, this solid is known as a d8, one of the more common Polyhedral dice.
- If each edge of an octahedron is replaced by a one ohm resistor, the resistance between opposite vertices is 1/2 ohms, and that between adjacent vertices 5/12 ohms.[1]
- Natural crystals of diamond, alum or fluorite are commonly octahedral.
# Other octahedra
The regular octahedron has 6 vertices and 12 edges, the minimum for an octahedron; nonregular octahedra may have as many as 12 vertices and 18 edges.[1]
- Hexagonal prism: 6 squares, 2 hexagons
- Heptagonal pyramid: 7 triangles, 1 heptagon
- Tetragonal bipyramid: 8 triangles, usually isosceles)
The regular octahedron is a special case with equilateral triangles
- The regular octahedron is a special case with equilateral triangles
- Truncated tetrahedron: 4 triangles, 4 hexagons
- Tetragonal trapezohedron - 8 kites | https://www.wikidoc.org/index.php/Octahedron | |
40c97ed3c4acdbfd90a92e2e821e39b3e195edb4 | wikidoc | Octopamine | Octopamine
# Overview
Octopamine is a biogenic amine which is closely related to noradrenaline, and has a similar action to dopamine.
# Role in invertebrates
Octopamine was first discovered by Italian scientist Vittorio Erspamer in 1948 in the salivary glands of the octopus and has since been found to act as neurotransmitter, neurohormone and neuromodulator in invertebrates. It is widely used in energetically demanding behaviours by all insects, crustaceans (crabs, lobsters, crayfish) and spiders. Such behaviours include flying, egg-laying and jumping.
The best understood role for octopamine is in the locust jump. Here it modulates muscle activity, making the leg muscles contract more effectively. This is at least in part due to an increase in the rate of contraction and of relaxation.
In the honey bee and fruit fly, octopamine has a major role in learning and memory. In the firefly, octopamine release leads to light production in the lantern.
Octopamine also plays a role in mollusks, though the role of octopamine has only been examined in the central nervous system of the model organism, the pond snail.
Heberlein et al have conducted studies of alcohol tolerance in fruit flies; they found that a mutation that caused octopamine deficiency also caused lower alcohol tolerance.
# Role in vertebrates
In vertebrates, octopamine also replaces norepinephrine in sympathetic neurons with chronic use of monoamine oxidase inhibitors. It is responsible for the common side effect profile of orthostatic hypotension with these agents.
In mammals, octopamine may mobilise the release of fat from adipocytes (fat cells), and this has led to its promotion on the internet as a slimming aid. However, the released fat is likely to be promptly taken up into other cells, and there is no evidence that octopamine facilitates weight loss. Octopamine may also increase blood pressure significantly when combined with other stimulants, as in some weight loss supplements.
# Use in humans
In some countries octopamine is gaining increased commercial interest as an ingredient in benzylpiperazine free 'party pills' due to the fact that in countries such as New Zealand where it is currently legal, BZP faces a probable ban before the end of 2007. It should be noted however that the structure of octopamine falls within the definition of an "amphetamine analogue" in Class C7 of the New Zealand Misuse of Drugs Act, and so would probably be considered an illegal drug if it were tested in court, although no prosecutions involving this compound have been carried out so far. | Octopamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Octopamine is a biogenic amine which is closely related to noradrenaline, and has a similar action to dopamine.
# Role in invertebrates
Octopamine was first discovered by Italian scientist Vittorio Erspamer in 1948[1] in the salivary glands of the octopus and has since been found to act as neurotransmitter, neurohormone and neuromodulator in invertebrates. It is widely used in energetically demanding behaviours by all insects, crustaceans (crabs, lobsters, crayfish) and spiders. Such behaviours include flying, egg-laying and jumping.
The best understood role for octopamine is in the locust jump. Here it modulates muscle activity, making the leg muscles contract more effectively. This is at least in part due to an increase in the rate of contraction and of relaxation.
In the honey bee and fruit fly, octopamine has a major role in learning and memory. In the firefly, octopamine release leads to light production in the lantern.
Octopamine also plays a role in mollusks, though the role of octopamine has only been examined in the central nervous system of the model organism, the pond snail.
Heberlein et al [2] have conducted studies of alcohol tolerance in fruit flies; they found that a mutation that caused octopamine deficiency also caused lower alcohol tolerance.[3][4][5][6]
# Role in vertebrates
In vertebrates, octopamine also replaces norepinephrine in sympathetic neurons with chronic use of monoamine oxidase inhibitors. It is responsible for the common side effect profile of orthostatic hypotension with these agents.
In mammals, octopamine may mobilise the release of fat from adipocytes (fat cells), and this has led to its promotion on the internet as a slimming aid. However, the released fat is likely to be promptly taken up into other cells, and there is no evidence that octopamine facilitates weight loss. Octopamine may also increase blood pressure significantly when combined with other stimulants, as in some weight loss supplements.
[7]
[8]
# Use in humans
In some countries octopamine is gaining increased commercial interest as an ingredient in benzylpiperazine free 'party pills' [9] due to the fact that in countries such as New Zealand where it is currently legal, BZP faces a probable ban before the end of 2007. It should be noted however that the structure of octopamine falls within the definition of an "amphetamine analogue" in Class C7 of the New Zealand Misuse of Drugs Act, and so would probably be considered an illegal drug if it were tested in court, although no prosecutions involving this compound have been carried out so far. | https://www.wikidoc.org/index.php/Octopamine | |
c4bccfd61b05deb995818e34f95fdcef2cd8f082 | wikidoc | Octreotide | Octreotide
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# Overview
Octreotide is a somatostatin analogue that is FDA approved for the treatment of acromegaly, severe diarrhea/flushing episodes associated with metastatic carcinoid tumors, profuse watery diarrhea associated with VIP-secreting tumors. Common adverse reactions include diarrhea, cholelithiasis, abdominal pain, flatulence, back pain, fatigue, headache, abdominal pain, nausea, dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Patients Not Currently Receiving Octreotide Acetate
- Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily.
- Patients should be maintained on Sandostatin Injection subcutaneous for at least 2 weeks to determine tolerance to octreotide. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug can then be switched to Sandostatin LAR Depot in the dosage scheme described below (Patients Currently Receiving Sandostatin Injection).
- Patients Currently Receiving Sandostatin Injection
- Patients currently receiving Sandostatin Injection can be switched directly to Sandostatin LAR Depot in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months. After 3 months, dosage may be adjusted as follows:
GH ≤2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain Sandostatin LAR Depot dosage at 20 mg every 4 weeks.
GH >2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase Sandostatin LAR Depot dosage to 30 mg every 4 weeks.
GH ≤1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce Sandostatin LAR Depot dosage to 10 mg every 4 weeks.
If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended.
- GH ≤2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain Sandostatin LAR Depot dosage at 20 mg every 4 weeks.
- GH >2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase Sandostatin LAR Depot dosage to 30 mg every 4 weeks.
- GH ≤1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce Sandostatin LAR Depot dosage to 10 mg every 4 weeks.
- If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended.
- In patients who have received pituitary irradiation, Sandostatin LAR Depot should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, Sandostatin LAR Depot therapy may be resumed.
- Dosing Information
- Patients Not Currently Receiving Octreotide Acetate
- Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). Some patients may require doses up to 1500 mcg/day. The suggested daily dosage for VIPomas is 200-300 mcg in 2-4 divided doses (range 150-750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required.
- Sandostatin Injection should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to octreotide acetate and who tolerate the drug may be switched to Sandostatin LAR Depot in the dosage regimen as described below (Patients Currently Receiving Sandostatin Injection).
- Patients Currently Receiving Sandostatin Injection
- Patients currently receiving Sandostatin Injection can be switched to Sandostatin LAR Depot in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of Sandostatin LAR Depot, carcinoid tumor and VIPoma patients should continue to receive Sandostatin Injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms. (Some patients may require 3 or 4 weeks of such therapy.)
- After 2 months, dosage may be adjusted as follows:
If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dose every 4 weeks.
If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
Dosages higher than 30 mg are not recommended.
- If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dose every 4 weeks.
- If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
- Dosages higher than 30 mg are not recommended.
- Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on Sandostatin Injection or Sandostatin LAR Depot). During these periods they may be given Sandostatin Injection subcutaneously for a few days at the dosage they were receiving prior to switching to Sandostatin LAR Depot. When symptoms are again controlled, the Sandostatin Injection subcutaneous can be discontinued.
- Special Populations: Renal Impairment
- In patients with renal failure requiring dialysis, the starting dose should be 10 mg every 4 weeks. In other patients with renal impairment, the starting dose should be similar to a nonrenal patient (i.e., 20 mg every 4 weeks).
- Special Populations: Hepatic Impairment – Cirrhotic Patients
- In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Octreotide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Octreotide in doses of 50 mcg twice daily to 100 mcg 3 times daily subcutaneously.
- Dosing Information
- Octreotide (50 mcg IV bolus followed by a continuous IV infusion of octreotide at 50 mcg/hour for 5 days.
- Dosing Information
- Octreotide (100 mcg initially as an IV bolus, followed by continuous IV infusion of 10 to 100 mcg/hour).
- Dosing Information
- Continuous subcutaneous infusion of octreotide 200 mcg/24 hours for 6 to 12 months.
- Dosing Information
- Single dose of octreotide 75 mcg subQ.
- Dosing Information
- Subcutaneous octreotide 100 mcg.
- Dosing Information
- SUBQ octreotide 5 mcg/kg/day divided into 3 daily doses with bimonthly increases of 5 mcg/kg/d to a maximum of 15 mcg/kg/d.
- Dosing Information
- SUBQ octreotide (0.1 mg 3 times daily for 5 days.
- Dosing Information
- Octreotide 100 mcg three times daily for 10 days.
- Dosing Information
- Octreotide LAR 30 mg (n=42) intramuscularly every 28 days.
- Dosing Information
- Subcutaneous octreotide acetate 100 mcg 3 times per day.
- Dosing Information
- Octreotide 50 mcg subcutaneously every 8 hours for 1 week and 100 mcg every 8 hours for the rest of the 4-month.
- Dosing Information
- Octreotide 100 mcg/8 hours.
- Dosing Information
- Subcutaneous administration of octreotideat 50 mcg daily, the dose was increased to 200 mcg three times daily.
- Dosing Information
- Octreotide in doses of 400 to 500 mcg subcutaneously daily for up to 12 months.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Octreotide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Octreotide in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Octreotide 10 mcg/kg/day in 3 divided doses.
# Contraindications
- None
# Warnings
### Precautions
- Cholelithiasis and Gallbladder Sludge
- Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically.
- Hyperglycemia and Hypoglycemia
- Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic treatment should be adjusted accordingly.
- Thyroid Function Abnormalities
- Octreotide suppresses the secretion of thyroid-stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotide therapy.
- Cardiac Function Abnormalities
- In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other ECG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta-blockers that have bradycardic effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of Sandostatin Injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.
- Nutrition
- Octreotide may alter absorption of dietary fats.
- Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot.
- Octreotide has been investigated for the reduction of excessive fluid loss from the GI tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels.
- Monitoring: Laboratory Tests
- Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy.
- Acromegaly: Growth Hormone, IGF-1 (somatomedin C)
- Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P
- VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T4 measurements should be performed during chronic therapy
# 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 trial of another drug and may not reflect the rates observed in practice.
- Acromegaly
- The safety of Sandostatin LAR in the treatment of acromegaly has been evaluated in three phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. Sandostatin LAR was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14-81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10-60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug.
- The safety of Sandostatin LAR in the treatment of acromegaly was also evaluated in a postmarketing randomized phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of Sandostatin LAR. All the patients were treatment naïve (‘de novo’). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to Sandostatin LAR were exposed to Sandostatin LAR up to 1 year. The population age range was between 20-76 years old, 45% were female, 93% were Caucasian, and 1% black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug.
- Gallbladder Abnormalities
- Single doses of Sandostatin Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure.
- In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR Depot for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones.
- Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide, 1% of patients developed acute symptoms requiring cholecystectomy.
- Glucose Metabolism - Hypoglycemia/Hyperglycemia
- In acromegaly patients treated with either Sandostatin Injection or Sandostatin LAR Depot, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients.
- Hypothyroidism
- In acromegaly patients receiving Sandostatin Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin Injection. In acromegalics treated with Sandostatin LAR Depot, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving Sandostatin LAR Depot required initiation of thyroid hormone replacement therapy.
- Cardiac
- In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease.
- Gastrointestinal
- The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3.
- Only 2.6% of the patients on Sandostatin Injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Sandostatin LAR Depot discontinued therapy for a GI event.
- In patients receiving Sandostatin LAR Depot, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin LAR Depot. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity.
- In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding.
- Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4%-6% of patients.
- In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27%-38% and constipation or vomiting in 15%-21% of patients treated with Sandostatin LAR Depot. Diarrhea was reported as an adverse event in 14% of patients but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea.
- Pain at the Injection Site
- Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalics receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of Sandostatin LAR Depot. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30%-50% at the 20-mg and 30-mg dose.
- Antibodies to Octreotide
- Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in two acromegalic patients who received Sandostatin Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with Sandostatin LAR Depot.
- Carcinoid and VIPomas
- The safety of Sandostatin LAR in the treatment of carcinoid tumors and VIPomas has been evaluated in one phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to Sandostatin LAR 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25-78 years old and 44% were female, 95% were Caucasian and 3% black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. 80 patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in >15% of patients regardless of presumed causality to study drug.
- Gallbladder Abnormalities
- In clinical trials, 62% of malignant carcinoid patients who received Sandostatin LAR Depot for up to 18 months developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients.
- Glucose Metabolism - Hypoglycemia/Hyperglycemia
- In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with Sandostatin LAR Depot.
- Hypothyroidism
- In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported.
- Cardiac
- Electrocardiograms were performed only in carcinoid patients receiving Sandostatin LAR Depot. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease.
- Other Clinical Studies Adverse Events
- Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving Sandostatin LAR Depot were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion.
## Postmarketing Experience
- The following adverse reactions have been identified during the postapproval use of Sandostatin. 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.
- Myocardial infarction has been observed in the postmarketing setting, mainly in patients with cardiovascular risk factors. Hypoadrenalism has been reported in some reports in patients 18 months of age and under.
- Additional events reported in the postmarketing setting include anaphylactoid reactions, including anaphylactic shock, cardiac arrest, renal failure, renal insufficiency, convulsions, atrial fibrillation, aneurysm, hepatitis, increased liver enzymes, gastrointestinal hemorrhage, pancreatitis, pancytopenia, thrombocytopenia, arterial thrombosis of the arm, retinal vein thrombosis, intracranial hemorrhage, hemiparesis, paresis, deafness, visual field defect, aphasia, scotoma, status asthmaticus, pulmonary hypertension, diabetes mellitus, intestinal obstruction, peptic/gastric ulcer, appendicitis, creatinine increased, CK increased, arthritis, joint effusion, pituitary apoplexy, breast carcinoma, suicide attempt, paranoia, migraines, urticaria, facial edema, generalized edema, hematuria, orthostatic hypotension, Raynaud’s syndrome, glaucoma, pulmonary nodule, pneumothorax aggravated, cellulitis, Bell’s palsy, diabetes insipidus, gynecomastia, galactorrhea, gallbladder polyp, fatty liver, abdomen enlarged, libido decrease, and petechiae.
# Drug Interactions
- Cyclosporine
- Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.
- Insulin and Oral Hypoglycemic Drugs
- Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.
- Bromocriptine
- Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.
- Other Concomitant Drug Therapy
- Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary.
- Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.
- Drug Metabolism Interactions
- Limited published data 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 octreotide 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.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose and have revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Octreotide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Octreotide during labor and delivery.
### Nursing Mothers
- It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Sandostatin LAR Depot is administered to a nursing woman.
### Pediatric Use
- Safety and efficacy of Sandostatin LAR Depot in the pediatric population have not been demonstrated.
- No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin LAR Depot in pediatric patients under 6 years of age. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying comorbid conditions.
- The efficacy and safety of Sandostatin LAR Depot was examined in a single randomized, double-blind, placebo-controlled, 6-month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/mL. Steady-state concentrations were achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin LAR Depot was dosed at 10 to 30 mg once a month.
### Geriatic Use
- Clinical studies of Sandostatin did not include sufficient numbers of subjects age 65 years 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.
### Gender
There is no FDA guidance on the use of Octreotide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Octreotide with respect to specific racial populations.
### Renal Impairment
- In patients with renal failure requiring dialysis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. In patients with mild, moderate, or severe renal impairment there is no need to adjust the starting dose of Sandostatin. The maintenance dose should be adjusted thereafter based on clinical response and tolerability as in nonrenal patients.
### Hepatic Impairment
- In patients with established liver cirrhosis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. Once at a higher dose, patient should be maintained or dose adjusted based on response and tolerability as in any noncirrhotic patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Octreotide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Octreotide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
### Monitoring
- Glucose monitoring is recommended and antidiabetic treatment may need adjustment
- Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot.
- Patients on TPN and octreotide should have periodic monitoring of zinc levels.
# IV Compatibility
There is limited information regarding IV Compatibility of Octreotide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No frank overdose has occurred in any patient to date. Sandostatin Injection given in intravenous bolus doses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. Doses of 2.5 mg (2500 mcg) of Sandostatin Injection subcutaneously have, however, caused hypoglycemia, flushing, dizziness, and nausea.
- Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®.
- Mortality occurred in mice and rats given 72 mg/kg and 18 mg/kg intravenously, respectively, of octreotide.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Octreotide in the drug label.
# Pharmacology
## Mechanism of Action
- Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.
- By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).
## Structure
- Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N--, cyclic (2→7)-disulfide; .
- Sandostatin LAR Depot is available in a vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability.
- Sandostatin LAR Depot is available as: sterile 5-mL vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each vial of Sandostatin LAR Depot delivers:
The molecular weight of octreotide is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is:
## Pharmacodynamics
- Octreotide substantially reduces and in many cases can normalize growth hormone and/or IGF-1 (somatomedin C) levels in patients with acromegaly.
- Single doses of Sandostatin Injection given subcutaneously have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased.
- Octreotide may cause clinically significant suppression of thyroid-stimulating hormone (TSH).
## Pharmacokinetics
- Sandostatin Injection
- According to data obtained with the immediate-release formulation, Sandostatin Injection solution, after subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous and subcutaneous doses were found to be bioequivalent. Peak concentrations and area-under-the-curve (AUC) values were dose proportional both after subcutaneous or intravenous single doses up to 400 mcg and with multiple doses of 200 mcg three times daily (600 mcg/day). Clearance was reduced by about 66% suggesting nonlinear kinetics of the drug at daily doses of 600 mcg/day compared to 150 mcg/day. The relative decrease in clearance with doses above 600 mcg/day is not defined.
- In healthy volunteers, the distribution of octreotide from plasma was rapid (tα1/2=0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L and the total body clearance was 10 L/h.
- In blood, the distribution of octreotide into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.
- The elimination of octreotide from plasma had an apparent half-life of 1.7 hours, compared with the 1-3 minutes with the natural hormone, somatostatin. The duration of action of subcutaneously administered Sandostatin Injection solution is variable but extends up to 12 hours depending upon the type of tumor, necessitating multiple daily dosing with this immediate-release dosage form. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug.
- In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The Vdss was estimated to be 21.6 ± 8.5 L and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.
- The half-life in renal-impaired patients was slightly longer than normal subjects (2.4-3.1 h versus 1.9 h). The clearance in renal-impaired patients was 7.3-8.8 L/h as compared to 8.3 L/h in healthy subjects. In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in healthy subjects (from approximately 10 L/h to 4.5 L/h).
- Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide half-life increasing to 3.7 h and total body clearance decreasing to 5.9 L/h, whereas patients with fatty liver disease showed half-life increasing to 3.4 h and total body clearance of 8.4 L/h. In normal subjects, octreotide half-life is 1.9 h and the clearance is 8.3 L/h which is comparable with the clearance in fatty-liver patients.
- Sandostatin LAR Depot
- The magnitude and duration of octreotide serum concentrations after an intramuscular injection of the long-acting depot formulation Sandostatin LAR Depot reflect the release of drug from the microsphere polymer matrix. Drug release is governed by the slow biodegration of the microspheres in the muscle, but once present in the systemic circulation, octreotide distributes and is eliminated according to its known pharmacokinetic properties which are as follows.
- After a single IM injection of the long-acting depot dosage form Sandostatin LAR Depot in healthy volunteer subjects, the serum octreotide concentration reached a transient initial peak of about 0.03 ng/mL/mg within 1 hour after administration progressively declining over the following 3-5 days to a nadir of <0.01 ng/mL/mg, then slowly increasing and reaching a plateau about 2-3 weeks postinjection. Plateau concentrations were maintained over a period of nearly 2-3 weeks, showing dose proportional peak concentrations of about 0.07 ng/mL/mg. After about 6 weeks postinjection, octreotide concentration slowly decreased, to <0.01 ng/mL/mg by Weeks 12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. The relative bioavailability of the long-acting release Sandostatin LAR Depot compared to immediate-release Sandostatin Injection solution given subcutaneously was 60%-63%.
- In patients with acromegaly, the octreotide concentrations after single doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot were dose proportional. The transient Day 1 peak, amounting to 0.3 ng/mL, 0.8 ng/mL, and 1.3 ng/mL, respectively, was followed by plateau concentrations of 0.5 ng/mL, 1.3 ng/mL, and 2.0 ng/mL, respectively, achieved about 3 weeks postinjection. These plateau concentrations were maintained for nearly 2 weeks.
- Following multiple doses of Sandostatin LAR Depot given every 4 weeks, steady-state octreotide serum concentrations were achieved after the third injection. Concentrations were dose proportional and higher by a factor of approximately 1.6 to 2.0 compared to the concentrations after a single dose. The steady-state octreotide concentrations were 1.2 ng/mL and 2.1 ng/mL, respectively, at trough and 1.6 ng/mL and 2.6 ng/mL, respectively, at peak with 20 mg and 30 mg Sandostatin LAR Depot given every 4 weeks. No accumulation of octreotide beyond that expected from the overlapping release profiles occurred over a duration of up to 28 monthly injections of Sandostatin LAR Depot. With the long-acting depot formulation Sandostatin LAR Depot administered IM every 4 weeks the peak-to-trough variation in octreotide concentrations ranged from 44%-68%, compared to the 163%-209% variation encountered with the daily subcutaneous three times daily regimen of Sandostatin Injection solution.
- In patients with carcinoid tumors, the mean octreotide concentrations after 6 doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot administered by IM injection every 4 weeks were 1.2 ng/mL, 2.5 ng/mL, and 4.2 ng/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after 2 injections of 20 mg and 30 mg and after 3 injections of 10 mg.
- Sandostatin LAR Depot has not been studied in patients with renal impairment.
- Sandostatin LAR Depot has not been studied in patients with hepatic impairment.
## Nonclinical Toxicology
- Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin. No mutagenic potential of the polymeric carrier in Sandostatin LAR Depot, D,L-lactic and glycolic acids copolymer, was observed in the Ames mutagenicity test.
- No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks at doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous study in rats administered octreotide, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin Injection for at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.
- Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area.
- Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose based on body surface area and have revealed no evidence of harm to the fetus due to octreotide.
# Clinical Studies
- Acromegaly
- The clinical trials of Sandostatin LAR Depot were performed in patients who had been receiving Sandostatin Injection for a period of weeks to as long as 10 years. The acromegaly studies with Sandostatin LAR Depot described below were performed in patients who achieved GH levels of 50% on subcutaneous Sandostatin Injection compared to the untreated state, although not suppressed to <5 ng/mL.
- Sandostatin LAR Depot was evaluated in three clinical trials in acromegalic patients.
- In two of the clinical trials, a total of 101 patients were entered who had, in most cases, achieved a GH level <5 ng/mL on Sandostatin Injection given in doses of 100 mcg or 200 mcg three times daily. Most patients were switched to 20 mg or 30 mg doses of Sandostatin LAR Depot given once every 4 weeks for up to 27 to 28 injections. A few patients received doses of 10 mg and a few required doses of 40 mg. Growth hormone and IGF-1 levels were at least as well controlled with Sandostatin LAR Depot as they had been on Sandostatin Injection and this level of control remained for the entire duration of the trials.
- A third trial was a 12-month study that enrolled 151 patients who had a GH level <10 ng/mL after treatment with Sandostatin Injection (most had levels <5 ng/mL). The starting dose of Sandostatin LAR Depot was 20 mg every 4 weeks for 3 doses. Thereafter, patients received 10 mg, 20 mg, or 30 mg every 4 weeks, depending upon the degree of GH suppression. Growth hormone and IGF-1 were at least as well controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.
- Table 5 summarizes the data on hormonal control (GH and IGF-1) for those patients in the first two clinical trials who received all 27 to 28 injections of Sandostatin LAR Depot.
- For the 88 patients in Table 5, a mean GH level of <2.5 ng/mL was observed in 47% receiving Sandostatin LAR Depot. Over the course of the trials, 42% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels.
- Table 6 summarizes the data on hormonal control (GH and IGF-1) for those patients in the third clinical trial who received all 12 injections of Sandostatin LAR Depot.
- For the 122 patients in Table 6, who received all 12 injections in the third trial, a mean GH level of <2.5 ng/mL was observed in 66% receiving Sandostatin LAR Depot. Over the course of the trial, 57% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels. In comparing the hormonal response in these trials, note that a higher percentage of patients in the third trial suppressed their mean GH to <5 ng/mL on subcutaneous Sandostatin Injection, 95%, compared to 78% across the two previous trials.
- In all three trials, GH, IGF-1, and clinical symptoms were similarly controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.
- Of the 25 patients who completed the trials and were partial responders to Sandostatin Injection (GH >5.0 ng/mL but reduced by >50% relative to untreated levels), 1 patient (4%) responded to Sandostatin LAR Depot with a reduction of GH to <2.5 ng/mL and 8 patients (32%) responded with a reduction of GH to <5.0 ng/mL.
- Two open-label clinical studies investigated a 48-week treatment with Sandostatin LAR Depot in 143 untreated (de novo) acromegalic patients. The median reduction in tumor volume was 20.6% in Study 1 (49 patients) at 24 weeks and 24.5% in Study 2 (94 patients) at 24 weeks and 36.2% at 48 weeks.
- Carcinoid Syndrome
- A 6-month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been shown to be responsive to Sandostatin Injection. Sixty-seven (67) patients were randomized at baseline to receive double-blind doses of 10 mg, 20 mg, or 30 mg Sandostatin LAR Depot every 28 days and 26 patients continued, unblinded, on their previous Sandostatin Injection regimen (100-300 mcg three times daily).
- In any given month after steady-state levels of octreotide were reached, approximately 35%-40% of the patients who received Sandostatin LAR Depot required supplemental subcutaneous Sandostatin Injection therapy usually for a few days, to control exacerbation of carcinoid symptoms. In any given month, the percentage of patients randomized to subcutaneous Sandostatin Injection who required supplemental treatment with an increased dose of Sandostatin Injection was similar to the percentage of patients randomized to Sandostatin LAR Depot. Over the 6-month treatment period, approximately 50%-70% of patients who completed the trial on Sandostatin LAR Depot required subcutaneous Sandostatin Injection supplemental therapy to control exacerbation of carcinoid symptoms although steady-state serum Sandostatin LAR Depot levels had been reached.
- Table 7 presents the average number of daily stools and flushing episodes in malignant carcinoid patients.
- Overall, mean daily stool frequency was as well controlled on Sandostatin LAR Depot as on Sandostatin Injection (approximately 2-2.5 stools/day).
- Mean daily flushing episodes were similar at all doses of Sandostatin LAR Depot and on Sandostatin Injection (approximately 0.5-1 episode/day).
- In a subset of patients with variable severity of disease, median 24 hour urinary 5-HIAA (5-hydroxyindole acetic acid) levels were reduced by 38%-50% in the groups randomized to Sandostatin LAR Depot.
- The reductions are within the range reported in the published literature for patients treated with octreotide (about 10%-50%).
- Seventy-eight (78) patients with malignant carcinoid syndrome who had participated in this 6-month trial, subsequently participated in a 12-month extension study in which they received 12 injections of Sandostatin LAR Depot at 4-week intervals. For those who remained in the extension trial, diarrhea and flushing were as well controlled as during the 6-month trial. Because malignant carcinoid disease is progressive, as expected, a number of deaths (8 patients: 10%) occurred due to disease progression or complications from the underlying disease. An additional 22% of patients prematurely discontinued Sandostatin LAR Depot due to disease progression or worsening of carcinoid symptoms.
# How Supplied
- Sandostatin LAR Depot is available in single-use kits containing a 5-mL vial of 10 mg, 20 mg or 30 mg strength, a syringe containing 2.5 mL of diluent, one sterile 1½” 19 gauge standard needle for transfer and drug product reconstitution, and one sterile 1½” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.
- Drug Product Kits
- 10 mg kit NDC 0078-0340-61
- 20 mg kit NDC 0078-0341-61
- 30 mg kit NDC 0078-0342-61
- Demonstration kit NDC 0078-9342-61
- For prolonged storage, Sandostatin LAR Depot should be stored at refrigerated temperatures between 2°C-8°C (36°F-46°F) and protected from light until the time of use. Sandostatin LAR Depot drug product kit should remain at room temperature for 30-60 minutes prior to preparation of the drug suspension. However, after preparation the drug suspension must be administered immediately.
## Storage
There is limited information regarding Octreotide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms.
- Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady control of GH and IGF-1 levels.
# Precautions with Alcohol
- Alcohol-Octreotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sandostatin LAR®
# Look-Alike Drug Names
- SandoSTATIN® — SandIMMUNE®
- SandoSTATIN LAR Depot® — SandIMMUNE®
# Drug Shortage Status
# Price | Octreotide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Octreotide is a somatostatin analogue that is FDA approved for the treatment of acromegaly, severe diarrhea/flushing episodes associated with metastatic carcinoid tumors, profuse watery diarrhea associated with VIP-secreting tumors. Common adverse reactions include diarrhea, cholelithiasis, abdominal pain, flatulence, back pain, fatigue, headache, abdominal pain, nausea, dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Patients Not Currently Receiving Octreotide Acetate
- Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily.
- Patients should be maintained on Sandostatin Injection subcutaneous for at least 2 weeks to determine tolerance to octreotide. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug can then be switched to Sandostatin LAR Depot in the dosage scheme described below (Patients Currently Receiving Sandostatin Injection).
- Patients Currently Receiving Sandostatin Injection
- Patients currently receiving Sandostatin Injection can be switched directly to Sandostatin LAR Depot in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months. After 3 months, dosage may be adjusted as follows:
GH ≤2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain Sandostatin LAR Depot dosage at 20 mg every 4 weeks.
GH >2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase Sandostatin LAR Depot dosage to 30 mg every 4 weeks.
GH ≤1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce Sandostatin LAR Depot dosage to 10 mg every 4 weeks.
If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended.
- GH ≤2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain Sandostatin LAR Depot dosage at 20 mg every 4 weeks.
- GH >2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase Sandostatin LAR Depot dosage to 30 mg every 4 weeks.
- GH ≤1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce Sandostatin LAR Depot dosage to 10 mg every 4 weeks.
- If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended.
- In patients who have received pituitary irradiation, Sandostatin LAR Depot should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, Sandostatin LAR Depot therapy may be resumed.
- Dosing Information
- Patients Not Currently Receiving Octreotide Acetate
- Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). Some patients may require doses up to 1500 mcg/day. The suggested daily dosage for VIPomas is 200-300 mcg in 2-4 divided doses (range 150-750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required.
- Sandostatin Injection should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to octreotide acetate and who tolerate the drug may be switched to Sandostatin LAR Depot in the dosage regimen as described below (Patients Currently Receiving Sandostatin Injection).
- Patients Currently Receiving Sandostatin Injection
- Patients currently receiving Sandostatin Injection can be switched to Sandostatin LAR Depot in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of Sandostatin LAR Depot, carcinoid tumor and VIPoma patients should continue to receive Sandostatin Injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms. (Some patients may require 3 or 4 weeks of such therapy.)
- After 2 months, dosage may be adjusted as follows:
If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dose every 4 weeks.
If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
Dosages higher than 30 mg are not recommended.
- If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dose every 4 weeks.
- If symptoms are not adequately controlled, increase Sandostatin LAR Depot to 30 mg every 4 weeks. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks.
- Dosages higher than 30 mg are not recommended.
- Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on Sandostatin Injection or Sandostatin LAR Depot). During these periods they may be given Sandostatin Injection subcutaneously for a few days at the dosage they were receiving prior to switching to Sandostatin LAR Depot. When symptoms are again controlled, the Sandostatin Injection subcutaneous can be discontinued.
- Special Populations: Renal Impairment
- In patients with renal failure requiring dialysis, the starting dose should be 10 mg every 4 weeks. In other patients with renal impairment, the starting dose should be similar to a nonrenal patient (i.e., 20 mg every 4 weeks).
- Special Populations: Hepatic Impairment – Cirrhotic Patients
- In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Octreotide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Octreotide in doses of 50 mcg twice daily to 100 mcg 3 times daily subcutaneously.
- Dosing Information
- Octreotide (50 mcg IV bolus followed by a continuous IV infusion of octreotide at 50 mcg/hour for 5 days.
- Dosing Information
- Octreotide (100 mcg initially as an IV bolus, followed by continuous IV infusion of 10 to 100 mcg/hour).
- Dosing Information
- Continuous subcutaneous infusion of octreotide 200 mcg/24 hours for 6 to 12 months.
- Dosing Information
- Single dose of octreotide 75 mcg subQ.[1]
- Dosing Information
- Subcutaneous octreotide 100 mcg.
- Dosing Information
- SUBQ octreotide 5 mcg/kg/day divided into 3 daily doses with bimonthly increases of 5 mcg/kg/d to a maximum of 15 mcg/kg/d.
- Dosing Information
- SUBQ octreotide (0.1 mg 3 times daily for 5 days.
- Dosing Information
- Octreotide 100 mcg three times daily for 10 days.
- Dosing Information
- Octreotide LAR 30 mg (n=42) intramuscularly every 28 days.[2]
- Dosing Information
- Subcutaneous octreotide acetate 100 mcg 3 times per day.
- Dosing Information
- Octreotide 50 mcg subcutaneously every 8 hours for 1 week and 100 mcg every 8 hours for the rest of the 4-month.
- Dosing Information
- Octreotide 100 mcg/8 hours.
- Dosing Information
- Subcutaneous administration of octreotideat 50 mcg daily, the dose was increased to 200 mcg three times daily.
- Dosing Information
- Octreotide in doses of 400 to 500 mcg subcutaneously daily for up to 12 months.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Octreotide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Octreotide in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Octreotide 10 mcg/kg/day in 3 divided doses.
# Contraindications
- None
# Warnings
### Precautions
- Cholelithiasis and Gallbladder Sludge
- Sandostatin may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Patients should be monitored periodically.
- Hyperglycemia and Hypoglycemia
- Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone, which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Sandostatin LAR treatment is initiated, or when the dose is altered. Antidiabetic treatment should be adjusted accordingly.
- Thyroid Function Abnormalities
- Octreotide suppresses the secretion of thyroid-stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotide therapy.
- Cardiac Function Abnormalities
- In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other ECG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs such as beta-blockers that have bradycardic effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of Sandostatin Injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.
- Nutrition
- Octreotide may alter absorption of dietary fats.
- Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot.
- Octreotide has been investigated for the reduction of excessive fluid loss from the GI tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels.
- Monitoring: Laboratory Tests
- Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy.
- Acromegaly: Growth Hormone, IGF-1 (somatomedin C)
- Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P
- VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T4 measurements should be performed during chronic therapy
# 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 trial of another drug and may not reflect the rates observed in practice.
- Acromegaly
- The safety of Sandostatin LAR in the treatment of acromegaly has been evaluated in three phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. Sandostatin LAR was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14-81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10-60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug.
- The safety of Sandostatin LAR in the treatment of acromegaly was also evaluated in a postmarketing randomized phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of Sandostatin LAR. All the patients were treatment naïve (‘de novo’). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to Sandostatin LAR were exposed to Sandostatin LAR up to 1 year. The population age range was between 20-76 years old, 45% were female, 93% were Caucasian, and 1% black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug.
- Gallbladder Abnormalities
- Single doses of Sandostatin Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure.
- In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR Depot for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones.
- Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide, 1% of patients developed acute symptoms requiring cholecystectomy.
- Glucose Metabolism - Hypoglycemia/Hyperglycemia
- In acromegaly patients treated with either Sandostatin Injection or Sandostatin LAR Depot, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients.
- Hypothyroidism
- In acromegaly patients receiving Sandostatin Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin Injection. In acromegalics treated with Sandostatin LAR Depot, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving Sandostatin LAR Depot required initiation of thyroid hormone replacement therapy.
- Cardiac
- In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease.
- Gastrointestinal
- The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3.
- Only 2.6% of the patients on Sandostatin Injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving Sandostatin LAR Depot discontinued therapy for a GI event.
- In patients receiving Sandostatin LAR Depot, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with Sandostatin LAR Depot. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity.
- In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding.
- Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4%-6% of patients.
- In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27%-38% and constipation or vomiting in 15%-21% of patients treated with Sandostatin LAR Depot. Diarrhea was reported as an adverse event in 14% of patients but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea.
- Pain at the Injection Site
- Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalics receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of Sandostatin LAR Depot. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30%-50% at the 20-mg and 30-mg dose.
- Antibodies to Octreotide
- Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in two acromegalic patients who received Sandostatin Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with Sandostatin LAR Depot.
- Carcinoid and VIPomas
- The safety of Sandostatin LAR in the treatment of carcinoid tumors and VIPomas has been evaluated in one phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to Sandostatin LAR 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25-78 years old and 44% were female, 95% were Caucasian and 3% black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. 80 patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in >15% of patients regardless of presumed causality to study drug.
- Gallbladder Abnormalities
- In clinical trials, 62% of malignant carcinoid patients who received Sandostatin LAR Depot for up to 18 months developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients.
- Glucose Metabolism - Hypoglycemia/Hyperglycemia
- In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with Sandostatin LAR Depot.
- Hypothyroidism
- In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported.
- Cardiac
- Electrocardiograms were performed only in carcinoid patients receiving Sandostatin LAR Depot. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease.
- Other Clinical Studies Adverse Events
- Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving Sandostatin LAR Depot were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion.
## Postmarketing Experience
- The following adverse reactions have been identified during the postapproval use of Sandostatin. 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.
- Myocardial infarction has been observed in the postmarketing setting, mainly in patients with cardiovascular risk factors. Hypoadrenalism has been reported in some reports in patients 18 months of age and under.
- Additional events reported in the postmarketing setting include anaphylactoid reactions, including anaphylactic shock, cardiac arrest, renal failure, renal insufficiency, convulsions, atrial fibrillation, aneurysm, hepatitis, increased liver enzymes, gastrointestinal hemorrhage, pancreatitis, pancytopenia, thrombocytopenia, arterial thrombosis of the arm, retinal vein thrombosis, intracranial hemorrhage, hemiparesis, paresis, deafness, visual field defect, aphasia, scotoma, status asthmaticus, pulmonary hypertension, diabetes mellitus, intestinal obstruction, peptic/gastric ulcer, appendicitis, creatinine increased, CK increased, arthritis, joint effusion, pituitary apoplexy, breast carcinoma, suicide attempt, paranoia, migraines, urticaria, facial edema, generalized edema, hematuria, orthostatic hypotension, Raynaud’s syndrome, glaucoma, pulmonary nodule, pneumothorax aggravated, cellulitis, Bell’s palsy, diabetes insipidus, gynecomastia, galactorrhea, gallbladder polyp, fatty liver, abdomen enlarged, libido decrease, and petechiae.
# Drug Interactions
- Cyclosporine
- Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.
- Insulin and Oral Hypoglycemic Drugs
- Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Sandostatin LAR treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.
- Bromocriptine
- Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.
- Other Concomitant Drug Therapy
- Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary.
- Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.
- Drug Metabolism Interactions
- Limited published data 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 octreotide 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.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose and have revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Octreotide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Octreotide during labor and delivery.
### Nursing Mothers
- It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Sandostatin LAR Depot is administered to a nursing woman.
### Pediatric Use
- Safety and efficacy of Sandostatin LAR Depot in the pediatric population have not been demonstrated.
- No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin LAR Depot in pediatric patients under 6 years of age. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying comorbid conditions.
- The efficacy and safety of Sandostatin LAR Depot was examined in a single randomized, double-blind, placebo-controlled, 6-month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/mL. Steady-state concentrations were achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin LAR Depot was dosed at 10 to 30 mg once a month.
### Geriatic Use
- Clinical studies of Sandostatin did not include sufficient numbers of subjects age 65 years 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.
### Gender
There is no FDA guidance on the use of Octreotide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Octreotide with respect to specific racial populations.
### Renal Impairment
- In patients with renal failure requiring dialysis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. In patients with mild, moderate, or severe renal impairment there is no need to adjust the starting dose of Sandostatin. The maintenance dose should be adjusted thereafter based on clinical response and tolerability as in nonrenal patients.
### Hepatic Impairment
- In patients with established liver cirrhosis, the starting dose should be 10 mg. This dose should be up titrated based on clinical response and speed of response as deemed necessary by the physician. Once at a higher dose, patient should be maintained or dose adjusted based on response and tolerability as in any noncirrhotic patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Octreotide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Octreotide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
### Monitoring
- Glucose monitoring is recommended and antidiabetic treatment may need adjustment
- Depressed vitamin B12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot.
- Patients on TPN and octreotide should have periodic monitoring of zinc levels.
# IV Compatibility
There is limited information regarding IV Compatibility of Octreotide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No frank overdose has occurred in any patient to date. Sandostatin Injection given in intravenous bolus doses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. Doses of 2.5 mg (2500 mcg) of Sandostatin Injection subcutaneously have, however, caused hypoglycemia, flushing, dizziness, and nausea.
- Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®**.
- Mortality occurred in mice and rats given 72 mg/kg and 18 mg/kg intravenously, respectively, of octreotide.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Octreotide in the drug label.
# Pharmacology
## Mechanism of Action
- Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.
- By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).
## Structure
- Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1- (hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)].
- Sandostatin LAR Depot is available in a vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability.
- Sandostatin LAR Depot is available as: sterile 5-mL vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each vial of Sandostatin LAR Depot delivers:
The molecular weight of octreotide is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is:
## Pharmacodynamics
- Octreotide substantially reduces and in many cases can normalize growth hormone and/or IGF-1 (somatomedin C) levels in patients with acromegaly.
- Single doses of Sandostatin Injection given subcutaneously have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased.
- Octreotide may cause clinically significant suppression of thyroid-stimulating hormone (TSH).
## Pharmacokinetics
- Sandostatin Injection
- According to data obtained with the immediate-release formulation, Sandostatin Injection solution, after subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous and subcutaneous doses were found to be bioequivalent. Peak concentrations and area-under-the-curve (AUC) values were dose proportional both after subcutaneous or intravenous single doses up to 400 mcg and with multiple doses of 200 mcg three times daily (600 mcg/day). Clearance was reduced by about 66% suggesting nonlinear kinetics of the drug at daily doses of 600 mcg/day compared to 150 mcg/day. The relative decrease in clearance with doses above 600 mcg/day is not defined.
- In healthy volunteers, the distribution of octreotide from plasma was rapid (tα1/2=0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L and the total body clearance was 10 L/h.
- In blood, the distribution of octreotide into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.
- The elimination of octreotide from plasma had an apparent half-life of 1.7 hours, compared with the 1-3 minutes with the natural hormone, somatostatin. The duration of action of subcutaneously administered Sandostatin Injection solution is variable but extends up to 12 hours depending upon the type of tumor, necessitating multiple daily dosing with this immediate-release dosage form. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug.
- In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The Vdss was estimated to be 21.6 ± 8.5 L and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.
- The half-life in renal-impaired patients was slightly longer than normal subjects (2.4-3.1 h versus 1.9 h). The clearance in renal-impaired patients was 7.3-8.8 L/h as compared to 8.3 L/h in healthy subjects. In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in healthy subjects (from approximately 10 L/h to 4.5 L/h).
- Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide half-life increasing to 3.7 h and total body clearance decreasing to 5.9 L/h, whereas patients with fatty liver disease showed half-life increasing to 3.4 h and total body clearance of 8.4 L/h. In normal subjects, octreotide half-life is 1.9 h and the clearance is 8.3 L/h which is comparable with the clearance in fatty-liver patients.
- Sandostatin LAR Depot
- The magnitude and duration of octreotide serum concentrations after an intramuscular injection of the long-acting depot formulation Sandostatin LAR Depot reflect the release of drug from the microsphere polymer matrix. Drug release is governed by the slow biodegration of the microspheres in the muscle, but once present in the systemic circulation, octreotide distributes and is eliminated according to its known pharmacokinetic properties which are as follows.
- After a single IM injection of the long-acting depot dosage form Sandostatin LAR Depot in healthy volunteer subjects, the serum octreotide concentration reached a transient initial peak of about 0.03 ng/mL/mg within 1 hour after administration progressively declining over the following 3-5 days to a nadir of <0.01 ng/mL/mg, then slowly increasing and reaching a plateau about 2-3 weeks postinjection. Plateau concentrations were maintained over a period of nearly 2-3 weeks, showing dose proportional peak concentrations of about 0.07 ng/mL/mg. After about 6 weeks postinjection, octreotide concentration slowly decreased, to <0.01 ng/mL/mg by Weeks 12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. The relative bioavailability of the long-acting release Sandostatin LAR Depot compared to immediate-release Sandostatin Injection solution given subcutaneously was 60%-63%.
- In patients with acromegaly, the octreotide concentrations after single doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot were dose proportional. The transient Day 1 peak, amounting to 0.3 ng/mL, 0.8 ng/mL, and 1.3 ng/mL, respectively, was followed by plateau concentrations of 0.5 ng/mL, 1.3 ng/mL, and 2.0 ng/mL, respectively, achieved about 3 weeks postinjection. These plateau concentrations were maintained for nearly 2 weeks.
- Following multiple doses of Sandostatin LAR Depot given every 4 weeks, steady-state octreotide serum concentrations were achieved after the third injection. Concentrations were dose proportional and higher by a factor of approximately 1.6 to 2.0 compared to the concentrations after a single dose. The steady-state octreotide concentrations were 1.2 ng/mL and 2.1 ng/mL, respectively, at trough and 1.6 ng/mL and 2.6 ng/mL, respectively, at peak with 20 mg and 30 mg Sandostatin LAR Depot given every 4 weeks. No accumulation of octreotide beyond that expected from the overlapping release profiles occurred over a duration of up to 28 monthly injections of Sandostatin LAR Depot. With the long-acting depot formulation Sandostatin LAR Depot administered IM every 4 weeks the peak-to-trough variation in octreotide concentrations ranged from 44%-68%, compared to the 163%-209% variation encountered with the daily subcutaneous three times daily regimen of Sandostatin Injection solution.
- In patients with carcinoid tumors, the mean octreotide concentrations after 6 doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot administered by IM injection every 4 weeks were 1.2 ng/mL, 2.5 ng/mL, and 4.2 ng/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after 2 injections of 20 mg and 30 mg and after 3 injections of 10 mg.
- Sandostatin LAR Depot has not been studied in patients with renal impairment.
- Sandostatin LAR Depot has not been studied in patients with hepatic impairment.
## Nonclinical Toxicology
- Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin. No mutagenic potential of the polymeric carrier in Sandostatin LAR Depot, D,L-lactic and glycolic acids copolymer, was observed in the Ames mutagenicity test.
- No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks at doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous study in rats administered octreotide, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin Injection for at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.
- Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area.
- Reproduction studies have been performed in rats and rabbits at doses up to 16x the highest recommended human dose based on body surface area and have revealed no evidence of harm to the fetus due to octreotide.
# Clinical Studies
- Acromegaly
- The clinical trials of Sandostatin LAR Depot were performed in patients who had been receiving Sandostatin Injection for a period of weeks to as long as 10 years. The acromegaly studies with Sandostatin LAR Depot described below were performed in patients who achieved GH levels of <10 ng/mL (and, in most cases <5 ng/mL) while on subcutaneous Sandostatin Injection. However, some patients enrolled were partial responders to subcutaneous Sandostatin Injection, i.e., GH levels were reduced by >50% on subcutaneous Sandostatin Injection compared to the untreated state, although not suppressed to <5 ng/mL.
- Sandostatin LAR Depot was evaluated in three clinical trials in acromegalic patients.
- In two of the clinical trials, a total of 101 patients were entered who had, in most cases, achieved a GH level <5 ng/mL on Sandostatin Injection given in doses of 100 mcg or 200 mcg three times daily. Most patients were switched to 20 mg or 30 mg doses of Sandostatin LAR Depot given once every 4 weeks for up to 27 to 28 injections. A few patients received doses of 10 mg and a few required doses of 40 mg. Growth hormone and IGF-1 levels were at least as well controlled with Sandostatin LAR Depot as they had been on Sandostatin Injection and this level of control remained for the entire duration of the trials.
- A third trial was a 12-month study that enrolled 151 patients who had a GH level <10 ng/mL after treatment with Sandostatin Injection (most had levels <5 ng/mL). The starting dose of Sandostatin LAR Depot was 20 mg every 4 weeks for 3 doses. Thereafter, patients received 10 mg, 20 mg, or 30 mg every 4 weeks, depending upon the degree of GH suppression. Growth hormone and IGF-1 were at least as well controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.
- Table 5 summarizes the data on hormonal control (GH and IGF-1) for those patients in the first two clinical trials who received all 27 to 28 injections of Sandostatin LAR Depot.
- For the 88 patients in Table 5, a mean GH level of <2.5 ng/mL was observed in 47% receiving Sandostatin LAR Depot. Over the course of the trials, 42% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels.
- Table 6 summarizes the data on hormonal control (GH and IGF-1) for those patients in the third clinical trial who received all 12 injections of Sandostatin LAR Depot.
- For the 122 patients in Table 6, who received all 12 injections in the third trial, a mean GH level of <2.5 ng/mL was observed in 66% receiving Sandostatin LAR Depot. Over the course of the trial, 57% of patients maintained mean growth hormone levels of <2.5 ng/mL and mean normal IGF-1 levels. In comparing the hormonal response in these trials, note that a higher percentage of patients in the third trial suppressed their mean GH to <5 ng/mL on subcutaneous Sandostatin Injection, 95%, compared to 78% across the two previous trials.
- In all three trials, GH, IGF-1, and clinical symptoms were similarly controlled on Sandostatin LAR Depot as they had been on Sandostatin Injection.
- Of the 25 patients who completed the trials and were partial responders to Sandostatin Injection (GH >5.0 ng/mL but reduced by >50% relative to untreated levels), 1 patient (4%) responded to Sandostatin LAR Depot with a reduction of GH to <2.5 ng/mL and 8 patients (32%) responded with a reduction of GH to <5.0 ng/mL.
- Two open-label clinical studies investigated a 48-week treatment with Sandostatin LAR Depot in 143 untreated (de novo) acromegalic patients. The median reduction in tumor volume was 20.6% in Study 1 (49 patients) at 24 weeks and 24.5% in Study 2 (94 patients) at 24 weeks and 36.2% at 48 weeks.
- Carcinoid Syndrome
- A 6-month clinical trial of malignant carcinoid syndrome was performed in 93 patients who had previously been shown to be responsive to Sandostatin Injection. Sixty-seven (67) patients were randomized at baseline to receive double-blind doses of 10 mg, 20 mg, or 30 mg Sandostatin LAR Depot every 28 days and 26 patients continued, unblinded, on their previous Sandostatin Injection regimen (100-300 mcg three times daily).
- In any given month after steady-state levels of octreotide were reached, approximately 35%-40% of the patients who received Sandostatin LAR Depot required supplemental subcutaneous Sandostatin Injection therapy usually for a few days, to control exacerbation of carcinoid symptoms. In any given month, the percentage of patients randomized to subcutaneous Sandostatin Injection who required supplemental treatment with an increased dose of Sandostatin Injection was similar to the percentage of patients randomized to Sandostatin LAR Depot. Over the 6-month treatment period, approximately 50%-70% of patients who completed the trial on Sandostatin LAR Depot required subcutaneous Sandostatin Injection supplemental therapy to control exacerbation of carcinoid symptoms although steady-state serum Sandostatin LAR Depot levels had been reached.
- Table 7 presents the average number of daily stools and flushing episodes in malignant carcinoid patients.
- Overall, mean daily stool frequency was as well controlled on Sandostatin LAR Depot as on Sandostatin Injection (approximately 2-2.5 stools/day).
- Mean daily flushing episodes were similar at all doses of Sandostatin LAR Depot and on Sandostatin Injection (approximately 0.5-1 episode/day).
- In a subset of patients with variable severity of disease, median 24 hour urinary 5-HIAA (5-hydroxyindole acetic acid) levels were reduced by 38%-50% in the groups randomized to Sandostatin LAR Depot.
- The reductions are within the range reported in the published literature for patients treated with octreotide (about 10%-50%).
- Seventy-eight (78) patients with malignant carcinoid syndrome who had participated in this 6-month trial, subsequently participated in a 12-month extension study in which they received 12 injections of Sandostatin LAR Depot at 4-week intervals. For those who remained in the extension trial, diarrhea and flushing were as well controlled as during the 6-month trial. Because malignant carcinoid disease is progressive, as expected, a number of deaths (8 patients: 10%) occurred due to disease progression or complications from the underlying disease. An additional 22% of patients prematurely discontinued Sandostatin LAR Depot due to disease progression or worsening of carcinoid symptoms.
# How Supplied
- Sandostatin LAR Depot is available in single-use kits containing a 5-mL vial of 10 mg, 20 mg or 30 mg strength, a syringe containing 2.5 mL of diluent, one sterile 1½” 19 gauge standard needle for transfer and drug product reconstitution, and one sterile 1½” 19 gauge safety injection needle. An instruction booklet for the preparation of drug suspension for injection is also included with each kit.
- Drug Product Kits
- 10 mg kit NDC 0078-0340-61
- 20 mg kit NDC 0078-0341-61
- 30 mg kit NDC 0078-0342-61
- Demonstration kit NDC 0078-9342-61
- For prolonged storage, Sandostatin LAR Depot should be stored at refrigerated temperatures between 2°C-8°C (36°F-46°F) and protected from light until the time of use. Sandostatin LAR Depot drug product kit should remain at room temperature for 30-60 minutes prior to preparation of the drug suspension. However, after preparation the drug suspension must be administered immediately.
## Storage
There is limited information regarding Octreotide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled return visits for reinjection in order to minimize exacerbation of symptoms.
- Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady control of GH and IGF-1 levels.
# Precautions with Alcohol
- Alcohol-Octreotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sandostatin LAR®[3]
# Look-Alike Drug Names
- SandoSTATIN® — SandIMMUNE®[4]
- SandoSTATIN LAR Depot® — SandIMMUNE®[4]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Octreotide | |
cb1bf001dbbb7f159bfa721ce7b8d5d826a2d583 | wikidoc | Odds ratio | Odds ratio
The odds ratio is a measure of effect size particularly important in Bayesian statistics and logistic regression.
It is defined as the ratio of the odds of an event occurring in one group to the odds of it occurring in another group, or to a sample-based estimate of that ratio. These groups might be men and women, an experimental group and a control group, or any other dichotomous classification. If the probabilities of the event in each of the groups are p (first group) and q (second group), then the odds ratio is:
An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. The odds ratio must be greater than or equal to zero. As the odds of the first group approaches zero, the odds ratio approaches zero. As the odds of the second group approaches zero, the odds ratio approaches positive infinity.
For example, suppose that in a sample of 100 men, 90 have drunk wine in the previous week, while in a sample of 100 women only 20 have drunk wine in the same period. The odds of a man drinking wine are 90 to 10, or 9:1, while the odds of a woman drinking wine are only 20 to 80, or 1:4 = 0.25:1. Now, 9/0.25 = 36, so the odds ratio is 36, showing that men are much more likely to drink wine than women. Using the above formula for the calculation yields:
This example also shows how odds ra can sometimes seem to overstate relative positions: in this sample men are 4.5 times more likely to have drunk wine than women, but have 36 times the odds.
Taking the logarithm of the odds ratio ameliorates this effect, and also improves symmetry. For example, using natural logarithms, an odds ratio of 36 maps to 3.584, an odds ratio of one maps to zero, and an odds ratio of 1/36 maps to -3.584.
The logarithm of the odds ratio is the difference of the logits of the probabilities.
The increased use of logistic regression in medical and social science research means that the odds ratio is commonly used as a means of expressing the results in some forms of clinical trials, in survey research, and in epidemiology, such as in case-control studies. It is often abbreviated "OR" in reports. When data from multiple surveys is combined, it will often be expressed as "Pooled OR". | Odds ratio
The odds ratio is a measure of effect size particularly important in Bayesian statistics and logistic regression.
It is defined as the ratio of the odds of an event occurring in one group to the odds of it occurring in another group, or to a sample-based estimate of that ratio. These groups might be men and women, an experimental group and a control group, or any other dichotomous classification. If the probabilities of the event in each of the groups are p (first group) and q (second group), then the odds ratio is:
An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. The odds ratio must be greater than or equal to zero. As the odds of the first group approaches zero, the odds ratio approaches zero. As the odds of the second group approaches zero, the odds ratio approaches positive infinity.
For example, suppose that in a sample of 100 men, 90 have drunk wine in the previous week, while in a sample of 100 women only 20 have drunk wine in the same period. The odds of a man drinking wine are 90 to 10, or 9:1, while the odds of a woman drinking wine are only 20 to 80, or 1:4 = 0.25:1. Now, 9/0.25 = 36, so the odds ratio is 36, showing that men are much more likely to drink wine than women. Using the above formula for the calculation yields:
This example also shows how odds ra can sometimes seem to overstate relative positions: in this sample men are 4.5 times more likely to have drunk wine than women, but have 36 times the odds.
Taking the logarithm of the odds ratio ameliorates this effect, and also improves symmetry. For example, using natural logarithms, an odds ratio of 36 maps to 3.584, an odds ratio of one maps to zero, and an odds ratio of 1/36 maps to -3.584.
The logarithm of the odds ratio is the difference of the logits of the probabilities.
The increased use of logistic regression in medical and social science research means that the odds ratio is commonly used as a means of expressing the results in some forms of clinical trials, in survey research, and in epidemiology, such as in case-control studies. It is often abbreviated "OR" in reports. When data from multiple surveys is combined, it will often be expressed as "Pooled OR". | https://www.wikidoc.org/index.php/Odds_ratio | |
4dc6fd4c1aa860f3b62363fdbbdcb3e567391855 | wikidoc | Odevixibat | Odevixibat
# 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
Odevixibat is a ileal bile acid transporter inhibitor that is FDA approved for the treatment of pruritus. Common adverse reactions include abdominal pain,, fat-soluble vitamin deficiency, diarrhea, vomiting, and liver test abnormalities..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Recommended Dosage
- 40 mcg/kg once daily of Odevixibat is the recommended dosage.
- Dosage should be taken with a meal in the morning.
- Recommended dosage may be increased to 120 mcg/kg if there are no signs of pruritus improvement after 3 months of Odevixibat treatment.
- Patients with a weight less than 19.5 kilograms may use Odevixibat pellets.
- Patients with a weight of 19.5 kilograms or more may use Odevixibat capsules.
Table 1 shows Recommended Dosage for 40 mcg/kg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Odevixibat in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Odevixibat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Odevixibat 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 Odevixibat in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Odevixibat in pediatric patients.
# Contraindications
There are no contraindications associated with Odevixibat.
# Warnings
Liver Test Abnormalities
- Trial 1 clinical studies show elevations of liver tests or worsening of liver tests in comparison to baseline values for patients taking Odevixibat.
- Elevations of ALT, AST, or total and direct bilirubin were some of the abnormalities seen in the clinical studies.
- 3-120 days was the range of Odevixibat treatment interruption that occurred during the Trial 1 studies.
- Advise patients that treatment discontinuation of Odevixibat may be necessary if they experience persistent or recurrent liver test abnormalities.
Table 2 shows the Liver Test Data obtained in Trial 1 Clinical Studies.
Diarrhea
- 21% of patients receiving 120 mcg/kg/day of Odevixibat experienced diarrhea in Trial 1 clinical studies.
- 39% of patients receiving 40 mcg/kg/day of Odevixibat experienced diarrhea in Trial 1 clinical studies.
- 10% of placebo-treated patients experienced diarrhea in Trial 1 clinical studies.
- Treatment interruption was seen in patients receiving 120 mcg/kg/day of Odevixibat in Trial 1 clinical studies.
- Monitor patients for dehydration if they experience diarrhea and treat accordingly.
- Advise patients that interruption of Odevixibat treatment may be necessary if diarrhea persists.
Fat-Soluble Vitamin (FSV) Deficiency
- Advise patients that absorption of fat-soluble vitamins may occur during Odevixibat treatment.
- No patients receiving 40 mcg/kg/day of Odevixibat experienced new onset or worsening of existing FSV deficiency in Trial 1 clinical studies.
- 16% of patients receiving 120 mcg/kg/day of Odevixibat experienced new onset or worsening of existing FSV deficiency in Trial 1 clinical studies.
- 5% of placebo-treated patients experienced new onset or worsening of existing FSV deficiency in Trial 1 clinical studies.
- Monitor patients serum FSV levels at baseline and during Odevixibat treatment.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
- Trial 1 clinical study is a randomized, double-blind, placebo-controlled, 24-week study that looked into the effects of administering 40 mcg/kg vs 120 mcg/kg of Odevixibat. The study consisted of 62 patients that either received a placebo (20), 40 mcg/kg of Odevixibat (23), or 120 mcg/kg of Odevixibat (19).
- 85% of patients experienced AEs in Trial 1 Study.
- Abdominal pain, liver test abnormalities, fat-soluble vitamin deficiency, diarrhea, and vomiting were the most common adverse reactions reported by patients in Trial 1 clinical studies.
Table 3 shows the Clinical Adverse Reactions reported by patients in Trial 1 clinical studies.
- Trial 2 is a 72-week, open-label, single-arm trial that looked into the effects of Odevixibat in PFIC type 1, 2, and 3 patients. 79 patients were part of this trial with an age that ranged from 4 months to 25 years. Patients received 120 mcg/kg/day of Odevixibat once daily.
- Abdominal pain, liver test abnormalities, fat-soluble vitamin deficiency, diarrhea, and vomiting were the most common adverse reactions reported by patients in Trial 2 clinical studies.
- Liver test abnormalities led to Odevixibat treatment interruptions.
- 12 patients had to discontinue Odevixibat treatment in Trial 2 studies.
## Postmarketing Experience
There is limited information regarding Odevixibat Postmarketing Experience in the drug label.
# Drug Interactions
Bile Acid Binding Resins
- When taking Odevixibat, administration of bile acid binding resins at least 4 hours before or 4 hours after administration of Odevixibat.
- Odevixibat efficacy may be reduced if the bile acid binding resins binds with Odevixibat in the gut.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no data done on pregnant women treated with Odevixibat to determine the effects of Odevixibat on miscarriage, fetal outcomes, major birth defects, and adverse maternal outcomes. Cardiac malformations may occur in the fetus during pregnancy based on animal studies. Pregnant rabbit studies show how Odevixibat can increase malformations in fetal heart, great blood vessels, and other vascular sites in the fetus. During the period of organogenesis, fetus in pregnant rabbits experienced malformations of 5-chambered heart, small ventricle, large atrium, ventricular septum defect, misshapen aortic valve, dilated aortic arch, right sided and retroesophageal aortic arch, fusion of aortic arch and pulmonary trunk, ductus arteriosus atresia, and absence of subclavian artery when given 2.1 times the maximum recommended dose of Odevixibat. Increase in skeletal variations was seen in pregnant rat studies testing the effects of Odevixibat on the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Odevixibat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Odevixibat during labor and delivery.
### Nursing Mothers
Nursing should not cause exposure of Odevixibat to infants. No data is present on the effects done on the breastfed child and the effects on milk production when treated with Odevixibat. Absorption of fat-soluble vitamins may occur when taking Odevixibat. Monitor patients and the breastfed infant fat-soluble vitamins levels during nursing.
### Pediatric Use
Studies done on pediatric patients 3 months to 17 years of age for the treatment of pruritus in PFIC looked into the safety and effectiveness of Odevixibat. Trial studies show that patients treated with Odevixibat had greater improvement in pruritus than patients receiving the placebo. Gastrointestinal symptoms, liver test abnormalities, and fat-soluble vitamin deficiency were the most common adverse reactions reported in Trial 1 and 2 patients. There are no studies done on pediatric patients less than 3 months of age that test the safety and effectiveness of Odevixibat.
### Geriatic Use
Studies have not been conducted on PFIC in adult patients that look at the safety and effectiveness of Odevixibat.
### Gender
There is no FDA guidance on the use of Odevixibat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Odevixibat with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Odevixibat in patients with renal impairment.
### Hepatic Impairment
Studies have not been conducted on PFIC patients with clinically significant portal hypertension and in patients with decompensated cirrhosis to look at the safety and effectiveness of Odevixibat. Hepatic function may be impaired in patients with PFIC at baseline.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Odevixibat in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Odevixibat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Preparation and Administration Instructions
- Take Odevixibat at least 4 hours before or 4 hours after taking a bile acid binding resin.
- Advise patients that capsules should not be crushed or chewed.
Oral Pellet Administration
- Odevixibat should be taken during morning meal.
- Contents of oral pellet should be mixed in soft food by gently tapping oral pellet.
- Administer dosage immediately after gently mixing contents of the pellet.
- Advise patients that shell containing oral pellets should not be swallowed whole.
- Odevixibat should not be taken by patients who are exclusively on liquid food.
Capsule Administration
- Advise patients that Odevixibat should be taken in the morning with a meal.
- Advise patients to swallow capsule whole with water.
### Monitoring
Dose Modification for Management of Adverse Events
- Monitor patients Liver tests and watch for new onset liver test abnormalities during Odevixibat treatment.
- Liver tests include looking at AST, ALT, Total Bilirubin, Direct Bilirubin, and International Normalized Ratio.
- Advise patients that dosage interruptions may occur if patient experiences symptoms consistent with clinical hepatitis or new onset liver test abnormalities.
- Advise patients that the discontinuation of Odevixibat should occur if patient experiences a hepatic decompensation event.
# IV Compatibility
There is limited information regarding the compatibility of Odevixibat and IV administrations.
# Overdosage
There is limited information regarding Odevixibat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Odevixibat is a reversible inhibitor of the ileal bile acid transporter.
- The role of Odevixibat in the terminal ileum is to decrease the reabsorption of bile acids.
- Inhibition of IBAT may be the mechanism of Odevixibat that may improve pruritus in PFIC patients.
## Structure
- Odevixibat is a reversible inhibitor of the ileal bile acid transporter. It has an empirical formula of C37H48N4O8S2.
- The molecular weight is 740.9 g/mol.
## Pharmacodynamics
- PFIC patients experience a reduction of serum bile acids when taking Odevixibat.
- 88.7% of patients in Trial 1 clinical studies had elevated serum bile acids above 100 µmol/L at baseline which eventually decreased in 4-8 weeks of Odevixibat treatment.
- Serum bile acids reduction were similar in patients receiving either 40 or 120 mcg/kg of Odevixibat.
## Pharmacokinetics
- 0.06 to 0.72 ng/mL was the range of measurable Odevixibat concentrations in pediatric patients with PFIC receiving 40 mcg/kg or 120 mcg/kg once daily of Odevixibat.
- Plasma concentrations were below the limit of quantification in healthy adults receiving 0.1 to 3 mg of Odevixibat.
- 0.47 ng/mL is the mean Cmax in patients who were given a single administration of 7.2 mg of Odevixibat.
- 2.19 ng*h/mL is the AUC0-24h in patients who were given a single administration of 7.2 mg of Odevixibat.
Absorption
- 1 to 5 hours is when Cmax is reached in healthy adults receiving 7.2 mg of Odevixibat.
- Sprinkling of apple sauce on pellets caused a 39% decrease in Cmax when patients were given 9.6 mg of Odevixibat.
- Sprinkling of apple sauce on pellets caused a 35% decrease in AUC0-24h when patients were given 9.6 mg of Odevixibat.
- Sprinkling of apple sauce on pellets caused a 3 hours to 4.5 hours delay in median Tmax when patients were given 9.6 mg of Odevixibat.
Effect of Food
- 3 hours to 4.5 hours is the range of the delay of median Tmax with the co-administration of 9.6 mg of Odevixibat with a high-fat meal.
- There is a 72% reduction in Cmax with the co-administration of 9.6 mg of Odevixibat with a high-fat meal.
- There is a 62% reduction in AUC0-24h with the co-administration of 9.6 mg of Odevixibat with a high-fat meal.
Distribution
- In vitro, the human plasma protein binding is greater than 99% for Odevixibat.
Elimination
- 2.36 hours is the mean half-life in patients who were given 7.2 mg Odevixibat.
Metabolism
- Mono-hydroxylation metabolizes Odevixibat in vitro.
Excretion
- 82.9% of Odevixibat was recovered in feces in which 97% was found unchanged after patients were given a single radiolabeled Odevixibat 3 mg oral dose.
- Less than 0.002% of Odevixibat was recovered in urine after patients were given a single radiolabeled Odevixibat 3 mg oral dose.
Drug Interaction Studies
Effect of Other Drugs on Odevixibat:
- Odevixibat is a substrate of P-glycoprotein.
- Odevixibat is not a substrate of breast cancer resistance protein.
- 66% increase of AUC0-24h was seen with the co-administration of 7.2 mg of Odevixibat and itraconazole.
- 52% increase of Cmax was seen with the co-administration of 7.2 mg of Odevixibat and itraconazole.
Effect of Odevixibat on Other Drugs:
- CYP isoforms 2B6, 2C8, 2C9, 2D6, 1A2, or 2C19 are not inhibited by Odevixibat in vitro studies.
- CYP isoforms 1A2, 2B6, or 3A4 are not induced by Odevixibat in vitro studies.
- 29% decrease in AUC0-24h of Midazolam was seen with the co-administration of 7.2 mg of Odevixibat and oral midazolam.
- 13% decrease in 1-OH midazolam was seen with the co-administration of 7.2 mg of Odevixibat and oral midazolam.
- Transporters P-gp; BCRP; organic anion transporter polypeptide 1B1 and 1B3(OATP1B1 and OATP1B3); organic anion transporter (OAT)1, OAT3; organic cation transporter 2 (OCT2), multidrug and toxin extrusion transporter 1 and 2K (MATE1 and MATE2K) are not inhibited by Odevixibat in vitro.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis:
- When rats or mice were given doses up to 100 mg/kg/day, Odevixibat was not tumorigenic.
- 231 and 459 times is the systemic exposure to Odevixibat in rats and mice.
Mutagenesis:
- Odevixibat was negative in the vitro mouse lymphoma cell gene mutation assay, vitro bacterial reverse mutation (Ames) assay, and in vivo rat micronucleus test.
Impairment of Fertility
- Male and female rats did not experience any effects on fertility or reproductive function when given Odevixibat oral doses of up to 1000 mg/kg/day.
# Clinical Studies
Trial 1
- Trial 1 is a 24-week, randomized, double-blind, placebo-controlled trial.
- 62 pediatric patients with PFIC type 1 or type 2 were part of the Trial 1 study.
- Patients were either part of the placebo group, 40 mcg/kg of Odevixibat group, or 120 mcg/kg of Odevixibat group.
- The patient population was largely Caucasian (84%), included 50% of males, and had a mean age of 3.2 years of age.
- 19% of patients in the Odevixibat groups had to discontinue treatment due to adverse reactions or no improvement in pruritus was seen from Trial 1 clinical studies.
- 25% of patients in the placebo group had to discontinue treatment due to adverse reactions or no improvement in pruritus was seen from Trial 1 clinical studies.
- Patients scratching was measured using a single-item observer-reported outcome during the Trial 1 studies.
- Scratching was measured on a 5 point scale where 0 is no scratching to 4 which is the worst possible scratching.
Table 4 displays Efficacy Results Over the 24-Week Treatment Period in Patients with PFIC Type 1 or 2 in Trial 1.
Figure 1 shows the Mean of the Worst Weekly Average Scratching Scores for Each Month.
# How Supplied
Oral Pellets
- 200 mcg Oral Pellets: Ivory opaque cap and white opaque bod.
- 600 mcg Oral Pellets: Ivory opaque cap and body
Capsules
- 400 mcg Capsule: Medium orange opaque cap and white opaque body.
- 1200 mcg Capsule: Medium orange opaque cap and body.
## Storage
- Store at 20° to 25°C (68° to 77°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Risks
- Advise patients that symptoms associated with Odevixibat treatment include vomiting, dehydration, abdominal pain, and diarrhea.
- Advise patients that elevations of liver tests may be a result of Odevixibat treatment.
- Monitor patients liver test results before and during Odevixibat treatment.
- Advise patients to report any signs of liver problems and worsening diarrhea to their healthcare provider.
- Advise patients that the absorption of fat-soluble vitamins during Odevixibat treatment.
Administration
- Advise patients that Odevixibat should not be mixed with liquids.
- Advise patients that the 200 mcg or 600 mcg capsule pellets should not be swallowed whole.
- Advise patients who are taking bile acid binding resins to wait at least 4 hours before or 4 hours after taking a bile acid binding resin to take Odevixibat.
# Precautions with Alcohol
Alcohol-Odevixibat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Bylvay
# Look-Alike Drug Names
There is limited information regarding Odevixibat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Odevixibat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra
# 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
Odevixibat is a ileal bile acid transporter inhibitor that is FDA approved for the treatment of pruritus. Common adverse reactions include abdominal pain,, fat-soluble vitamin deficiency, diarrhea, vomiting, and liver test abnormalities..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Recommended Dosage
- 40 mcg/kg once daily of Odevixibat is the recommended dosage.
- Dosage should be taken with a meal in the morning.
- Recommended dosage may be increased to 120 mcg/kg if there are no signs of pruritus improvement after 3 months of Odevixibat treatment.
- Patients with a weight less than 19.5 kilograms may use Odevixibat pellets.
- Patients with a weight of 19.5 kilograms or more may use Odevixibat capsules.
Table 1 shows Recommended Dosage for 40 mcg/kg/day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Odevixibat in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Odevixibat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Odevixibat 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 Odevixibat in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Odevixibat in pediatric patients.
# Contraindications
There are no contraindications associated with Odevixibat.
# Warnings
Liver Test Abnormalities
- Trial 1 clinical studies show elevations of liver tests or worsening of liver tests in comparison to baseline values for patients taking Odevixibat.
- Elevations of ALT, AST, or total and direct bilirubin were some of the abnormalities seen in the clinical studies.
- 3-120 days was the range of Odevixibat treatment interruption that occurred during the Trial 1 studies.
- Advise patients that treatment discontinuation of Odevixibat may be necessary if they experience persistent or recurrent liver test abnormalities.
Table 2 shows the Liver Test Data obtained in Trial 1 Clinical Studies.
Diarrhea
- 21% of patients receiving 120 mcg/kg/day of Odevixibat experienced diarrhea in Trial 1 clinical studies.
- 39% of patients receiving 40 mcg/kg/day of Odevixibat experienced diarrhea in Trial 1 clinical studies.
- 10% of placebo-treated patients experienced diarrhea in Trial 1 clinical studies.
- Treatment interruption was seen in patients receiving 120 mcg/kg/day of Odevixibat in Trial 1 clinical studies.
- Monitor patients for dehydration if they experience diarrhea and treat accordingly.
- Advise patients that interruption of Odevixibat treatment may be necessary if diarrhea persists.
Fat-Soluble Vitamin (FSV) Deficiency
- Advise patients that absorption of fat-soluble vitamins may occur during Odevixibat treatment.
- No patients receiving 40 mcg/kg/day of Odevixibat experienced new onset or worsening of existing FSV deficiency in Trial 1 clinical studies.
- 16% of patients receiving 120 mcg/kg/day of Odevixibat experienced new onset or worsening of existing FSV deficiency in Trial 1 clinical studies.
- 5% of placebo-treated patients experienced new onset or worsening of existing FSV deficiency in Trial 1 clinical studies.
- Monitor patients serum FSV levels at baseline and during Odevixibat treatment.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
- Trial 1 clinical study is a randomized, double-blind, placebo-controlled, 24-week study that looked into the effects of administering 40 mcg/kg vs 120 mcg/kg of Odevixibat. The study consisted of 62 patients that either received a placebo (20), 40 mcg/kg of Odevixibat (23), or 120 mcg/kg of Odevixibat (19).
- 85% of patients experienced AEs in Trial 1 Study.
- Abdominal pain, liver test abnormalities, fat-soluble vitamin deficiency, diarrhea, and vomiting were the most common adverse reactions reported by patients in Trial 1 clinical studies.
Table 3 shows the Clinical Adverse Reactions reported by patients in Trial 1 clinical studies.
- Trial 2 is a 72-week, open-label, single-arm trial that looked into the effects of Odevixibat in PFIC type 1, 2, and 3 patients. 79 patients were part of this trial with an age that ranged from 4 months to 25 years. Patients received 120 mcg/kg/day of Odevixibat once daily.
- Abdominal pain, liver test abnormalities, fat-soluble vitamin deficiency, diarrhea, and vomiting were the most common adverse reactions reported by patients in Trial 2 clinical studies.
- Liver test abnormalities led to Odevixibat treatment interruptions.
- 12 patients had to discontinue Odevixibat treatment in Trial 2 studies.
## Postmarketing Experience
There is limited information regarding Odevixibat Postmarketing Experience in the drug label.
# Drug Interactions
Bile Acid Binding Resins
- When taking Odevixibat, administration of bile acid binding resins at least 4 hours before or 4 hours after administration of Odevixibat.
- Odevixibat efficacy may be reduced if the bile acid binding resins binds with Odevixibat in the gut.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no data done on pregnant women treated with Odevixibat to determine the effects of Odevixibat on miscarriage, fetal outcomes, major birth defects, and adverse maternal outcomes. Cardiac malformations may occur in the fetus during pregnancy based on animal studies. Pregnant rabbit studies show how Odevixibat can increase malformations in fetal heart, great blood vessels, and other vascular sites in the fetus. During the period of organogenesis, fetus in pregnant rabbits experienced malformations of 5-chambered heart, small ventricle, large atrium, ventricular septum defect, misshapen aortic valve, dilated aortic arch, right sided and retroesophageal aortic arch, fusion of aortic arch and pulmonary trunk, ductus arteriosus atresia, and absence of subclavian artery when given 2.1 times the maximum recommended dose of Odevixibat. Increase in skeletal variations was seen in pregnant rat studies testing the effects of Odevixibat on the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Odevixibat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Odevixibat during labor and delivery.
### Nursing Mothers
Nursing should not cause exposure of Odevixibat to infants. No data is present on the effects done on the breastfed child and the effects on milk production when treated with Odevixibat. Absorption of fat-soluble vitamins may occur when taking Odevixibat. Monitor patients and the breastfed infant fat-soluble vitamins levels during nursing.
### Pediatric Use
Studies done on pediatric patients 3 months to 17 years of age for the treatment of pruritus in PFIC looked into the safety and effectiveness of Odevixibat. Trial studies show that patients treated with Odevixibat had greater improvement in pruritus than patients receiving the placebo. Gastrointestinal symptoms, liver test abnormalities, and fat-soluble vitamin deficiency were the most common adverse reactions reported in Trial 1 and 2 patients. There are no studies done on pediatric patients less than 3 months of age that test the safety and effectiveness of Odevixibat.
### Geriatic Use
Studies have not been conducted on PFIC in adult patients that look at the safety and effectiveness of Odevixibat.
### Gender
There is no FDA guidance on the use of Odevixibat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Odevixibat with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Odevixibat in patients with renal impairment.
### Hepatic Impairment
Studies have not been conducted on PFIC patients with clinically significant portal hypertension and in patients with decompensated cirrhosis to look at the safety and effectiveness of Odevixibat. Hepatic function may be impaired in patients with PFIC at baseline.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Odevixibat in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Odevixibat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Preparation and Administration Instructions
- Take Odevixibat at least 4 hours before or 4 hours after taking a bile acid binding resin.
- Advise patients that capsules should not be crushed or chewed.
Oral Pellet Administration
- Odevixibat should be taken during morning meal.
- Contents of oral pellet should be mixed in soft food by gently tapping oral pellet.
- Administer dosage immediately after gently mixing contents of the pellet.
- Advise patients that shell containing oral pellets should not be swallowed whole.
- Odevixibat should not be taken by patients who are exclusively on liquid food.
Capsule Administration
- Advise patients that Odevixibat should be taken in the morning with a meal.
- Advise patients to swallow capsule whole with water.
### Monitoring
Dose Modification for Management of Adverse Events
- Monitor patients Liver tests and watch for new onset liver test abnormalities during Odevixibat treatment.
- Liver tests include looking at AST, ALT, Total Bilirubin, Direct Bilirubin, and International Normalized Ratio.
- Advise patients that dosage interruptions may occur if patient experiences symptoms consistent with clinical hepatitis or new onset liver test abnormalities.
- Advise patients that the discontinuation of Odevixibat should occur if patient experiences a hepatic decompensation event.
# IV Compatibility
There is limited information regarding the compatibility of Odevixibat and IV administrations.
# Overdosage
There is limited information regarding Odevixibat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Odevixibat is a reversible inhibitor of the ileal bile acid transporter.
- The role of Odevixibat in the terminal ileum is to decrease the reabsorption of bile acids.
- Inhibition of IBAT may be the mechanism of Odevixibat that may improve pruritus in PFIC patients.
## Structure
- Odevixibat is a reversible inhibitor of the ileal bile acid transporter. It has an empirical formula of C37H48N4O8S2.
- The molecular weight is 740.9 g/mol.
## Pharmacodynamics
- PFIC patients experience a reduction of serum bile acids when taking Odevixibat.
- 88.7% of patients in Trial 1 clinical studies had elevated serum bile acids above 100 µmol/L at baseline which eventually decreased in 4-8 weeks of Odevixibat treatment.
- Serum bile acids reduction were similar in patients receiving either 40 or 120 mcg/kg of Odevixibat.
## Pharmacokinetics
- 0.06 to 0.72 ng/mL was the range of measurable Odevixibat concentrations in pediatric patients with PFIC receiving 40 mcg/kg or 120 mcg/kg once daily of Odevixibat.
- Plasma concentrations were below the limit of quantification in healthy adults receiving 0.1 to 3 mg of Odevixibat.
- 0.47 ng/mL is the mean Cmax in patients who were given a single administration of 7.2 mg of Odevixibat.
- 2.19 ng*h/mL is the AUC0-24h in patients who were given a single administration of 7.2 mg of Odevixibat.
Absorption
- 1 to 5 hours is when Cmax is reached in healthy adults receiving 7.2 mg of Odevixibat.
- Sprinkling of apple sauce on pellets caused a 39% decrease in Cmax when patients were given 9.6 mg of Odevixibat.
- Sprinkling of apple sauce on pellets caused a 35% decrease in AUC0-24h when patients were given 9.6 mg of Odevixibat.
- Sprinkling of apple sauce on pellets caused a 3 hours to 4.5 hours delay in median Tmax when patients were given 9.6 mg of Odevixibat.
Effect of Food
- 3 hours to 4.5 hours is the range of the delay of median Tmax with the co-administration of 9.6 mg of Odevixibat with a high-fat meal.
- There is a 72% reduction in Cmax with the co-administration of 9.6 mg of Odevixibat with a high-fat meal.
- There is a 62% reduction in AUC0-24h with the co-administration of 9.6 mg of Odevixibat with a high-fat meal.
Distribution
- In vitro, the human plasma protein binding is greater than 99% for Odevixibat.
Elimination
- 2.36 hours is the mean half-life in patients who were given 7.2 mg Odevixibat.
Metabolism
- Mono-hydroxylation metabolizes Odevixibat in vitro.
Excretion
- 82.9% of Odevixibat was recovered in feces in which 97% was found unchanged after patients were given a single radiolabeled Odevixibat 3 mg oral dose.
- Less than 0.002% of Odevixibat was recovered in urine after patients were given a single radiolabeled Odevixibat 3 mg oral dose.
Drug Interaction Studies
Effect of Other Drugs on Odevixibat:
- Odevixibat is a substrate of P-glycoprotein.
- Odevixibat is not a substrate of breast cancer resistance protein.
- 66% increase of AUC0-24h was seen with the co-administration of 7.2 mg of Odevixibat and itraconazole.
- 52% increase of Cmax was seen with the co-administration of 7.2 mg of Odevixibat and itraconazole.
Effect of Odevixibat on Other Drugs:
- CYP isoforms 2B6, 2C8, 2C9, 2D6, 1A2, or 2C19 are not inhibited by Odevixibat in vitro studies.
- CYP isoforms 1A2, 2B6, or 3A4 are not induced by Odevixibat in vitro studies.
- 29% decrease in AUC0-24h of Midazolam was seen with the co-administration of 7.2 mg of Odevixibat and oral midazolam.
- 13% decrease in 1-OH midazolam was seen with the co-administration of 7.2 mg of Odevixibat and oral midazolam.
- Transporters P-gp; BCRP; organic anion transporter polypeptide 1B1 and 1B3(OATP1B1 and OATP1B3); organic anion transporter (OAT)1, OAT3; organic cation transporter 2 (OCT2), multidrug and toxin extrusion transporter 1 and 2K (MATE1 and MATE2K) are not inhibited by Odevixibat in vitro.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis:
- When rats or mice were given doses up to 100 mg/kg/day, Odevixibat was not tumorigenic.
- 231 and 459 times is the systemic exposure to Odevixibat in rats and mice.
Mutagenesis:
- Odevixibat was negative in the vitro mouse lymphoma cell gene mutation assay, vitro bacterial reverse mutation (Ames) assay, and in vivo rat micronucleus test.
Impairment of Fertility
- Male and female rats did not experience any effects on fertility or reproductive function when given Odevixibat oral doses of up to 1000 mg/kg/day.
# Clinical Studies
Trial 1
- Trial 1 is a 24-week, randomized, double-blind, placebo-controlled trial.
- 62 pediatric patients with PFIC type 1 or type 2 were part of the Trial 1 study.
- Patients were either part of the placebo group, 40 mcg/kg of Odevixibat group, or 120 mcg/kg of Odevixibat group.
- The patient population was largely Caucasian (84%), included 50% of males, and had a mean age of 3.2 years of age.
- 19% of patients in the Odevixibat groups had to discontinue treatment due to adverse reactions or no improvement in pruritus was seen from Trial 1 clinical studies.
- 25% of patients in the placebo group had to discontinue treatment due to adverse reactions or no improvement in pruritus was seen from Trial 1 clinical studies.
- Patients scratching was measured using a single-item observer-reported outcome during the Trial 1 studies.
- Scratching was measured on a 5 point scale where 0 is no scratching to 4 which is the worst possible scratching.
Table 4 displays Efficacy Results Over the 24-Week Treatment Period in Patients with PFIC Type 1 or 2 in Trial 1.
Figure 1 shows the Mean of the Worst Weekly Average Scratching Scores for Each Month.
# How Supplied
Oral Pellets
- 200 mcg Oral Pellets: Ivory opaque cap and white opaque bod.
- 600 mcg Oral Pellets: Ivory opaque cap and body
Capsules
- 400 mcg Capsule: Medium orange opaque cap and white opaque body.
- 1200 mcg Capsule: Medium orange opaque cap and body.
## Storage
- Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Risks
- Advise patients that symptoms associated with Odevixibat treatment include vomiting, dehydration, abdominal pain, and diarrhea.
- Advise patients that elevations of liver tests may be a result of Odevixibat treatment.
- Monitor patients liver test results before and during Odevixibat treatment.
- Advise patients to report any signs of liver problems and worsening diarrhea to their healthcare provider.
- Advise patients that the absorption of fat-soluble vitamins during Odevixibat treatment.
Administration
- Advise patients that Odevixibat should not be mixed with liquids.
- Advise patients that the 200 mcg or 600 mcg capsule pellets should not be swallowed whole.
- Advise patients who are taking bile acid binding resins to wait at least 4 hours before or 4 hours after taking a bile acid binding resin to take Odevixibat.
-
# Precautions with Alcohol
Alcohol-Odevixibat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Bylvay
# Look-Alike Drug Names
There is limited information regarding Odevixibat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Odevixibat | |
0098350cfc358a0383d68d4fecd7a7192055db3d | wikidoc | Ofatumumab | Ofatumumab
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# Black Box Warning
# Overview
Ofatumumab is a CD20-directed cytolytic monoclonal antibody that is FDA approved for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) in combination with chlorambucil and patients with CLL refractory to fludarabine and alemtuzumab. There is a Black Box Warning for this drug as shown here. Common adverse reactions include infusion reactions, neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate .
- The recommended dosage and schedule is:
- 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 (Cycle 1) followed by
- 1,000 mg on Day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles.
- ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.
- The recommended dosage and schedule is 12 doses administered as follows:
- 300 mg initial dose (Dose 1), followed 1 week later by
- 2,000 mg weekly for 7 doses (Doses 2 through 8), followed 4 weeks later by
- 2,000 mg every 4 weeks for 4 doses (Doses 9 through 12).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ofatumumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ofatumumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ofatumumab in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ofatumumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ofatumumab in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Infusion Reactions
- ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment.
- Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.
- Hepatitis B Virus Reactivation
- Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody positive).
- HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.
- Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
- Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy.
- In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation.
- Hepatitis B Virus Infection
- Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.
- Progressive Multifocal Leukoencephalopathy
- Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.
- Tumor Lysis Syndrome
- Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.
- Cytopenias
- Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.
- Immunizations
- The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6.
- The data described in Table 3 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 4 includes relevant hematologic laboratory abnormalities.
- Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 and 23% on Day 8 ) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients.
- Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone.
- Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open‑label, non‑randomized, single‑arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 ) or 3 doses (Study 3 ).
- The data described in Table 5 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.
- Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions.
- Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine‑ and alemtuzumab‑refractory group was 17%.
- Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.
- Immunogenicity
- There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA. There was no formation of anti‑ofatumumab antibodies in patients with CLL after treatment with ofatumumab.
- Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA 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 ARZERRA. 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.
- Infusion-related Cardiac Events: Cardiac arrest.
- Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.
# Drug Interactions
- Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate or well‑controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ofatumumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ofatumumab during labor and delivery.
### Nursing Mothers
- It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of ARZERRA have not been established in children.
### Geriatic Use
- In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%). In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients.
- In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ofatumumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ofatumumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ofatumumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ofatumumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ofatumumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ofatumumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Ofatumumab in the drug label.
# IV Compatibility
- Do not shake product.
- Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. ARZERRA should be a clear to opalescent, colorless solution. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.
- Preparation of Solution:
- 300-mg dose: Withdraw and discard 15 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 5 mL from each of 3 single-use 100-mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
- 1,000-mg dose: Withdraw and discard 50 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50 mL from 1 single-use 1,000-mg vial of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
- 2,000-mg dose: Withdraw and discard 100 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50 mL from each of 2 single-use 1,000-mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
- Store diluted solution between 2° to 8°C (36° to 46°F).
- No incompatibilities between ARZERRA and polyvinylchloride or polyolefin bags and administration sets have been observed.
- Administration Instructions:
- Do not mix ARZERRA with, or administer as an infusion with, other medicinal products.
- Administer using an infusion pump and an administration set.
- Flush the intravenous line with 0.9% Sodium Chloride Injection, USP before and after each dose.
- Start infusion within 12 hours of preparation.
- Discard prepared solution after 24 hours.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ofatumumab in the drug label.
# Pharmacology
## Mechanism of Action
- Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre–B- to mature B-lymphocyte) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding.
- The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.
## Structure
- ARZERRA (ofatumumab) is an IgG1κ human monoclonal antibody with a molecular weight of approximately 149 kDa. The antibody was generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line (NS0) using standard mammalian cell cultivation and purification technologies.
- ARZERRA is a sterile, clear to opalescent, colorless, preservative-free liquid concentrate for intravenous administration. ARZERRA is supplied at a concentration of 20 mg/mL in single-use vials. Each single-use vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution.
- Inactive ingredients include: 10 mg/mL arginine, diluted hydrochloric acid, 0.019 mg/mL edetate disodium, 0.2 mg/mL polysorbate 80, 6.8 mg/mL sodium acetate, 2.98 mg/mL sodium chloride, and Water for Injection, USP. The pH is 5.5.
## Pharmacodynamics
- B-Cell Depletion: In patients with previously untreated CLL, at 6 months after the last dose, the median reductions in CD19‑positive B cells were >99% (n = 155) for ARZERRA in combination with chlorambucil and 94% (n = 121) for chlorambucil alone.
- In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating CD19‑positive B cells was 91% (n = 50) with the 8th infusion and 85% (n = 32) with the 12th infusion. The time to recovery of lymphocytes, including CD19‑positive B cells, to normal levels has not been determined.
- Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B cells in solid organs or in malignant deposits. B-cell depletion has not been shown to be directly correlated to clinical response.
- Cardiac Electrophysiology: The effect of multiple doses of ARZERRA on the QTc interval was evaluated in a pooled analysis of 3 open-label studies in patients with CLL (N = 85). Patients received ARZERRA 300 mg on Day 1 followed by either 1,000 mg or 2,000 mg for subsequent doses. No large changes in the mean QTc interval (i.e., >20 milliseconds) were detected in the pooled analysis.
## Pharmacokinetics
- Ofatumumab is eliminated through both a target‑independent route and a B cell‑mediated route. Ofatumumab exhibited dose‑dependent clearance in the dose range of 100 to 2,000 mg. Due to the depletion of B cells, the clearance of ofatumumab decreased substantially after subsequent infusions compared with the first infusion.
- Pharmacokinetic data were obtained after repeated administration (4, 5, 8, or 12 infusions) of 1,000 mg or 2,000 mg doses in 381 patients with CLL (Studies 1, 2, and 3). The geometric mean (%CV) values for clearance, volume of distribution at steady state (Vss), and half-life for ofatumumab in these patients were 12.9 mL/hour (76%), 5.7 L (65%), and 15.6 days (90%). The pharmacokinetic profile was similar across doses in patients with CLL.
- Specific Populations:Effects of Body Size, Gender, Age, and Renal Impairment: Based on population pharmacokinetic analyses, body size, gender, age, and renal impairment (evaluated in patients with a calculated creatinine clearance ≥30 mL/min) do not have a clinically meaningful effect on the pharmacokinetics of ofatumumab.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat‑dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.
- Reproductive and Developmental Toxicology
- Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab‑treated dams exhibited decreases in mean peripheral B‑cell counts (decreased to approximately 10% of control values), splenic B‑cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low‑dose and by 30% for the high‑dose group, compared with control values). Fetuses from treated dams exhibiting anti‑ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti‑ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown.
- The kinetics of B‑lymphocyte recovery and the potential long-term effects of perinatal B‑cell depletion in offspring from ofatumumab‑treated dams have not been studied in animals.
# Clinical Studies
- The efficacy of ARZERRA was evaluated in a randomized, open-label, parallel-arm study; 447 patients previously untreated for CLL were randomized to receive either ARZERRA as monthly intravenous infusions (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; subsequent cycles: 1,000 mg on Day 1 every 28 days) in combination with chlorambucil (10 mg/m2 orally on Days 1 to 7 every 28 days) or chlorambucil alone (10 mg/m2 orally on Days 1 to 7 every 28 days). Patients received treatment for a minimum of 3 cycles. Treatment was continued for 3 cycles beyond maximal response (2 consecutive response assessments of stable disease, partial response, or complete response) for up to 12 cycles. Approximately 60% of patients received 3 to 6 cycles of ARZERRA and 30% received 7 to 12 cycles.
- This trial enrolled patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that included advanced age or presence of co-morbidities. In the overall trial population, the median age was 69 years (range: 35 to 92 years) and 69% of patients in both arms were at least 65 years of age. In the overall trial population, 72% of patients had 2 or more co-morbidities and 48% of patients had a creatinine clearance of less than 70 mL/min. Sixty-three percent of patients were male and 89% were white. Elevated beta-2 microglobulin (β2m) >3,500 mcg/L was present in 72% of patients at baseline.
- The primary endpoint was progression-free-survival (PFS) as assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). ARZERRA plus chlorambucil resulted in statistically significant improvement in IRC-assessed median PFS compared with chlorambucil alone (22.4 months versus 13.1 months; hazard ratio: 0.57 ) (Table 6; Figure 1).
- Secondary efficacy endpoints, including overall response (OR), complete response (CR), and duration of response, were also assessed by the IRC using the 2008 IWCLL Guidelines (Table 6).
### =Refractory CLL
- Study 2 was a single‑arm, multicenter study in 154 patients with relapsed or refractory CLL. ARZERRA was administered by intravenous infusion according to the following schedule: 300 mg (Week 0), 2,000 mg weekly for 7 infusions (Weeks 1 through 7), and 2,000 mg every 4 weeks for 4 infusions (Weeks 12 through 24). Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy population. Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab. The main efficacy outcome was durable objective tumor response rate. Objective tumor responses were determined using the 1996 NCI-WG Guidelines for CLL.
- In patients with CLL refractory to fludarabine and alemtuzumab, the median age was 64 years (range: 41 to 86 years), 75% were male, and 95% were white. The median number of prior therapies was 5; 93% received prior alkylating agents, 59% received prior rituximab, and all received prior fludarabine and alemtuzumab. Eighty-eight percent of patients received at least 8 infusions of ARZERRA and 54% received 12 infusions.
- The investigator‑determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). There were no complete responses. Anti‑tumor activity was also observed in additional patients in Study 2 and in a multicenter, open‑label, dose-escalation study (Study 3) conducted in patients with relapsed or refractory CLL.
# How Supplied
- ARZERRA (ofatumumab) is a sterile, clear to opalescent, colorless, preservative-free liquid concentrate (20 mg/mL) for dilution and intravenous administration provided in single-use glass vials with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution.
- ARZERRA is available as follows:
- Store ARZERRA refrigerated between 2° to 8°C (36° to 46°F). Do not freeze. Vials should be protected from light.
## Storage
There is limited information regarding Ofatumumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to contact a healthcare professional for any of the following:
- Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion.
- Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes.
- New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems.
- Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue.
- Signs of infections including fever and cough.
- Pregnancy or nursing.
- Advise patients of the need for:
- Monitoring and possible need for treatment if they have a history of hepatitis B infection (based on the blood test).
- Periodic monitoring for blood counts.
- Avoiding vaccination with live viral vaccines.
# Precautions with Alcohol
- Alcohol-Ofatumumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARZERRA®
# Look-Alike Drug Names
There is limited information regarding Ofatumumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ofatumumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Ofatumumab is a CD20-directed cytolytic monoclonal antibody that is FDA approved for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) in combination with chlorambucil and patients with CLL refractory to fludarabine and alemtuzumab. There is a Black Box Warning for this drug as shown here. Common adverse reactions include infusion reactions, neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [seeClinical Studies (14.1)].
- The recommended dosage and schedule is:
- 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 (Cycle 1) followed by
- 1,000 mg on Day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles.
- ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.
- The recommended dosage and schedule is 12 doses administered as follows:
- 300 mg initial dose (Dose 1), followed 1 week later by
- 2,000 mg weekly for 7 doses (Doses 2 through 8), followed 4 weeks later by
- 2,000 mg every 4 weeks for 4 doses (Doses 9 through 12).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ofatumumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ofatumumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ofatumumab in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ofatumumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ofatumumab in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Infusion Reactions
- ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment.
- Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.
- Hepatitis B Virus Reactivation
- Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).
- HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.
- Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
- Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy.
- In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation.
- Hepatitis B Virus Infection
- Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.
- Progressive Multifocal Leukoencephalopathy
- Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.
- Tumor Lysis Syndrome
- Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.
- Cytopenias
- Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.
- Immunizations
- The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6.
- The data described in Table 3 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 4 includes relevant hematologic laboratory abnormalities.
- Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients.
- Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone.
- Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open‑label, non‑randomized, single‑arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]).
- The data described in Table 5 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.
- Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions.
- Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine‑ and alemtuzumab‑refractory group was 17%.
- Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.
- Immunogenicity
- There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA. There was no formation of anti‑ofatumumab antibodies in patients with CLL after treatment with ofatumumab.
- Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA 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 ARZERRA. 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.
- Infusion-related Cardiac Events: Cardiac arrest.
- Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.
# Drug Interactions
- Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate or well‑controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ofatumumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ofatumumab during labor and delivery.
### Nursing Mothers
- It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of ARZERRA have not been established in children.
### Geriatic Use
- In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%). In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients.
- In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ofatumumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ofatumumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ofatumumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ofatumumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ofatumumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ofatumumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Ofatumumab in the drug label.
# IV Compatibility
- Do not shake product.
- Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. ARZERRA should be a clear to opalescent, colorless solution. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.
- Preparation of Solution:
- 300-mg dose: Withdraw and discard 15 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 5 mL from each of 3 single-use 100-mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
- 1,000-mg dose: Withdraw and discard 50 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50 mL from 1 single-use 1,000-mg vial of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
- 2,000-mg dose: Withdraw and discard 100 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50 mL from each of 2 single-use 1,000-mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
- Store diluted solution between 2° to 8°C (36° to 46°F).
- No incompatibilities between ARZERRA and polyvinylchloride or polyolefin bags and administration sets have been observed.
- Administration Instructions:
- Do not mix ARZERRA with, or administer as an infusion with, other medicinal products.
- Administer using an infusion pump and an administration set.
- Flush the intravenous line with 0.9% Sodium Chloride Injection, USP before and after each dose.
- Start infusion within 12 hours of preparation.
- Discard prepared solution after 24 hours.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ofatumumab in the drug label.
# Pharmacology
## Mechanism of Action
- Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre–B- to mature B-lymphocyte) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding.
- The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.
## Structure
- ARZERRA (ofatumumab) is an IgG1κ human monoclonal antibody with a molecular weight of approximately 149 kDa. The antibody was generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line (NS0) using standard mammalian cell cultivation and purification technologies.
- ARZERRA is a sterile, clear to opalescent, colorless, preservative-free liquid concentrate for intravenous administration. ARZERRA is supplied at a concentration of 20 mg/mL in single-use vials. Each single-use vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution.
- Inactive ingredients include: 10 mg/mL arginine, diluted hydrochloric acid, 0.019 mg/mL edetate disodium, 0.2 mg/mL polysorbate 80, 6.8 mg/mL sodium acetate, 2.98 mg/mL sodium chloride, and Water for Injection, USP. The pH is 5.5.
## Pharmacodynamics
- B-Cell Depletion: In patients with previously untreated CLL, at 6 months after the last dose, the median reductions in CD19‑positive B cells were >99% (n = 155) for ARZERRA in combination with chlorambucil and 94% (n = 121) for chlorambucil alone.
- In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating CD19‑positive B cells was 91% (n = 50) with the 8th infusion and 85% (n = 32) with the 12th infusion. The time to recovery of lymphocytes, including CD19‑positive B cells, to normal levels has not been determined.
- Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B cells in solid organs or in malignant deposits. B-cell depletion has not been shown to be directly correlated to clinical response.
- Cardiac Electrophysiology: The effect of multiple doses of ARZERRA on the QTc interval was evaluated in a pooled analysis of 3 open-label studies in patients with CLL (N = 85). Patients received ARZERRA 300 mg on Day 1 followed by either 1,000 mg or 2,000 mg for subsequent doses. No large changes in the mean QTc interval (i.e., >20 milliseconds) were detected in the pooled analysis.
## Pharmacokinetics
- Ofatumumab is eliminated through both a target‑independent route and a B cell‑mediated route. Ofatumumab exhibited dose‑dependent clearance in the dose range of 100 to 2,000 mg. Due to the depletion of B cells, the clearance of ofatumumab decreased substantially after subsequent infusions compared with the first infusion.
- Pharmacokinetic data were obtained after repeated administration (4, 5, 8, or 12 infusions) of 1,000 mg or 2,000 mg doses in 381 patients with CLL (Studies 1, 2, and 3). The geometric mean (%CV) values for clearance, volume of distribution at steady state (Vss), and half-life for ofatumumab in these patients were 12.9 mL/hour (76%), 5.7 L (65%), and 15.6 days (90%). The pharmacokinetic profile was similar across doses in patients with CLL.
- Specific Populations:Effects of Body Size, Gender, Age, and Renal Impairment: Based on population pharmacokinetic analyses, body size, gender, age, and renal impairment (evaluated in patients with a calculated creatinine clearance ≥30 mL/min) do not have a clinically meaningful effect on the pharmacokinetics of ofatumumab.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat‑dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.
- Reproductive and Developmental Toxicology
- Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab‑treated dams exhibited decreases in mean peripheral B‑cell counts (decreased to approximately 10% of control values), splenic B‑cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low‑dose and by 30% for the high‑dose group, compared with control values). Fetuses from treated dams exhibiting anti‑ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti‑ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown.
- The kinetics of B‑lymphocyte recovery and the potential long-term effects of perinatal B‑cell depletion in offspring from ofatumumab‑treated dams have not been studied in animals.
# Clinical Studies
- The efficacy of ARZERRA was evaluated in a randomized, open-label, parallel-arm study; 447 patients previously untreated for CLL were randomized to receive either ARZERRA as monthly intravenous infusions (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; subsequent cycles: 1,000 mg on Day 1 every 28 days) in combination with chlorambucil (10 mg/m2 orally on Days 1 to 7 every 28 days) or chlorambucil alone (10 mg/m2 orally on Days 1 to 7 every 28 days). Patients received treatment for a minimum of 3 cycles. Treatment was continued for 3 cycles beyond maximal response (2 consecutive response assessments of stable disease, partial response, or complete response) for up to 12 cycles. Approximately 60% of patients received 3 to 6 cycles of ARZERRA and 30% received 7 to 12 cycles.
- This trial enrolled patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that included advanced age or presence of co-morbidities. In the overall trial population, the median age was 69 years (range: 35 to 92 years) and 69% of patients in both arms were at least 65 years of age. In the overall trial population, 72% of patients had 2 or more co-morbidities and 48% of patients had a creatinine clearance of less than 70 mL/min. Sixty-three percent of patients were male and 89% were white. Elevated beta-2 microglobulin (β2m) >3,500 mcg/L was present in 72% of patients at baseline.
- The primary endpoint was progression-free-survival (PFS) as assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). ARZERRA plus chlorambucil resulted in statistically significant improvement in IRC-assessed median PFS compared with chlorambucil alone (22.4 months versus 13.1 months; hazard ratio: 0.57 [0.45, 0.72]) (Table 6; Figure 1).
- Secondary efficacy endpoints, including overall response (OR), complete response (CR), and duration of response, were also assessed by the IRC using the 2008 IWCLL Guidelines (Table 6).
### =Refractory CLL
- Study 2 was a single‑arm, multicenter study in 154 patients with relapsed or refractory CLL. ARZERRA was administered by intravenous infusion according to the following schedule: 300 mg (Week 0), 2,000 mg weekly for 7 infusions (Weeks 1 through 7), and 2,000 mg every 4 weeks for 4 infusions (Weeks 12 through 24). Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy population. Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab. The main efficacy outcome was durable objective tumor response rate. Objective tumor responses were determined using the 1996 NCI-WG Guidelines for CLL.
- In patients with CLL refractory to fludarabine and alemtuzumab, the median age was 64 years (range: 41 to 86 years), 75% were male, and 95% were white. The median number of prior therapies was 5; 93% received prior alkylating agents, 59% received prior rituximab, and all received prior fludarabine and alemtuzumab. Eighty-eight percent of patients received at least 8 infusions of ARZERRA and 54% received 12 infusions.
- The investigator‑determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). There were no complete responses. Anti‑tumor activity was also observed in additional patients in Study 2 and in a multicenter, open‑label, dose-escalation study (Study 3) conducted in patients with relapsed or refractory CLL.
# How Supplied
- ARZERRA (ofatumumab) is a sterile, clear to opalescent, colorless, preservative-free liquid concentrate (20 mg/mL) for dilution and intravenous administration provided in single-use glass vials with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution.
- ARZERRA is available as follows:
- Store ARZERRA refrigerated between 2° to 8°C (36° to 46°F). Do not freeze. Vials should be protected from light.
## Storage
There is limited information regarding Ofatumumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to contact a healthcare professional for any of the following:
- Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion.
- Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes.
- New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems.
- Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue.
- Signs of infections including fever and cough.
- Pregnancy or nursing.
- Advise patients of the need for:
- Monitoring and possible need for treatment if they have a history of hepatitis B infection (based on the blood test).
- Periodic monitoring for blood counts.
- Avoiding vaccination with live viral vaccines.
# Precautions with Alcohol
- Alcohol-Ofatumumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARZERRA®[1]
# Look-Alike Drug Names
There is limited information regarding Ofatumumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ofatumumab | |
6e3e25cd40ea015efff707474ed355704f42b3ee | wikidoc | Olanzepine | Olanzepine
Olanzapine (Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of: schizophrenia on 1996-09-30 ; depressive episodes associated with bipolar disorder, as part of the Symbyax formulation, on 2003-12-24; acute manic episodes and maintenance treatment in bipolar disorder on 2004-01-14. Off-label uses are listed below.
The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company, whose patent for olanzapine proper expires in 2011.
# Pharmacology
Olanzapine is structurally similar to clozapine, and is classified as a thienobenzodiazepine. Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamine receptors.
Like most atypical antipsychotics, compared to the older typical ones, olanzapine has a lower affinity for histamine, cholinergic muscarinic and alpha adrenergic receptors.
The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism at serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia, and with therapeutic effects. Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at 5-HT2C receptors have also been implicated in weight gain.
# Dosing and administration
Olanzapine is available as a tablet in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg and orally disintegrating wafers (known as Zydis), which dissolve on the tongue, in strengths of 5 mg, 10 mg, 15 mg and 20 mg. It is also available as a rapid-acting intramuscular injection for short-term acute use.
Dose may be adjusted depending on the person's response to the drug. The dose also will depend on certain medical problems the person may have. It is generally recommended to be taken once daily before bed as it is highly sedating.
# Pharmacokinetics
Olanzapine displays linear kinetics. Its elimination half-life ranges from 21 to 54 hours. Steady state plasma concentrations are achieved in about a week. Olanzapine undergoes extensive first pass metabolism and bioavailability is not affected by food.
In cases of acute agitiation, olanzapine can also be administered by intramuscular injection in doses up to 10 milligrams.
Olanzapine injection should not be given by the intravenous route, and should not be co-administered with benzodiazepines.
# Metabolism
Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be increased or decreased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamine or ciprofloxacin) CYP1A2 activity respectively.
# Side effects
As with all neuroleptic drugs, olanzapine can cause tardive dyskinesia and rare, but life-threatening, neuroleptic malignant syndrome.
Other recognised side effects may include:
- akathisia inability to remain still
- dry mouth
- dizziness
- sedation
- insomnia
- orthostatic hypotension
- weight gain (90% of users experience weight gain) (see below)
- increased appetite
- runny nose
- low blood pressure
- impaired judgment, thinking, and motor skills
- impaired spatial orientation
- impaired responses to senses
- seizure
- trouble swallowing
- dental problems and discoloration of teeth
- missed periods
- problems with keeping body temperature regulated
- apathy, lack of emotion
## Weight gain
Of the atypical antipsychotics, olanzapine and clozapine are the most likely to induce weight gain. The effect is more pronounced if high doses of olanzapine are used. Smaller amounts of weight gain are induced by risperidone and quetiapine. Ziprasidone and aripiprazole are considered to be weight neutral antipsychotics.
Recently the Food and Drug Administration required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with these drugs. These effects may be related to the drugs' ability to induce weight gain, although there are some reports of metabolic changes in the absence of weight gain, and recent (2007) evidence suggests that olanzapine may directly affect adipocyte function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis. There are data that suggest that olanzapine can decrease insulin sensitivity., though there are other studies that seem to refute this
Triglyceride levels rose from 99 to 166 in one year with olanzapine, in the CAFE ("Comparison of Atypicals for First-Episode Psychosis") study. Of the three drugs administered in that study, "olanzapine was associated with the greatest increases in body weight and related measures." In the same study, where the median patient age was 23, 46% of male patients on Zyprexa had a waist size of 40" or greater after one year, and "80% gained 7% or more over their baseline weight compared with 57.6% of those receiving risperidone and 50% of those receiving quetiapine." Impaired glucose metabolism, high triglycerides, and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease.
The results of a large, random-design study funded by NIH's
National Institute of Mental Health were published in September
2005. The 18-month study, which involved 1,400 participants at 57
sites around the country, found that "patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those participants taking the other drugs." However, the study also found that olanzapine helped more patients control symptoms for significantly longer than the other drugs. Specifically, after 18 months, the researchers found, "64 percent of the patients taking olanzapine had stopped, while at least 74 percent had quit each of the other medications."
Data from a small, open-label, non-randomized study seem to suggest that taking olanzapine by orally dissolving tablets may not be associated with the same degree of weight gain as conventional tablet formulations; however this has not been substantiated in a blinded experimental setting.
# Off-label uses
Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. generalized anxiety disorder, panic disorder, post-traumatic stress disorder); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette's syndrome and stuttering.
Olanzapine has been marketed for dementia by Eli Lilly though it has never been shown to help with the symptoms of dementia. According to internal documents obtained by the New York Times, Lilly instructed its sales representatives to suggest that physicians prescribe Zyprexa to older patients with symptoms of dementia. One such document states "dementia should be first message" for primary care doctors, since they "do not treat bipolar" or schizophrenia, but "do treat dementia". Three months after its launch, Lilly's Zyprexa campaign, called "Viva Zyprexa", led to 49,000 new prescriptions. In 2002, the company changed the name of the primary care campaign to "Zyprexa Limitless" and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed, despite the fact that Zyprexa has been FDA approved only for the treatment of mania in bipolar disorder, not depression.
## Use in elderly
Citing an increased risk of stroke, in 2004 the Committee on the Safety of Medicines (CSM) in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis.
# Overdose
Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 1500 mg. There is no specific, known antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.
# PRIME
The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.
In this study, patients receiving olanzapine had a lower risk of progressing to psychosis, although the difference did not reach statistical significance. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.
# Legal
According to a New York Times article published on December 17 2006, Eli Lilly has engaged in a decade-long effort to play down the health risks of Zyprexa, its best-selling medication for schizophrenia, according to hundreds of internal Lilly documents and e-mail messages among top company managers. These documents and e-mail messages were soon made publicly available as a location hidden Tor service, and then made available on the public Internet. Eli Lilly got a temporary restraining order from a US District Court signed on January 4 2007 to stop the dissemination or downloading of Eli Lilly documents about Zyprexa, and this allowed them to get a few US-based websites to remove them; on January 8 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order. The documents can now only be downloaded from public Internet sites outside the US.These health risks include an increased risk for diabetes through Zyprexa's links to obesity and its tendency to raise blood sugar. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.
The documents, given to The New York Times by Jim Gottstein, a lawyer representing mentally ill patients, show that Lilly executives kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes. The Times of London also obtained copies of the documents and reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. In another document, dated October 9 2000, senior Lilly research physician Robert Baker noted that an academic advisory board he belonged to was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."
Lilly’s own published data, which it told its sales representatives to play down in conversations with doctors, has shown that 30 percent of patients taking Zyprexa gain 22 pounds or more after a year on the drug, another study showed 16% of Zyprexa patients gained at least 30kg (66 pounds) in one year, and some patients have reported gaining 100 pounds or more. But Lilly was concerned that Zyprexa’s sales would be hurt if the company was more forthright about the fact that the drug might cause unmanageable weight gain or diabetes, according to the documents, which cover the period 1995 to 2004. In 2006, Lilly paid $700 million to settle 8,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending.
In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings.
Eli Lilly agreed on January 4 2007 to pay up to $500 million to settle 18,000 lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa. Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who claim they were injured by the drug. At least 1,200 suits are still pending, the company said. About 20 million people worldwide have taken Zyprexa since its introduction in 1996. | Olanzepine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]
Olanzapine (Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA for the treatment of: schizophrenia on 1996-09-30 [1]; depressive episodes associated with bipolar disorder, as part of the Symbyax formulation, on 2003-12-24[2]; acute manic episodes and maintenance treatment in bipolar disorder on 2004-01-14[3]. Off-label uses are listed below.
The olanzapine formulations are manufactured and marketed by the pharmaceutical company Eli Lilly and Company, whose patent for olanzapine proper expires in 2011.
# Pharmacology
Olanzapine is structurally similar to clozapine, and is classified as a thienobenzodiazepine. Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamine receptors.
Like most atypical antipsychotics, compared to the older typical ones, olanzapine has a lower affinity for histamine, cholinergic muscarinic and alpha adrenergic receptors.
The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism at serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia, and with therapeutic effects. Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at 5-HT2C receptors have also been implicated in weight gain.
# Dosing and administration
Olanzapine is available as a tablet in strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg and orally disintegrating wafers (known as Zydis), which dissolve on the tongue, in strengths of 5 mg, 10 mg, 15 mg and 20 mg. It is also available as a rapid-acting intramuscular injection for short-term acute use.
Dose may be adjusted depending on the person's response to the drug. The dose also will depend on certain medical problems the person may have. It is generally recommended to be taken once daily before bed as it is highly sedating.
# Pharmacokinetics
Olanzapine displays linear kinetics. Its elimination half-life ranges from 21 to 54 hours. Steady state plasma concentrations are achieved in about a week. Olanzapine undergoes extensive first pass metabolism and bioavailability is not affected by food.
In cases of acute agitiation, olanzapine can also be administered by intramuscular injection in doses up to 10 milligrams.
Olanzapine injection should not be given by the intravenous route, and should not be co-administered with benzodiazepines.
# Metabolism
Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be increased or decreased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamine or ciprofloxacin) CYP1A2 activity respectively.
# Side effects
As with all neuroleptic drugs, olanzapine can cause tardive dyskinesia and rare, but life-threatening, neuroleptic malignant syndrome.
Other recognised side effects may include:
- akathisia inability to remain still
- dry mouth
- dizziness
- sedation
- insomnia
- orthostatic hypotension
- weight gain (90% of users experience weight gain) (see below)
- increased appetite
- runny nose
- low blood pressure
- impaired judgment, thinking, and motor skills
- impaired spatial orientation
- impaired responses to senses
- seizure
- trouble swallowing
- dental problems and discoloration of teeth
- missed periods
- problems with keeping body temperature regulated
- apathy, lack of emotion
## Weight gain
Of the atypical antipsychotics, olanzapine and clozapine are the most likely to induce weight gain.[4] The effect is more pronounced if high doses of olanzapine are used.[5] Smaller amounts of weight gain are induced by risperidone and quetiapine. Ziprasidone and aripiprazole are considered to be weight neutral antipsychotics.
Recently the Food and Drug Administration required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with these drugs. These effects may be related to the drugs' ability to induce weight gain, although there are some reports of metabolic changes in the absence of weight gain, and recent (2007) evidence suggests that olanzapine may directly affect adipocyte function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis.[6] There are data that suggest that olanzapine can decrease insulin sensitivity.[7], though there are other studies that seem to refute this[8]
Triglyceride levels rose from 99 to 166 in one year with olanzapine, in the CAFE ("Comparison of Atypicals for First-Episode Psychosis") study.[citation needed] Of the three drugs administered in that study, "olanzapine was associated with the greatest increases in body weight and related measures."[9] In the same study, where the median patient age was 23, 46% of male patients on Zyprexa had a waist size of 40" or greater after one year,[citation needed] and "80% gained 7% or more over their baseline weight compared with 57.6% of those receiving risperidone and 50% of those receiving quetiapine."[10] Impaired glucose metabolism, high triglycerides, and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease.
The results of a large, random-design study funded by NIH's
National Institute of Mental Health were published in September
2005. The 18-month study, which involved 1,400 participants at 57
sites around the country, found that "patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those participants taking the other drugs."[11] However, the study also found that olanzapine helped more patients control symptoms for significantly longer than the other drugs. Specifically, after 18 months, the researchers found, "64 percent of the patients taking olanzapine had stopped, while at least 74 percent had quit each of the other medications."[12]
Data from a small, open-label, non-randomized study seem to suggest that taking olanzapine by orally dissolving tablets may not be associated with the same degree of weight gain as conventional tablet formulations;[13] however this has not been substantiated in a blinded experimental setting.
# Off-label uses
Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. generalized anxiety disorder,[14] panic disorder,[15] post-traumatic stress disorder[16]); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette's syndrome and stuttering.
Olanzapine has been marketed for dementia by Eli Lilly though it has never been shown to help with the symptoms of dementia. According to internal documents obtained by the New York Times, Lilly instructed its sales representatives to suggest that physicians prescribe Zyprexa to older patients with symptoms of dementia. One such document states "dementia should be first message" for primary care doctors, since they "do not treat bipolar" or schizophrenia, but "do treat dementia". Three months after its launch, Lilly's Zyprexa campaign, called "Viva Zyprexa", led to 49,000 new prescriptions. In 2002, the company changed the name of the primary care campaign to "Zyprexa Limitless" and began to focus on people with mild bipolar disorder who had previously been diagnosed as depressed, despite the fact that Zyprexa has been FDA approved only for the treatment of mania in bipolar disorder, not depression.[17]
## Use in elderly
Citing an increased risk of stroke, in 2004 the Committee on the Safety of Medicines (CSM) in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis.[18]
# Overdose
Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 1500 mg.[19] There is no specific, known antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.[19]
# PRIME
The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.[20]
In this study, patients receiving olanzapine had a lower risk of progressing to psychosis, although the difference did not reach statistical significance. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.[21]
# Legal
According to a New York Times article published on December 17 2006,[22] Eli Lilly has engaged in a decade-long effort to play down the health risks of Zyprexa, its best-selling medication for schizophrenia, according to hundreds of internal Lilly documents and e-mail messages among top company managers. These documents and e-mail messages were soon made publicly available as a location hidden Tor service[23], and then made available on the public Internet. Eli Lilly got a temporary restraining order from a US District Court signed on January 4 2007 to stop the dissemination or downloading of Eli Lilly documents about Zyprexa, and this allowed them to get a few US-based websites to remove them; on January 8 2007, Judge Jack B. Weinstein refused the Electronic Frontier Foundation's motion to stay his order[24]. The documents can now only be downloaded from public Internet sites outside the US.[25][26][27]These health risks include an increased risk for diabetes through Zyprexa's links to obesity and its tendency to raise blood sugar. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.
The documents, given to The New York Times by Jim Gottstein, a lawyer representing mentally ill patients, show that Lilly executives kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes. The Times of London also obtained copies of the documents and reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales.[28] In another document, dated October 9 2000, senior Lilly research physician Robert Baker noted that an academic advisory board he belonged to was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."
Lilly’s own published data, which it told its sales representatives to play down in conversations with doctors, has shown that 30 percent of patients taking Zyprexa gain 22 pounds or more after a year on the drug, another study showed 16% of Zyprexa patients gained at least 30kg (66 pounds) in one year, and some patients have reported gaining 100 pounds or more. But Lilly was concerned that Zyprexa’s sales would be hurt if the company was more forthright about the fact that the drug might cause unmanageable weight gain or diabetes, according to the documents, which cover the period 1995 to 2004. In 2006, Lilly paid $700 million to settle 8,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending.[29]
In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings.
Eli Lilly agreed on January 4 2007 to pay up to $500 million to settle 18,000 lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa. Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who claim they were injured by the drug. At least 1,200 suits are still pending, the company said. About 20 million people worldwide have taken Zyprexa since its introduction in 1996.[30] | https://www.wikidoc.org/index.php/Olanzepine | |
be85c05b85b926062bbcf23092f42295a341f6d2 | wikidoc | Oleic acid | Oleic acid
# Overview
Oleic acid is a monounsaturated omega-9 fatty acid found in various animal and vegetable sources. It has the formula C18H34O2 (or CH3(CH2)7CH=CH(CH2)7COOH). The saturated form of this acid is stearic acid.
Oleic acid makes up 55-80% of olive oil, though there may be only 0.5-2.5% or so as actual free acid, and 15-20% of grape seed oil and Sea buckthorn oil.
Reduction of oleic acid at the carboxyl end yields oleyl alcohol.
Oleic acid is emitted by the decaying corpses of a number of insects, including bees and Pogonomyrmex ants and triggers the instincts of living workers to remove the dead bodies from the hive. If a live bee or ant is daubed with oleic acid, it is dragged off as if it were dead. | Oleic acid
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Oleic acid is a monounsaturated omega-9 fatty acid found in various animal and vegetable sources. It has the formula C18H34O2 (or CH3(CH2)7CH=CH(CH2)7COOH).[1] The saturated form of this acid is stearic acid.
Oleic acid makes up 55-80% of olive oil, though there may be only 0.5-2.5% or so as actual free acid, and 15-20% of grape seed oil and Sea buckthorn oil.[2]
Reduction of oleic acid at the carboxyl end yields oleyl alcohol.
Oleic acid is emitted by the decaying corpses of a number of insects, including bees and Pogonomyrmex ants and triggers the instincts of living workers to remove the dead bodies from the hive. If a live bee[3] or ant[4] is daubed with oleic acid, it is dragged off as if it were dead. | https://www.wikidoc.org/index.php/Oleate | |
ab24448e6abe93c4e4dd480062821e8e79124af0 | wikidoc | Oligomycin | Oligomycin
Oligomycins are macrolides created by Streptomyces that can be poisonous to other organisms.
# Function
They have use as antibiotics.
In addition, oligimycin inhibits ATP synthase by blocking its proton channel, which is necessary for oxidative phosphorylation of ADP to ATP (energy production).
Administering oligomycin to an individual can result in very high levels of lactate accumulating in the blood and urine.
hu:Oligomicin | Oligomycin
Template:Chembox new
Oligomycins are macrolides created by Streptomyces that can be poisonous to other organisms.
# Function
They have use as antibiotics.
In addition, oligimycin inhibits ATP synthase by blocking its proton channel, which is necessary for oxidative phosphorylation of ADP to ATP (energy production).
Administering oligomycin to an individual can result in very high levels of lactate accumulating in the blood and urine.[citation needed]
hu:Oligomicin
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Oligomycin | |
a694110d8c057a135d6e2b3eb4ecaeb8e574f5a2 | wikidoc | Olive tree | Olive tree
# Overview
The olive (/ˈɑːləv/ or /ˈɒlv/, Olea europaea, meaning "Oil from/of Europe") is a species of small tree in the family Oleaceae, native to the coastal areas of the eastern Mediterranean Basin (the adjoining coastal areas of southeastern Europe, western Asia and northern Africa) as well as northern Iraq, and northern Iran at the south end of the Caspian Sea.
Its fruit, also called the olive, is of major agricultural importance in the Mediterranean region as the source of olive oil. The tree and its fruit give its name to the plant family, which also includes species such as lilacs, jasmine, Forsythia and the true ash trees (Fraxinus). The word derives from Latin olīva which in turn comes from the Greek ἐλαία (elaía) ultimately from Mycenaean Greek 𐀁𐀨𐀷 e-ra-wa ("elaiva"), attested in Linear B syllabic script. The word 'oil' in multiple languages ultimately derives from the name of this tree and its fruit.
# Nutritional information
100g of green olives contains:
- Calories: 145
- Fat(g): 15.32
- Carbohydrates(g): 3.84
- Fiber(g): 3.3
- Protein(g): 1.03
- Cholesterol(mg): 0
# Paleobotany
The place, time and immediate ancestry of the cultivated olive are unknown. It is assumed that Olea europaea may have arisen from O. chrysophylla in northern tropical Africa and that it was introduced into the countries of the Mediterranean Basin via Egypt and then Crete or Palestine, Syria and Asia Minor. Fossil Olea pollen has been found in Macedonia, Greece, and other places around Mediterranean, indicating that this genus is an original element of the Mediterranean flora. Fossilized leaves of Olea were found in the palaeosols of the volcanic Greek island of Santorini (Thera) and were dated about 37,000 Before Present (BP). Imprints of larvae of olive whitefly Aleurolobus (Aleurodes) olivinus were found on the leaves. The same insect is commonly found today on olive leaves, showing that the plant-animal co-evolutionary relations have not changed since that time.
# History
The olive is one of the plants most often cited in western literature. In Homer's Odyssey, Odysseus crawls beneath two shoots of olive that grow from a single stock, and in the Iliad, (XVII.53ff) is a metaphoric description of a lone olive tree in the mountains, by a spring; the Greeks observed that the olive rarely thrives at a distance from the sea, which in Greece invariably means up mountain slopes. Greek myth attributed to the primordial culture-hero Aristaeus the understanding of olive husbandry, along with cheese-making and bee-keeping. Olive was one of the woods used to fashion the most primitive Greek cult figures, called xoana, referring to their wooden material; they were reverently preserved for centuries. It was purely a matter of local pride that the Athenians claimed that the olive grew first in Athens. In an archaic Athenian foundation myth, Athena won the patronship of Attica from Poseidon with the gift of the olive. Though, according to the 4th-century BC father of botany, Theophrastus, olive trees ordinarily attained an age of about 200 years, he mentions that the very olive tree of Athena still grew on the Acropolis; it was still to be seen there in the 2nd century AD; and when Pausanias was shown it, ca 170 AD, he reported "Legend also says that when the Persians fired Athens the olive was burnt down, but on the very day it was burnt it grew again to the height of two cubits." Indeed, olive suckers sprout readily from the stump, and the great age of some existing olive trees shows that it was perfectly possible that the olive tree of the Acropolis dated to the Bronze Age. The olive was sacred to Athena and appeared on the Athenian coinage.
According to Pliny the Elder a vine, a fig and an olive tree grew in the middle of the Roman Forum, the latter was planted to provide shade (the garden plot was recreated in the 20th century). The Roman poet Horace mentions it in reference to his own diet, which he describes as very simple: "As for me, olives, endives, and smooth mallows provide sustenance." Lord Monboddo comments on the olive in 1779 as one of the foods preferred by the ancients and as one of the most perfect foods.
The leafy branches of the olive tree – the olive branch as a symbol of abundance, glory and peace – were used to crown the victors of friendly games and bloody wars. As emblems of benediction and purification, they were also ritually offered to deities and powerful figures; some were even found in Tutankhamen's tomb.
Olive oil has long been considered sacred; it was used to anoint kings and athletes in ancient Greece. It was burnt in the sacred lamps of temples as well as being the "eternal flame" of the original Olympic Games. Victors in these games were crowned with its leaves. Today, it is still used in many religious ceremonies. Over the years, the olive has been the symbol of peace, wisdom, glory, fertility, power and purity.
The olive was one of the main elements in ancient Israelite cuisine. Olive oil was used for not only food and cooking, but also lighting, sacrificial offerings, ointment, and anointment for priestly or royal office.
The olive tree and olives are mentioned over 30 times in the Bible, in both the New and Old Testaments. It is one of the first plants mentioned in the Bible, and one of the most significant. For example, it was an olive leaf that a dove brought back to Noah to demonstrate that the flood was over. The olive is listed in the Hebrew Bible (Template:Bibleverse) as one of the seven species that are noteworthy products of the Land of Israel.
The Mount of Olives east of Jerusalem is mentioned several times. The Allegory of the Olive Tree in St. Paul's Epistle to the Romans (which reappears in greatly expanded form in the Book of Jacob in the Book of Mormon) refers to the scattering and gathering of Israel. It compares the Israelites and gentiles to tame and wild olive trees. The olive tree itself, as well as olive oil and olives, play an important role in the Bible.
The olive tree and olive oil are mentioned seven times in the Quran, and the olive is praised as a precious fruit. Most notably, it is mentioned in one of the most famous verses of the Quran, Ayat an-Nur: "Allah is the Light of the heavens and the earth. The metaphor of His Light is that of a niche in which is a lamp, the lamp inside a glass, the glass like a brilliant star, lit from a blessed tree, an olive, neither of the east nor of the west, its oil all but giving off light even if no fire touches it. Light upon Light. Allah guides to His Light whoever He wills and Allah makes metaphors for mankind and Allah has knowledge of all things." (Quran, 24:35). Olive tree and olive-oil health benefits have been propounded in Prophetic medicine. The Prophet Mohamed is reported to have said: "Take oil of olive and massage with it – it is a blessed tree" (Sunan al-Darimi, 69:103).
Olives are subsititutes for dates (if not available) during Ramadan fasting, and olive tree leaves are used as incense in some Muslim Mediterranean countries.
The olive tree is native to the Mediterranean region and Western Asia, and spread to nearby countries from there. It is estimated the cultivation of olive trees began more than 7000 years ago. As far back as 3000 BC, olives were grown commercially in Crete; they may have been the source of the wealth of the Minoan civilization. The ancient Greeks used to smear olive oil on their bodies and hair as a matter of grooming and good health.
Theophrastus, in On the Nature of Plants, does not give as systematic and detailed an account of olive husbandry as he does of the vine, but he makes clear (in 1.16.10) that the cultivated olive must be vegetatively propagated; indeed, the pits give rise to thorny, wild-type olives, spread far and wide by birds. Theophrastus reports how the bearing olive can be grafted on the wild olive, for which the Greeks had a separate name, kotinos.
The Spanish colonists brought the olive to the New World where its cultivation prospered in present-day Peru and Chile. The first precious seedlings from Spain were planted in Lima by Antonio de Rivera in 1560. Olive tree cultivation quickly spread along the valleys of South America's dry Pacific coast where the climate was similar to the Mediterranean. The Spanish missionaries established the tree in the 18th century in California. It was first cultivated at Mission San Diego de Alcalá in 1769 or later around 1795. Orchards were started at other missions but in 1838 an inspection found only two olive orchard in California. Oil tree cultivation gradually became a highly successful commercial venture from the 1860s onwards. In Japan the first successful planting of olive trees happened in 1908 on Shodo Island which became the cradle of olive cultivation. It is estimated that there are about 865 million olive trees in the world today (as of 2005), and the vast majority of these are found in Mediterranean countries, although traditionally marginal areas account for no more than 25% of olive planted area and 10% of oil production.
# Old olive trees
The olive tree, Olea europaea, is very hardy: drought-, disease- and fire-resistant, it can live to a great age. Its root system is robust and capable of regenerating the tree even if the above-ground structure is destroyed. The older an olive tree is, the broader and more gnarled its trunk appears. Many olive trees in the groves around the Mediterranean are said to be hundreds of years old, while an age of 2,000 years is claimed for a number of individual trees; in some cases, this has been scientifically verified.
Pliny the Elder told about a sacred Greek olive tree that was 1,600 years old. An olive tree in west Athens, named "Plato's Olive Tree", was said to be a remnant of the grove within which Plato's Academy was situated, which would make it approximately 2,400 years old. The tree comprised a cavernous trunk from which a few branches were still sprouting in 1975, when a traffic accident caused a bus to fall on and uproot it. Since then, the trunk has been preserved and displayed in the nearby Agricultural University of Athens. A supposedly older tree, the "Peisistratos Tree", is located by the banks of the Cephisus River, in the municipality of Agioi Anargyroi, and is said to be a remnant of an olive grove that was planted by Athenian tyrant Peisistratos in the 6th century BC. Numerous ancient olive trees also exist near Pelion in Greece. The age of an olive tree in Crete, claimed to be over 2,000 years old, has been confirmed on the basis of tree ring analysis.
An olive tree in Algarve, Portugal, is 2000 years old, according to radiocarbon dating.
An olive tree in Bar, Montenegro, is claimed to be over 2,000 years old.
The town of Bshaale, Lebanon claims to have the oldest olive trees in the world (4000 BC for the oldest), but no scientific study supports these claims. Other trees in the towns of Amioun appear to be at least 1,500 years old.
According to a recent scientific survey, there are dozens of ancient olive trees throughout Israel and Palestine, 1,600–2,000 years old. Ancient trees include two giant olive trees in Arraba and five trees in Deir Hanna, both in the Galilee region, which have been determined to be over 3,000 years old, although the credibility of the study that produced these dates has been questioned. All seven trees continue to produce olives.
Several trees in the Garden of Gethsemane (from the Hebrew words "gat shemanim" or olive press) in Jerusalem are claimed to date back to the time of Jesus.
Some Italian olive trees are believed to date back to Roman times, although identifying progenitor trees in ancient sources is difficult. A tree located in Santu Baltolu di Carana (municipality of Luras) in Sardinia, Italy, named with respect as the Ozzastru by the inhabitants of the region, is claimed to be 3,000 to 4,000 years old according to different studies. There are several other trees of about 1,000 years old within the same garden. The 15th-century trees of Olivo della Linza located in Alliste province of Lecce in Puglia were noted by Bishop Ludovico de Pennis during his pastoral visit to the Roman Catholic Diocese of Nardò-Gallipoli in 1452.
# Cultivation and uses
The olive tree, Olea europaea, has been cultivated for olive oil, fine wood, olive leaf, and the olive fruit. The earliest evidence for the domestication of olives comes from the Chalcolithic Period archaeological site of Teleilat Ghassul in what is today modern Jordan.
Farmers in ancient times believed olive trees would not grow well if planted more than a short distance from the sea; Theophrastus gives 300 stadia (55.6 km/34.5482382752 mi) as the limit. Modern experience does not always confirm this, and, though showing a preference for the coast, they have long been grown further inland in some areas with suitable climates, particularly in the southwestern Mediterranean (Iberia, northwest Africa) where winters are mild.
Olives are now cultivated in many regions of the world with Mediterranean climates, such as South Africa, Chile, Peru, Australia, and California and in areas with temperate climates such as New Zealand, under irrigation in the Cuyo region in Argentina which has a desert climate. They are also grown in the Córdoba Province, Argentina, which has a temperate climate with rainy summers and dry winters (Cwa). The climate in Argentina changes the external characteristics of the plant but the fruit keeps its original features. The northernmost olive grove is placed in Anglesey, an island off the north west coast of Wales, in the United Kingdom: but it is too early to say if the growing will be successful, having been planted just five years ago.
Considerable research supports the health-giving benefits of consuming olives, olive leaf and olive oil (see external links below for research results). Olive leaves are used in medicinal teas.
Olives are now being looked at for use as a renewable energy source, using waste produced from the olive plants as an energy source that produces 2.5 times the energy generated by burning the same amount of wood. The same reference claims that the smoke released has no negative impact on neighbors or the environment, and the ash left in the stove can be used for fertilizing gardens and plants. The process has been patented in the Middle East and the US (for example).
## Subspecies
There are six natural subspecies of Olea europaea distributed over a wide range:
- Olea europaea subsp. europaea (Mediterranean Basin)
- Olea europaea subsp. cuspidata (from South Africa throughout East Africa, Arabia to South West China)
- Olea europaea subsp. guanchica (Canaries)
- Olea europaea subsp. cerasiformis (Madeira)
- Olea europaea subsp. maroccana Morocco
- Olea europaea subsp. laperrinei (Algeria, Sudan, Niger)
The subspecies maroccana and cerasiformis are respectively hexaploid and tetraploid.
## Cultivars
There are thousands of cultivars of the Olea europaea olive tree. In Italy alone at least three hundred cultivars have been enumerated, but only a few are grown to a large extent. None of these can be accurately identified with ancient descriptions, though it is not unlikely that some of the narrow-leaved cultivars most esteemed may be descendants of the Licinian olive. The Iberian olives are usually cured and eaten, often after being pitted, stuffed (with pickled pimento, anchovies, or other fillings) and packed in brine in jars or tins. Some also pickle olives at home.
Since many cultivars are self sterile or nearly so, they are generally planted in pairs with a single primary cultivar and a secondary cultivar selected for its ability to fertilize the primary one. In recent times, efforts have been directed at producing hybrid cultivars with qualities such as resistance to disease, quick growth and larger or more consistent crops.
Some particularly important cultivars of Olea europaea include:
- Amfissa is an excellent quality Greek table olive grown in Amfissa, Central Greece near the oracle of Delphi. Amfissa olives enjoy protected designation of origin (PDO) status, and are equally good for olive oil extraction. The olive grove of Amfissa, which consists of 1,200,000 olive trees is a part of a protected natural landscape.
- Arbequina is a small, brown olive grown in Aragon and Catalonia, Spain, good for eating and for oil.
- Barnea is a modern dual-purpose cultivar bred in Israel to be disease-resistant and to produce a generous crop. The oil has a strong flavour with a hint of green leaf. Barnea is widely grown in Israel and in the southern hemisphere, particularly in Australia and New Zealand.
- Bosana is the most common olive grown on Sardinia. It is used mostly for oils.
- Cornicabra, originating in Toledo, Spain, comprises about 12% of Spain's production. It is mainly used for oil.
- Empeltre, from Pedrola, Aragon, a medium-sized black olive grown in Spain. Especially in Aragon and the Balearic Islands, it is also dual-purpose.
- Frantoio and Leccino cultivars are the principal raw material for Italian olive oils from Tuscany. Leccino has a mild sweet flavour, while Frantoio is fruity with a stronger aftertaste. Due to their highly valued flavour, these cultivars are now grown in other countries.
- Gemlik is a variety from the Gemlik area of northern Turkey. They are small to medium sized black olives with a high oil content. This type of olive is very common in Turkey and is sold as a breakfast olive in the cured formats of either Yagli Sele, Salamura or Duble, though there are other less common curings. The sign of a traditionally cured Gemlik olive is that the flesh comes away from the pit easily.
- Hojiblanca originated in the province of Córdoba, Spain; its oil is widely appreciated for its slightly bitter flavour.
- Kalamata, a large, black olive with a smooth and meatlike taste, is named after the city of Kalamata, Greece, and is used as a table olive. These olives are usually preserved in wine, vinegar or olive oil. Kalamata olives enjoy PDO status.
- Koroneiki originated from the southern Peloponese, around Kalamata and Mani in Greece. This small olive, though difficult to cultivate, has a high yield of olive oil of exceptional quality.
- Manzanilla, a large, rounded-oval fruit, with purple-green skin, originated in Dos Hermanas, Seville, in southern Spain. "Manzanillas" means little apples in Spanish. Known for a rich taste and thick pulp, it is a prolific bearer, grown around the world.
- Lucques is found in the south of France (Aude département). They are green, large, and elongated. The stone has an arcuated (bow)shape. Their flavour is mild and nutty.
- Maalot (Hebrew for merits) is a disease-resistant, Eastern Mediterranean cultivar derived from the North African Chemlali cultivar in Israel. The olive is medium sized, round, has a fruity flavour and is used almost exclusively for oil production.
- Mission originated on the California Missions and is now grown throughout the state. They are black and generally used for table consumption.
- Nabali, an ancient Israeli cultivar also known locally as Baladi, which, along with Souri and Malissi, is considered to produce among the highest quality olive oil in the world.
- Patrinia olive, is a Greek variety of olive tree grown primarily in Aigialeia, Greece.
- Picholine, is grown in the south of France. It is green, medium size, and elongated. The flavour is mild and nutty.
- Picual, from southern Spain (province of Jaén), is the most widely cultivated olive in Spain, comprising about 50% of Spain's olive production and around 20% of world olive production. It has a strong but sweet flavour, and is widely used in Spain as a table olive.
- Souri, grown in Lebanon near the town of Sur (Tyre) and widespread in the Levant, has a high oil yield and exceptionally aromatic flavour.
- Bari Zaitoon -1, grown in Pakistan Recently approved.
- Bari Zaitoon -2, grown in Pakistan Recently approved.
## Growth and propagation
Olive trees, Olea europaea, show a marked preference for calcareous soils, flourishing best on limestone slopes and crags, and coastal climate conditions. They grow in any light soil, even on clay if well drained, but in rich soils they are predisposed to disease and produce poorer oil than in poorer soil. (This was noted by Pliny the Elder.) Olives like hot weather, and temperatures below −10 °C (14 °F) may injure even a mature tree. They tolerate drought well, thanks to their sturdy and extensive root system. Olive trees can live for several centuries, and can remain productive for as long if they are pruned correctly and regularly.
Olives grow very slowly, and over many years the trunk can attain a considerable diameter. A. P. de Candolle recorded one exceeding 10 metres (32.808399 ft) in girth. The trees rarely exceed 15 metres (49.2125985 ft) in height, and are generally confined to much more limited dimensions by frequent pruning. The yellow or light greenish-brown wood is often finely veined with a darker tint; being very hard and close-grained, it is valued by woodworkers. There are only a handlful of olive varieties that can be used to cross-pollinate. Pendolino olive trees are partially self-fertile, but pollenizers are needed for a large fruit crop. Other compatible olive tree pollenizers include Leccino and Maurino. Pendolino olive trees are used extensively as pollenizers in large olive tree groves.
Olives are propagated by various methods. The preferred ways are cuttings and layers; the tree roots easily in favourable soil and throws up suckers from the stump when cut down. However, yields from trees grown from suckers or seeds are poor; they must be budded or grafted onto other specimens to do well (Lewington and Parker, 114). Branches of various thickness cut into lengths of about 1 metre (3.2808399 ft) planted deeply in manured ground soon vegetate. Shorter pieces are sometimes laid horizontally in shallow trenches and, when covered with a few centimetres of soil, rapidly throw up sucker-like shoots. In Greece, grafting the cultivated tree on the wild tree is a common practice. In Italy, embryonic buds, which form small swellings on the stems, are carefully excised and planted under the soil surface, where they soon form a vigorous shoot.
The olive is also sometimes grown from seed. To facilitate germination, the oily pericarp is first softened by slight rotting, or soaked in hot water or in an alkaline solution.
Where the olive is carefully cultivated, as in Languedoc and Provence, the trees are regularly pruned. The pruning preserves the flower-bearing shoots of the preceding year, while keeping the tree low enough to allow the easy gathering of the fruit. The spaces between the trees are regularly fertilized. The crop from old trees is sometimes enormous, but they seldom bear well two years in succession, and in many cases a large harvest occurs every sixth or seventh season.
## Fruit harvest and processing
Olives are harvested in the autumn and winter. More specifically in the Northern hemisphere, green olives are picked at the end of September to about the middle of November. Blond olives are picked from the middle of October to the end of November and black olives are collected from the middle of November to the end of January or early February. In southern Europe, harvesting is done for several weeks in winter, but the time varies in each country, and with the season and the cultivar.
Most olives today are harvested by shaking the boughs or the whole tree. Using olives found lying on the ground can result in poor quality oil. Another method involves standing on a ladder and "milking" the olives into a sack tied around the harvester's waist. A third method uses a device called an oli-net that wraps around the tree trunk and opens to form an umbrella-like catcher from which workers collect the fruit. Another method uses an electric tool, the oliviera, that has large tongs that spin around quickly, removing fruit from the tree. Olives harvested by this method are used for oil. Table olive varieties are more difficult to harvest, as workers must take care not to damage the fruit; baskets that hang around the worker's neck are used. In some places in Italy and Greece, olives are harvested by hand because the terrain is too mountainous for machines. As a result, the fruit is not bruised, which leads to a superior finished product. The method also involves sawing off branches, which is healthy for future production.
## Traditional fermentation and curing
Olives are a naturally bitter fruit fermented or cured with lye or brine to make them more palatable.
Green olives and black olives are typically washed thoroughly in water to remove oleuropein, a bitter glycoside.
Green olives are allowed to ferment before being packed in a brine solution. American black ("California") olives are not fermented, which is why they taste milder than green olives.
In addition to oleuropein, freshly picked olives are not palatable because of phenolic compounds. (One exception is the throubes olive, which can be eaten fresh.) Traditional cures use the natural microflora on the fruit to aid in fermentation, which leads to three important outcomes: the leaching out and breakdown of oleuropein and phenolic compounds; the creation of lactic acid, which is a natural preservative; and a complex of flavoursome fermentation products. The result is a product which will store with or without refrigeration.
Curing can employ lye, salt, brine, or fresh water. Salt cured olives (also known as dry cured) are packed in plain salt for at least a month, which produces a salty and wrinkled olive. Brine cured olives are kept in a salt water solution for a few days or more. Fresh water cured olives are soaked in a succession of baths, changed daily. Green olives are usually firmer than black olives.
Olives can also be flavoured by soaking in a marinade or pitted and stuffed. Popular flavourings include herbs, spices, olive oil, chili, lemon zest, lemon juice, wine, vinegar, and juniper berries; popular stuffings include feta cheese, pimento, garlic cloves, almonds, and anchovies. Sometimes, the olives are lightly cracked with a hammer or a stone to trigger fermentation. This method of curing adds a slightly bitter taste.
# Pests, diseases, and weather
The most serious pest is the olive fruit fly dacus (Dacus olea) which lays its eggs in the olive most commonly just before it becomes ripe in the autumn. The region surrounding the puncture rots, becomes brown and takes a bitter taste making the olive unfit for eating or for oil. For controlling the pest the practice has been to spray with highly toxic organophosphates (e.g. dimethoate). However satisfactory environmentally friendly methods have now been developed using trapping, applying the bacterium bacillus Thuringiensis and spraying with kaolin. Such methods are obligatory for organic olives.
A fungus, Cycloconium oleaginum, can infect the trees for several successive seasons, causing great damage to plantations. A species of bacterium, Pseudomonas savastanoi pv. oleae, induces tumour growth in the shoots. Certain lepidopterous caterpillars feed on the leaves and flowers.
A pest which spreads through olive trees is the black scale bug, a small black scale insect that resembles a small black spot. They attach themselves firmly to olive trees and reduce the quality of the fruit; their main predators are wasps. The curculio beetle eats the edges of leaves, leaving sawtooth damage.
Rabbits eat the bark of olive trees and can do considerable damage, especially to young trees. If the bark is removed around the entire circumference of a tree it is likely to die.
At the northern edge of their cultivation zone, for instance in Southern France and north-central Italy, olive trees suffer occasionally from frost. Gales and long-continued rains during the gathering season also cause damage.
# Production
Olives are one of the most extensively cultivated fruit crops in the world. In 2010 there were 9.39 million hectares planted with olive trees, which is less than twice the amount of land devoted to apples, bananas or mangoes. Only coconut trees and oil palms command more space.
Other countries with a significant production are Peru, Israel, Australia, Albania, Chile, Croatia, Iran and France.
# As an invasive species
Since its first domestication, Olea europaea has been spreading back to the wild from planted groves. Its original wild populations in southern Europe have been largely swamped by feral plants.
In some other parts of the world where it has been introduced, most notably South Australia, the olive has become a major woody weed that displaces native vegetation. In South Australia, its seeds are spread by the introduced red fox and by many bird species, including the European starling and the native emu, into woodlands, where they germinate and eventually form a dense canopy that prevents regeneration of native trees. As the climate of South Australia is very dry and bushfire prone, the oil rich feral olive tree substantially increases the fire hazard of native sclerophyll woodlands. | Olive tree
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
The olive (/[invalid input: 'icon']ˈɑːləv/ or /ˈɒl[invalid input: 'ɨ']v/, Olea europaea, meaning "Oil from/of Europe") is a species of small tree in the family Oleaceae, native to the coastal areas of the eastern Mediterranean Basin (the adjoining coastal areas of southeastern Europe, western Asia and northern Africa) as well as northern Iraq, and northern Iran at the south end of the Caspian Sea.
Its fruit, also called the olive, is of major agricultural importance in the Mediterranean region as the source of olive oil. The tree and its fruit give its name to the plant family, which also includes species such as lilacs, jasmine, Forsythia and the true ash trees (Fraxinus). The word derives from Latin olīva which in turn comes from the Greek ἐλαία (elaía)[1][2] ultimately from Mycenaean Greek 𐀁𐀨𐀷 e-ra-wa ("elaiva"), attested in Linear B syllabic script.[3][4] The word 'oil' in multiple languages ultimately derives from the name of this tree and its fruit.
# Nutritional information
100g of green olives contains:[5]
- Calories: 145
- Fat(g): 15.32
- Carbohydrates(g): 3.84
- Fiber(g): 3.3
- Protein(g): 1.03
- Cholesterol(mg): 0
# Paleobotany
The place, time and immediate ancestry of the cultivated olive are unknown. It is assumed that Olea europaea may have arisen from O. chrysophylla in northern tropical Africa and that it was introduced into the countries of the Mediterranean Basin via Egypt and then Crete or Palestine, Syria and Asia Minor. Fossil Olea pollen has been found in Macedonia, Greece, and other places around Mediterranean, indicating that this genus is an original element of the Mediterranean flora. Fossilized leaves of Olea were found in the palaeosols of the volcanic Greek island of Santorini (Thera) and were dated about 37,000 Before Present (BP). Imprints of larvae of olive whitefly Aleurolobus (Aleurodes) olivinus were found on the leaves. The same insect is commonly found today on olive leaves, showing that the plant-animal co-evolutionary relations have not changed since that time.[6]
# History
The olive is one of the plants most often cited in western literature. In Homer's Odyssey, Odysseus crawls beneath two shoots of olive that grow from a single stock,[7] and in the Iliad, (XVII.53ff) is a metaphoric description of a lone olive tree in the mountains, by a spring; the Greeks observed that the olive rarely thrives at a distance from the sea, which in Greece invariably means up mountain slopes. Greek myth attributed to the primordial culture-hero Aristaeus the understanding of olive husbandry, along with cheese-making and bee-keeping.[8] Olive was one of the woods used to fashion the most primitive Greek cult figures, called xoana, referring to their wooden material; they were reverently preserved for centuries.[9] It was purely a matter of local pride that the Athenians claimed that the olive grew first in Athens.[10] In an archaic Athenian foundation myth, Athena won the patronship of Attica from Poseidon with the gift of the olive. Though, according to the 4th-century BC father of botany, Theophrastus, olive trees ordinarily attained an age of about 200 years,[11] he mentions that the very olive tree of Athena still grew on the Acropolis; it was still to be seen there in the 2nd century AD;[12] and when Pausanias was shown it, ca 170 AD, he reported "Legend also says that when the Persians fired Athens the olive was burnt down, but on the very day it was burnt it grew again to the height of two cubits."[13] Indeed, olive suckers sprout readily from the stump, and the great age of some existing olive trees shows that it was perfectly possible that the olive tree of the Acropolis dated to the Bronze Age. The olive was sacred to Athena and appeared on the Athenian coinage.
According to Pliny the Elder a vine, a fig and an olive tree grew in the middle of the Roman Forum, the latter was planted to provide shade (the garden plot was recreated in the 20th century).[14] The Roman poet Horace mentions it in reference to his own diet, which he describes as very simple: "As for me, olives, endives, and smooth mallows provide sustenance."[15] Lord Monboddo comments on the olive in 1779 as one of the foods preferred by the ancients and as one of the most perfect foods.[16]
The leafy branches of the olive tree – the olive branch as a symbol of abundance, glory and peace – were used to crown the victors of friendly games and bloody wars. As emblems of benediction and purification, they were also ritually offered to deities and powerful figures; some were even found in Tutankhamen's tomb.
Olive oil has long been considered sacred; it was used to anoint kings and athletes in ancient Greece. It was burnt in the sacred lamps of temples as well as being the "eternal flame" of the original Olympic Games. Victors in these games were crowned with its leaves. Today, it is still used in many religious ceremonies. Over the years, the olive has been the symbol of peace, wisdom, glory, fertility, power and purity.
The olive was one of the main elements in ancient Israelite cuisine. Olive oil was used for not only food and cooking, but also lighting, sacrificial offerings, ointment, and anointment for priestly or royal office.[17]
The olive tree and olives are mentioned over 30 times in the Bible, in both the New and Old Testaments. It is one of the first plants mentioned in the Bible, and one of the most significant. For example, it was an olive leaf that a dove brought back to Noah to demonstrate that the flood was over. The olive is listed in the Hebrew Bible (Template:Bibleverse) as one of the seven species that are noteworthy products of the Land of Israel.[18]
The Mount of Olives east of Jerusalem is mentioned several times. The Allegory of the Olive Tree in St. Paul's Epistle to the Romans (which reappears in greatly expanded form in the Book of Jacob in the Book of Mormon) refers to the scattering and gathering of Israel. It compares the Israelites and gentiles to tame and wild olive trees. The olive tree itself, as well as olive oil and olives, play an important role in the Bible.[19]
The olive tree and olive oil are mentioned seven times in the Quran,[20] and the olive is praised as a precious fruit. Most notably, it is mentioned in one of the most famous verses of the Quran, Ayat an-Nur: "Allah is the Light of the heavens and the earth. The metaphor of His Light is that of a niche in which is a lamp, the lamp inside a glass, the glass like a brilliant star, lit from a blessed tree, an olive, neither of the east nor of the west, its oil all but giving off light even if no fire touches it. Light upon Light. Allah guides to His Light whoever He wills and Allah makes metaphors for mankind and Allah has knowledge of all things." (Quran, 24:35). Olive tree and olive-oil health benefits have been propounded in Prophetic medicine. The Prophet Mohamed is reported to have said: "Take oil of olive and massage with it – it is a blessed tree" (Sunan al-Darimi, 69:103).
Olives are subsititutes for dates (if not available) during Ramadan fasting, and olive tree leaves are used as incense in some Muslim Mediterranean countries.[21]
The olive tree is native to the Mediterranean region and Western Asia, and spread to nearby countries from there. It is estimated the cultivation of olive trees began more than 7000 years ago. As far back as 3000 BC, olives were grown commercially in Crete; they may have been the source of the wealth of the Minoan civilization.[22] The ancient Greeks used to smear olive oil on their bodies and hair as a matter of grooming and good health.
Theophrastus, in On the Nature of Plants, does not give as systematic and detailed an account of olive husbandry as he does of the vine, but he makes clear (in 1.16.10) that the cultivated olive must be vegetatively propagated; indeed, the pits give rise to thorny, wild-type olives, spread far and wide by birds. Theophrastus reports how the bearing olive can be grafted on the wild olive, for which the Greeks had a separate name, kotinos.[23]
The Spanish colonists brought the olive to the New World where its cultivation prospered in present-day Peru and Chile. The first precious seedlings from Spain were planted in Lima by Antonio de Rivera in 1560. Olive tree cultivation quickly spread along the valleys of South America's dry Pacific coast where the climate was similar to the Mediterranean.[24] The Spanish missionaries established the tree in the 18th century in California. It was first cultivated at Mission San Diego de Alcalá in 1769 or later around 1795. Orchards were started at other missions but in 1838 an inspection found only two olive orchard in California. Oil tree cultivation gradually became a highly successful commercial venture from the 1860s onwards.[25] In Japan the first successful planting of olive trees happened in 1908 on Shodo Island which became the cradle of olive cultivation.[26] It is estimated that there are about 865 million olive trees in the world today (as of 2005), and the vast majority of these are found in Mediterranean countries, although traditionally marginal areas account for no more than 25% of olive planted area and 10% of oil production.[27]
# Old olive trees
The olive tree, Olea europaea, is very hardy: drought-, disease- and fire-resistant, it can live to a great age. Its root system is robust and capable of regenerating the tree even if the above-ground structure is destroyed. The older an olive tree is, the broader and more gnarled its trunk appears. Many olive trees in the groves around the Mediterranean are said to be hundreds of years old, while an age of 2,000 years is claimed for a number of individual trees; in some cases, this has been scientifically verified.[citation needed]
Pliny the Elder told about a sacred Greek olive tree that was 1,600 years old. An olive tree in west Athens, named "Plato's Olive Tree", was said[by whom?] to be a remnant of the grove within which Plato's Academy was situated, which would make it approximately 2,400 years old. The tree comprised a cavernous trunk from which a few branches were still sprouting in 1975, when a traffic accident caused a bus to fall on and uproot it. Since then, the trunk has been preserved and displayed in the nearby Agricultural University of Athens. A supposedly older tree, the "Peisistratos Tree", is located by the banks of the Cephisus[disambiguation needed] River, in the municipality of Agioi Anargyroi, and is said to be a remnant of an olive grove that was planted by Athenian tyrant Peisistratos in the 6th century BC. Numerous ancient olive trees also exist near Pelion in Greece[citation needed]. The age of an olive tree in Crete, claimed to be over 2,000 years old, has been confirmed on the basis of tree ring analysis.[28]
An olive tree in Algarve, Portugal, is 2000 years old, according to radiocarbon dating.[29]
An olive tree in Bar, Montenegro, is claimed to be over 2,000 years old.[30]
The town of Bshaale, Lebanon claims to have the oldest olive trees in the world (4000 BC for the oldest), but no scientific study supports these claims. Other trees in the towns of Amioun appear to be at least 1,500 years old.[31][32]
According to a recent scientific survey, there are dozens of ancient olive trees throughout Israel and Palestine, 1,600–2,000 years old.[33] Ancient trees include two giant olive trees in Arraba and five trees in Deir Hanna, both in the Galilee region, which have been determined to be over 3,000 years old,[33] although the credibility of the study that produced these dates has been questioned.[citation needed] All seven trees continue to produce olives.
Several trees in the Garden of Gethsemane (from the Hebrew words "gat shemanim" or olive press) in Jerusalem are claimed to date back to the time of Jesus.[34]
Some Italian olive trees are believed to date back to Roman times, although identifying progenitor trees in ancient sources is difficult. A tree located in Santu Baltolu di Carana (municipality of Luras) in Sardinia, Italy, named with respect as the Ozzastru by the inhabitants of the region, is claimed to be 3,000 to 4,000 years old according to different studies.[citation needed] There are several other trees of about 1,000 years old within the same garden. The 15th-century trees of Olivo della Linza located in Alliste province of Lecce in Puglia were noted by Bishop Ludovico de Pennis during his pastoral visit to the Roman Catholic Diocese of Nardò-Gallipoli in 1452.[35]
# Cultivation and uses
The olive tree, Olea europaea, has been cultivated for olive oil, fine wood, olive leaf, and the olive fruit. The earliest evidence for the domestication of olives comes from the Chalcolithic Period archaeological site of Teleilat Ghassul in what is today modern Jordan.
Farmers in ancient times believed olive trees would not grow well if planted more than a short distance from the sea; Theophrastus gives 300 stadia (55.6 km/34.5482382752 mi) as the limit. Modern experience does not always confirm this, and, though showing a preference for the coast, they have long been grown further inland in some areas with suitable climates, particularly in the southwestern Mediterranean (Iberia, northwest Africa) where winters are mild.
Olives are now cultivated in many regions of the world with Mediterranean climates, such as South Africa, Chile, Peru, Australia, and California and in areas with temperate climates such as New Zealand, under irrigation in the Cuyo region in Argentina which has a desert climate. They are also grown in the Córdoba Province, Argentina, which has a temperate climate with rainy summers and dry winters (Cwa).[36] The climate in Argentina changes the external characteristics of the plant but the fruit keeps its original features.[37] The northernmost olive grove is placed in Anglesey, an island off the north west coast of Wales, in the United Kingdom[38]: but it is too early to say if the growing will be successful, having been planted just five years ago.
Considerable research supports the health-giving benefits of consuming olives, olive leaf and olive oil (see external links below for research results). Olive leaves are used in medicinal teas.
Olives are now being looked at[39] for use as a renewable energy source, using waste produced from the olive plants as an energy source that produces 2.5 times the energy generated by burning the same amount of wood. The same reference claims that the smoke released has no negative impact on neighbors or the environment, and the ash left in the stove can be used for fertilizing gardens and plants. The process has been patented in the Middle East and the US (for example).[40]
## Subspecies
There are six natural subspecies of Olea europaea distributed over a wide range:[41][42]
- Olea europaea subsp. europaea (Mediterranean Basin)
- Olea europaea subsp. cuspidata (from South Africa throughout East Africa, Arabia to South West China)
- Olea europaea subsp. guanchica (Canaries)
- Olea europaea subsp. cerasiformis (Madeira)
- Olea europaea subsp. maroccana Morocco
- Olea europaea subsp. laperrinei (Algeria, Sudan, Niger)
The subspecies maroccana and cerasiformis are respectively hexaploid and tetraploid.[43]
## Cultivars
There are thousands of cultivars of the Olea europaea olive tree. In Italy alone at least three hundred cultivars have been enumerated, but only a few are grown to a large extent. None of these can be accurately identified with ancient descriptions, though it is not unlikely that some of the narrow-leaved cultivars most esteemed may be descendants of the Licinian olive. The Iberian olives are usually cured and eaten, often after being pitted, stuffed (with pickled pimento, anchovies, or other fillings) and packed in brine in jars or tins. Some also pickle olives at home.
Since many cultivars are self sterile or nearly so, they are generally planted in pairs with a single primary cultivar and a secondary cultivar selected for its ability to fertilize the primary one. In recent times, efforts have been directed at producing hybrid cultivars with qualities such as resistance to disease, quick growth and larger or more consistent crops.
Some particularly important cultivars of Olea europaea include:
- Amfissa is an excellent quality Greek table olive grown in Amfissa, Central Greece near the oracle of Delphi. Amfissa olives enjoy protected designation of origin (PDO) status, and are equally good for olive oil extraction. The olive grove of Amfissa, which consists of 1,200,000 olive trees is a part of a protected natural landscape.
- Arbequina is a small, brown olive grown in Aragon and Catalonia, Spain, good for eating and for oil.
- Barnea is a modern dual-purpose cultivar bred in Israel to be disease-resistant and to produce a generous crop. The oil has a strong flavour with a hint of green leaf. Barnea is widely grown in Israel and in the southern hemisphere, particularly in Australia and New Zealand.
- Bosana is the most common olive grown on Sardinia. It is used mostly for oils.
- Cornicabra, originating in Toledo, Spain, comprises about 12% of Spain's production. It is mainly used for oil.
- Empeltre, from Pedrola, Aragon, a medium-sized black olive grown in Spain. Especially in Aragon and the Balearic Islands, it is also dual-purpose.
- Frantoio and Leccino cultivars are the principal raw material for Italian olive oils from Tuscany. Leccino has a mild sweet flavour, while Frantoio is fruity with a stronger aftertaste. Due to their highly valued flavour, these cultivars are now grown in other countries.
- Gemlik is a variety from the Gemlik area of northern Turkey. They are small to medium sized black olives with a high oil content. This type of olive is very common in Turkey and is sold as a breakfast olive in the cured formats of either Yagli Sele, Salamura or Duble, though there are other less common curings. The sign of a traditionally cured Gemlik olive is that the flesh comes away from the pit easily.
- Hojiblanca originated in the province of Córdoba, Spain; its oil is widely appreciated for its slightly bitter flavour.
- Kalamata, a large, black olive with a smooth and meatlike taste, is named after the city of Kalamata, Greece, and is used as a table olive. These olives are usually preserved in wine, vinegar or olive oil. Kalamata olives enjoy PDO status.[44]
- Koroneiki originated from the southern Peloponese, around Kalamata and Mani in Greece. This small olive, though difficult to cultivate, has a high yield of olive oil of exceptional quality.
- Manzanilla, a large, rounded-oval fruit, with purple-green skin, originated in Dos Hermanas, Seville, in southern Spain. "Manzanillas" means little apples in Spanish. Known for a rich taste and thick pulp, it is a prolific bearer, grown around the world.
- Lucques is found in the south of France (Aude département). They are green, large, and elongated. The stone has an arcuated (bow)shape. Their flavour is mild and nutty.
- Maalot (Hebrew for merits) is a disease-resistant, Eastern Mediterranean cultivar derived from the North African Chemlali cultivar in Israel. The olive is medium sized, round, has a fruity flavour and is used almost exclusively for oil production.
- Mission originated on the California Missions and is now grown throughout the state. They are black and generally used for table consumption.
- Nabali, an ancient Israeli cultivar[45] also known locally as Baladi, which, along with Souri and Malissi, is considered to produce among the highest quality olive oil in the world.[46]
- Patrinia olive, is a Greek variety of olive tree grown primarily in Aigialeia, Greece.
- Picholine, is grown in the south of France. It is green, medium size, and elongated. The flavour is mild and nutty.
- Picual, from southern Spain (province of Jaén), is the most widely cultivated olive in Spain, comprising about 50% of Spain's olive production and around 20% of world olive production. It has a strong but sweet flavour, and is widely used in Spain as a table olive.
- Souri, grown in Lebanon near the town of Sur (Tyre) and widespread in the Levant, has a high oil yield and exceptionally aromatic flavour.
- Bari Zaitoon -1, grown in Pakistan Recently approved.
- Bari Zaitoon -2, grown in Pakistan Recently approved.
## Growth and propagation
Olive trees, Olea europaea, show a marked preference for calcareous soils, flourishing best on limestone slopes and crags, and coastal climate conditions. They grow in any light soil, even on clay if well drained, but in rich soils they are predisposed to disease and produce poorer oil than in poorer soil. (This was noted by Pliny the Elder.) Olives like hot weather, and temperatures below −10 °C (14 °F) may injure even a mature tree. They tolerate drought well, thanks to their sturdy and extensive root system. Olive trees can live for several centuries, and can remain productive for as long if they are pruned correctly and regularly.
Olives grow very slowly, and over many years the trunk can attain a considerable diameter. A. P. de Candolle recorded one exceeding 10 metres (32.808399 ft) in girth. The trees rarely exceed 15 metres (49.2125985 ft) in height, and are generally confined to much more limited dimensions by frequent pruning. The yellow or light greenish-brown wood is often finely veined with a darker tint; being very hard and close-grained, it is valued by woodworkers. There are only a handlful of olive varieties that can be used to cross-pollinate. Pendolino olive trees are partially self-fertile, but pollenizers are needed for a large fruit crop. Other compatible olive tree pollenizers include Leccino and Maurino. Pendolino olive trees are used extensively as pollenizers in large olive tree groves.
Olives are propagated by various methods. The preferred ways are cuttings and layers; the tree roots easily in favourable soil and throws up suckers from the stump when cut down. However, yields from trees grown from suckers or seeds are poor; they must be budded or grafted onto other specimens to do well (Lewington and Parker, 114). Branches of various thickness cut into lengths of about 1 metre (3.2808399 ft) planted deeply in manured ground soon vegetate. Shorter pieces are sometimes laid horizontally in shallow trenches and, when covered with a few centimetres of soil, rapidly throw up sucker-like shoots. In Greece, grafting the cultivated tree on the wild tree is a common practice. In Italy, embryonic buds, which form small swellings on the stems, are carefully excised and planted under the soil surface, where they soon form a vigorous shoot.
The olive is also sometimes grown from seed. To facilitate germination, the oily pericarp is first softened by slight rotting, or soaked in hot water or in an alkaline solution.
Where the olive is carefully cultivated, as in Languedoc and Provence, the trees are regularly pruned. The pruning preserves the flower-bearing shoots of the preceding year, while keeping the tree low enough to allow the easy gathering of the fruit. The spaces between the trees are regularly fertilized. The crop from old trees is sometimes enormous, but they seldom bear well two years in succession, and in many cases a large harvest occurs every sixth or seventh season.
## Fruit harvest and processing
Olives are harvested in the autumn and winter. More specifically in the Northern hemisphere, green olives are picked at the end of September to about the middle of November. Blond olives are picked from the middle of October to the end of November and black olives are collected from the middle of November to the end of January or early February. In southern Europe, harvesting is done for several weeks in winter, but the time varies in each country, and with the season and the cultivar.
Most olives today are harvested by shaking the boughs or the whole tree. Using olives found lying on the ground can result in poor quality oil. Another method involves standing on a ladder and "milking" the olives into a sack tied around the harvester's waist.[citation needed] A third method uses a device called an oli-net that wraps around the tree trunk and opens to form an umbrella-like catcher from which workers collect the fruit. Another method uses an electric tool, the oliviera, that has large tongs that spin around quickly, removing fruit from the tree. Olives harvested by this method are used for oil. Table olive varieties are more difficult to harvest, as workers must take care not to damage the fruit; baskets that hang around the worker's neck are used. In some places in Italy and Greece, olives are harvested by hand because the terrain is too mountainous for machines. As a result, the fruit is not bruised, which leads to a superior finished product. The method also involves sawing off branches, which is healthy for future production.[47]
## Traditional fermentation and curing
Olives are a naturally bitter fruit fermented or cured with lye or brine to make them more palatable.
Green olives and black olives are typically washed thoroughly in water to remove oleuropein, a bitter glycoside.
Green olives are allowed to ferment before being packed in a brine solution. American black ("California") olives are not fermented, which is why they taste milder than green olives.
In addition to oleuropein, freshly picked olives are not palatable because of phenolic compounds.[47] (One exception is the throubes olive, which can be eaten fresh.)[48][citation needed] Traditional cures use the natural microflora on the fruit to aid in fermentation, which leads to three important outcomes: the leaching out and breakdown of oleuropein and phenolic compounds; the creation of lactic acid, which is a natural preservative; and a complex of flavoursome fermentation products. The result is a product which will store with or without refrigeration.
Curing can employ lye, salt, brine, or fresh water. Salt cured olives (also known as dry cured) are packed in plain salt for at least a month, which produces a salty and wrinkled olive. Brine cured olives are kept in a salt water solution for a few days or more. Fresh water cured olives are soaked in a succession of baths, changed daily.[47] Green olives are usually firmer than black olives.
Olives can also be flavoured by soaking in a marinade or pitted and stuffed. Popular flavourings include herbs, spices, olive oil, chili, lemon zest, lemon juice, wine, vinegar, and juniper berries; popular stuffings include feta cheese, pimento, garlic cloves, almonds, and anchovies. Sometimes, the olives are lightly cracked with a hammer or a stone to trigger fermentation. This method of curing adds a slightly bitter taste.[citation needed]
# Pests, diseases, and weather
The most serious pest is the olive fruit fly dacus (Dacus olea) which lays its eggs in the olive most commonly just before it becomes ripe in the autumn. The region surrounding the puncture rots, becomes brown and takes a bitter taste making the olive unfit for eating or for oil. For controlling the pest the practice has been to spray with highly toxic organophosphates (e.g. dimethoate). However satisfactory environmentally friendly methods have now been developed using trapping, applying the bacterium bacillus Thuringiensis and spraying with kaolin. Such methods are obligatory for organic olives.
A fungus, Cycloconium oleaginum, can infect the trees for several successive seasons, causing great damage to plantations. A species of bacterium, Pseudomonas savastanoi pv. oleae,[49] induces tumour growth in the shoots. Certain lepidopterous caterpillars feed on the leaves and flowers.
A pest which spreads through olive trees is the black scale bug, a small black scale insect that resembles a small black spot. They attach themselves firmly to olive trees and reduce the quality of the fruit; their main predators are wasps. The curculio beetle eats the edges of leaves, leaving sawtooth damage.[50]
Rabbits eat the bark of olive trees and can do considerable damage, especially to young trees. If the bark is removed around the entire circumference of a tree it is likely to die.
At the northern edge of their cultivation zone, for instance in Southern France and north-central Italy, olive trees suffer occasionally from frost. Gales and long-continued rains during the gathering season also cause damage.
# Production
Olives are one of the most extensively cultivated fruit crops in the world.[51] In 2010 there were 9.39 million hectares planted with olive trees, which is less than twice the amount of land devoted to apples, bananas or mangoes. Only coconut trees and oil palms command more space.[52]
Other countries with a significant production are Peru, Israel, Australia, Albania, Chile, Croatia, Iran and France.
# As an invasive species
Since its first domestication, Olea europaea has been spreading back to the wild from planted groves. Its original wild populations in southern Europe have been largely swamped by feral plants.[53]
In some other parts of the world where it has been introduced, most notably South Australia, the olive has become a major woody weed that displaces native vegetation. In South Australia, its seeds are spread by the introduced red fox and by many bird species, including the European starling and the native emu, into woodlands, where they germinate and eventually form a dense canopy that prevents regeneration of native trees.[54] As the climate of South Australia is very dry and bushfire prone, the oil rich feral olive tree substantially increases the fire hazard of native sclerophyll woodlands.[55] | https://www.wikidoc.org/index.php/Olive_tree | |
22bb175397c84a122a2af22843938fd23fca8aad | wikidoc | Olodaterol | Olodaterol
- Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large, placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including olodaterol, the active ingredient in STRIVERDI RESPIMAT. The safety and efficacy of STRIVERDI RESPIMAT in patients with asthma have not been established. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.
- The recommended dose of STRIVERDI RESPIMAT is two inhalations once-daily at the same time of the day. Do not use STRIVERDI RESPIMAT more than two inhalations every 24 hours.
- Prior to first use, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally-impaired patients. There are no data available for use of STRIVERDI RESPIMAT in severe hepatically impaired patients.
- Asthma-Related Death
- Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.
- A 28-week, placebo-controlled US study comparing the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of long-acting beta2-adrenergic agonists, including STRIVERDI RESPIMAT. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with STRIVERDI RESPIMAT has been conducted. The safety and efficacy of STRIVERDI RESPIMAT in patients with asthma have not been established. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.
- Deterioration of Disease and Acute Episodes
- STRIVERDI RESPIMAT should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. STRIVERDI RESPIMAT has not been studied in patients with acutely deteriorating COPD. The use of STRIVERDI RESPIMAT in this setting is inappropriate.
- STRIVERDI RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STRIVERDI RESPIMAT has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.
- When beginning STRIVERDI RESPIMAT, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing STRIVERDI RESPIMAT, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
- COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If STRIVERDI RESPIMAT no longer controls symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of STRIVERDI RESPIMAT beyond the recommended dose is not appropriate in this situation.
- Excessive Use of STRIVERDI RESPIMAT and Use with Long-Acting Beta2-Agonists
- As with other inhaled drugs containing beta2-adrenergic agents, STRIVERDI RESPIMAT should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
- Paradoxical Bronchospasm
- As with other inhaled beta2-agonists, STRIVERDI RESPIMAT may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, STRIVERDI RESPIMAT should be discontinued immediately and alternative therapy instituted.
- Cardiovascular Effects
- STRIVERDI RESPIMAT, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms. If such effects occur, STRIVERDI RESPIMAT may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Long acting beta2-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension.
- Co-existing Conditions
- STRIVERDI RESPIMAT, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
- Hypokalemia and Hyperglycemia
- Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.
- In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility for cardiac arrhythmias.
- Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of STRIVERDI RESPIMAT with the rates similar to those for placebo controls. STRIVERDI RESPIMAT has not been investigated in patients whose diabetes mellitus is not well controlled.
- Hypersensitivity Reactions
- Immediate hypersensitivity reactions, including angioedema, may occur after administration of STRIVERDI RESPIMAT. If such a reaction occurs, therapy with STRIVERDI RESPIMAT should be stopped at once and alternative treatment should be considered.
- The STRIVERDI RESPIMAT clinical development program included seven dose-ranging trials and eight confirmatory trials. Four of the confirmatory trials were 6-week cross-over trials and four were 48-week parallel group trials. Adverse reactions observed in the dose-ranging trials and four 6-week cross-over trials were consistent with those observed in the 48-week parallel group trials, which formed the primary safety database.
- The primary safety database consisted of pooled data from the four 48-week double-blind, active and placebo-controlled, parallel group confirmatory clinical trials. These trials included 3104 adult COPD patients (77% males and 23% females) 40 years of age and older. Of these patients, 876 and 883 patients were treated with STRIVERDI RESPIMAT 5 mcg and 10 mcg once-daily, respectively. The STRIVERDI RESPIMAT groups were composed of mostly Caucasians (66%) with a mean age of 64 years and a mean percent predicted FEV1 at baseline of 44% for both the 5 mcg and 10 mcg treatment groups. Control arms for comparison included placebo in all four trials plus formoterol 12 mcg in two trials.
- In these four clinical trials, seventy-two percent (72%) of patients exposed to any dose of STRIVERDI RESPIMAT reported an adverse reaction compared to 71% in the placebo group. The proportion of patients who discontinued due to an adverse reaction was 7.2% for STRIVERDI RESPIMAT treated patients compared to 8.8% for placebo treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD. The most common serious adverse reactions were COPD exacerbation, pneumonia, and atrial fibrillation.
- Table 1 shows all adverse drug reactions reported by at least 2% of patients (and higher than placebo) who received STRIVERDI RESPIMAT 5 mcg during the 48-week trials.
- Additional adverse reactions that occurred in greater than 2% (and higher than placebo) of patients exposed to STRIVERDI RESPIMAT 10 mcg were pneumonia, constipation, and pyrexia.
- Lung cancers were reported in 6 (0.7%), 3 (0.3%), and 2 (0.2%) patients who received STRIVERDI RESPIMAT 10 mcg, 5 mcg, and placebo, respectively.
- If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of STRIVERDI RESPIMAT may be potentiated.
- Xanthine Derivatives, Steroids, or Diuretics
- Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of STRIVERDI RESPIMAT.
- Non-Potassium Sparing Diuretics
- The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium-sparing diuretics.
- Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs
- STRIVERDI RESPIMAT, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
- Beta-Blockers
- Beta-adrenergic receptor antagonists (beta-blockers) and STRIVERDI RESPIMAT may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
- Inhibitors of Cytochrome P450 and P-gp Efflux Transporter
- In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of maximum plasma concentrations and AUC was observed. STRIVERDI RESPIMAT was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment is necessary.
- There are no adequate and well-controlled studies with STRIVERDI RESPIMAT in pregnant women. STRIVERDI RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- STRIVERDI RESPIMAT was not teratogenic in rats at inhalation doses approximately 2,731 times the maximum recommended human daily inhalation dose (MRHDID) on an AUC basis (at a rat maternal inhalation dose of 1,054 mcg/kg/day). Placental transfer of STRIVERDI RESPIMAT was observed in pregnant rats.
- STRIVERDI RESPIMAT has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHDID in adults on an AUC basis (at a rabbit maternal inhalation dose of 2,489 mcg/kg/day). STRIVERDI RESPIMAT exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at an inhalation dose approximately 1,353 times the MRHDID in adults on an AUC basis (at a rabbit maternal inhalation dose of 974 mcg/kg/day).
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olodaterol in women who are pregnant.
- Of the 876 patients who received STRIVERDI RESPIMAT at the recommended dose of 5 mcg once-daily in the clinical studies from the pooled 1-year database, 485 were less than or equal to 65 years of age and 391 (44.6%) were greater than 65 years of age.
- No overall differences in effectiveness were observed, and in the 1-year pooled data, the adverse drug reaction profiles were similar in the older population compared to the patient population overall.
## Signs and Symptoms
- The expected signs and symptoms with overdosage of STRIVERDI RESPIMAT are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of STRIVERDI RESPIMAT.
## Management
- Treatment of overdosage consists of discontinuation of STRIVERDI RESPIMAT together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of STRIVERDI RESPIMAT. Cardiac monitoring is recommended in cases of overdosage.
# Chronic Overdose
There is limited information regarding Chronic Overdose of Olodaterol in the drug label.
- Beta-adrenoceptors are divided into three subtypes: beta1-adrenoceptors predominantly expressed on cardiac smooth muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle, and beta3-adrenoceptors predominantly expressed on adipose tissue. Beta2-agonists cause bronchodilation. Although the beta2-adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle, it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart. The precise function of beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-agonists may have cardiac effects.
- The structural formula is:
- The drug product, STRIVERDI RESPIMAT, is composed of a sterile, aqueous solution of olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STRIVERDI RESPIMAT cartridge) for use with the STRIVERDI RESPIMAT inhaler.
- Excipients include water for injection, benzalkonium chloride, edetate disodium, and anhydrous citric acid. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler. The STRIVERDI RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The STRIVERDI RESPIMAT inhaler has a yellow-colored cap.
- When used with the STRIVERDI RESPIMAT inhaler, each cartridge containing a minimum of 4 grams of a sterile aqueous solution, delivers 60 (or 28) metered actuations after preparation for use, the equivalent of 30 days’ or 14 days’ medication when used as two actuations once a day. Each dose (1 dose equals 2 actuations) from the STRIVERDI RESPIMAT inhaler delivers 5 mcg olodaterol in 22.1 mcL of solution from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).
- Prior to first use, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. When using for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- The major adverse effects of inhaled beta2-adrenergic agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium, and increases in plasma glucose.
- Changes in serum potassium were evaluated in COPD patients in double-blind phase 3 studies. In pooled data, at the recommended 5 mcg dose there was no clinically relevant change compared to placebo in serum potassium.
- Electrophysiology
- The effect of STRIVERDI RESPIMAT on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomized, placebo- and active (moxifloxacin)- controlled study at single doses of 10, 20, 30, and 50 mcg. Dose-dependent QTcI (individual subject corrected QT interval) prolongation was observed. The maximum mean (one-sided 95% upper confidence bound) difference in QTcI from placebo after baseline correction was 2.5 (5.6) ms, 6.1 (9.2) ms, 7.5 (10.7) ms and 8.5 (11.6) ms following doses of 10, 20, 30 and 50 mcg, respectively.
- The effect of 5 mcg and 10 mcg STRIVERDI RESPIMAT on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between STRIVERDI RESPIMAT 5 mcg, 10 mcg, and placebo.
- Absorption
- Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.
- Distribution
- Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of olodaterol to human plasma proteins is independent of concentration and is approximately 60%.
- Metabolism
- Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose.
- Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.
- Elimination
- Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. However, the effective half-life at daily dose of 5 μg calculated from Cmax from COPD patients is 7.5 hours.
- Following intravenous administration of -labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5% to 7% of the dose.
- Special Populations
- A pharmacokinetic meta-analysis showed that no dose adjustment is necessary based on the effect of age, gender, and weight on systemic exposure in COPD patients after inhalation of STRIVERDI RESPIMAT.
- Renal Impairment
- Olodaterol levels were increased by approximately 40% in subjects with severe renal impairment. A study in subjects with mild and moderate renal impairment was not performed.
- Hepatic Impairment
- Subjects with mild and moderate hepatic impairment showed no changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. A study in subjects with severe hepatic impairment was not performed.
- Drug-Drug Interactions
- Drug-drug interaction studies were carried out using fluconazole as a model inhibitor of CYP 2C9 and ketoconazole as a potent P-gp (and CYP3A4, 2C8, 2C9) inhibitor.
- Fluconazole: Co-administration of 400 mg fluconazole once a day for 14 days had no relevant effect on systemic exposure to olodaterol.
- Ketoconazole: Co-administration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.
- Tiotropium: Co-administration of tiotropium bromide, delivered as fixed-dose combination with olodaterol, for 21 days had no relevant effect on systemic exposure to olodaterol, and vice versa.
- Olodaterol was not mutagenic in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of micronuclei in rats after intravenous doses. The increased frequency of micronuclei was likely related to drug enhanced (compensatory) erythropoiesis. The mechanism for induction of micronuclei formation is likely not relevant at clinical exposures.
- Olodaterol did not impair male or female fertility in rats at inhalation doses up to 3,068 mcg/kg/day (approximately 2,322 times the MRHDID on an AUC basis).
- Dose-ranging trials
- The first COPD dose-ranging trial was a randomized, double-blind, placebo-controlled, single-dose, 5-way cross-over trial in 36 patients. Results demonstrated dose-related improvements in forced expiratory volume in one second (FEV1) compared to placebo. The difference in trough FEV1 from placebo for the 2, 5, 10, and 20 mcg doses were 0.07L (95% CI 0.03, 0.11), 0.10L (0.06, 0.14), 0.11L (0.07, 0.15), and 0.12L (0.08, 0.16), respectively. The second COPD dose-ranging trial was a 4-week, randomized, double-blind, placebo-controlled, parallel group trial in 405 patients. Dose-related improvements in lung function were also seen, with no added benefit of the 20 mcg dose over the 10 mcg dose (Figure 1). The third COPD dose-ranging trial was a randomized, double-blind, 4-way cross-over, dose-regimen trial in 47 patients. Treatment arms included 2 mcg twice-daily, 5 mcg once-daily, 5 mcg twice-daily, and 10 mcg once-daily. There was no clear difference in treatment effect when comparing twice-daily dosing to once-daily dosing.
- Four randomized, double-blind, placebo-controlled dose-ranging trials were performed in patients with asthma, evaluating doses from 2 to 20 mcg. Results from patients with asthma were consistent with results from dose-ranging trials in patients with COPD.
- STRIVERDI RESPIMAT is not indicated for asthma.
- Based upon the results of the dose-ranging trials, 5 and 10 mcg doses were further evaluated in the confirmatory COPD trials.
- Confirmatory Trials
- The eight confirmatory trials in the STRIVERDI RESPIMAT clinical development program were four pairs of replicate, randomized, double-blind, placebo-controlled trials in 3533 COPD patients (1281 received the 5 mcg dose, 1284 received the 10 mcg dose):
(i) two replicate, placebo-controlled, parallel group, 48 week trials (Trials 1 and 2)
(ii) two replicate, placebo- and active- ] 12 mcg twice-daily] controlled, parallel group, 48-week trials (Trials 3 and 4)
(iii) two replicate, placebo- and active- ] 12 mcg twice-daily] controlled, 6-week cross-over trials (Trials 5 and 6)
(iv) two replicate, placebo- and active- ] 18 mcg once-daily] controlled, 6-week cross-over trials (Trials 7 and 8).
- These eight trials enrolled patients who were 40 years of age or older with a clinical diagnosis of COPD, a smoking history of at least 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal and a post-bronchodilator FEV1 to FVC ratio of less than 70%).
- The majority of the 3104 patients in the 48-week trials (Trials 1 and 2, Trials 3 and 4) were male (77%), white (66%) or Asian (32%), with a mean age of 64 years. Mean post-bronchodilator FEV1 was 1.38 L (GOLD II , GOLD III , GOLD IV ). Mean beta2-agonist responsiveness was 15% of baseline (0.16 L). With the exception of other LABAs, all pulmonary medications were allowed as concomitant therapy (e.g., tiotropium , ipratropium , inhaled corticosteroids , xanthines ); patient enrollment was stratified by tiotropium use. In all four trials, the primary efficacy endpoints were change from pre-treatment baseline in FEV1 AUC0-3 and trough (pre-dose) FEV1 (after 12 weeks in Trials 1 and 2; after 24 weeks in Trials 3 and 4).
- In all four 48-week trials, STRIVERDI RESPIMAT 5 mcg demonstrated significant improvements in FEV1 AUC 0-3hr compared to placebo at week 12 (Table 2) and at week 24. In the four 48-week trials, STRIVERDI RESPIMAT 5 mcg demonstrated significant improvements in trough FEV1 compared to placebo at week 12 (Table 2; 3 of 4 trials) and at week 24 (4 trials). STRIVERDI RESPIMAT 5 mcg demonstrated a bronchodilatory treatment effect at 5 minutes after the first dose with a mean increase in FEV1 compared to placebo of 0.11L (range: 0.10L to 0.12L). The 10 mcg dose demonstrated no additional benefit over the 5 mcg dose (data not shown). Patients treated with STRIVERDI RESPIMAT 5 mcg used less rescue albuterol compared to patients treated with placebo.
- In Trials 1 and 2, serial spirometric evaluations were performed pre-dose and up to 12 hours after dosing in a sub-group of 562 patients (201 patients receiving STRIVERDI RESPIMAT 5 mcg, 192 patients receiving 10 mcg, and 169 patients receiving placebo) after 12 weeks of treatment. Dosing occurred at approximately the same time of the day in the morning. The spirometric curves from Trial 1 are displayed in Figure 2.
- The bronchodilatory profile of STRIVERDI RESPIMAT 5 mcg over the 24 hour dosing interval was evaluated in two pairs of replicate, placebo- and active-controlled, 6 week cross-over trials in 199 patients (Trials 5 and 6) and 230 patients (Trials 7 and 8) with moderate to very severe COPD. Mean beta2-agonist responsiveness ranged from 14% -21% of baseline (0.18 to 0.22 L). All pulmonary medications were allowed as concomitant therapy with the exception of other LABAs (all trials) and anti-cholinergics (Trials 7 and 8). In all four trials, the primary endpoints were change from pre-treatment baseline in FEV1 AUC0-12hr and FEV1 AUC12-24hr after 6 weeks; although not a primary endpoint, trough FEV1 was also measured after 6 weeks. Results are shown in Table 3.
- The STRIVERDI RESPIMAT cartridge is an aluminum cylinder with a tamper protection seal on the cap. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler.
- The STRIVERDI RESPIMAT inhaler is a cylindrical-shaped plastic inhalation device with a gray-colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The yellow colored cap and the written information on the label of the gray inhaler body indicates that it is labeled for use with the STRIVERDI RESPIMAT cartridge.
- STRIVERDI RESPIMAT Inhalation Spray is available as:
- STRIVERDI RESPIMAT Inhalation Spray: 60 metered actuations (NDC 0597-0192-61)
- STRIVERDI RESPIMAT Inhalation Spray: 28 metered actuations (NDC 0597-0192-31) (institutional pack)
- The STRIVERDI RESPIMAT cartridge has a net fill weight of at least 4 grams and when used with the STRIVERDI RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations (60 or 28) after preparation for use; which is respectively equivalent to 30 or 14 days of medication when used according to the directions for use (one dose equals two actuations).
- When the labeled number of metered actuations (60 or 28) has been dispensed from the inhaler, the STRIVERDI RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.
- After assembly, the STRIVERDI RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.
- Keep out of reach of children. Do not spray into eyes.
- Storage
- Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). Avoid freezing.
- Inform patients that LABA, such as STRIVERDI RESPIMAT, increase the risk of asthma-related death. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.
- Preparation for Use and Priming
- Instruct patients that priming STRIVERDI RESPIMAT is essential to ensure appropriate content of the medication in each actuation.
- When using the unit for the first time, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. STRIVERDI RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- Not for Acute Symptoms
- STRIVERDI RESPIMAT is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)
- Instruct patients to notify their physician immediately if they experience any of the following:
Worsening of symptoms
Decreasing effectiveness of inhaled, short-acting beta2-agonists
Need for more inhalations than usual of inhaled, short-acting beta2-agonists
Significant decrease in lung function as outlined by the physician
- Worsening of symptoms
- Decreasing effectiveness of inhaled, short-acting beta2-agonists
- Need for more inhalations than usual of inhaled, short-acting beta2-agonists
- Significant decrease in lung function as outlined by the physician
- Instruct patients not to stop therapy with STRIVERDI RESPIMAT without physician/provider guidance since symptoms may recur after discontinuation.
- Do Not Use Additional Long-Acting Beta2-Agonists
- Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.
- When patients are prescribed STRIVERDI RESPIMAT, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once-daily dose of STRIVERDI RESPIMAT. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
- Risks Associated with Beta2-Agonist Therapy
- Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
- ↑ "STRIVERDI RESPIMAT olodaterol respimat inhalation spray spray, metered"..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} | Olodaterol
- Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large, placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including olodaterol, the active ingredient in STRIVERDI RESPIMAT. The safety and efficacy of STRIVERDI RESPIMAT in patients with asthma have not been established. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.
- The recommended dose of STRIVERDI RESPIMAT is two inhalations once-daily at the same time of the day. Do not use STRIVERDI RESPIMAT more than two inhalations every 24 hours.
- Prior to first use, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally-impaired patients. There are no data available for use of STRIVERDI RESPIMAT in severe hepatically impaired patients.
- Asthma-Related Death
- Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.
- A 28-week, placebo-controlled US study comparing the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of long-acting beta2-adrenergic agonists, including STRIVERDI RESPIMAT. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with STRIVERDI RESPIMAT has been conducted. The safety and efficacy of STRIVERDI RESPIMAT in patients with asthma have not been established. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.
- Deterioration of Disease and Acute Episodes
- STRIVERDI RESPIMAT should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. STRIVERDI RESPIMAT has not been studied in patients with acutely deteriorating COPD. The use of STRIVERDI RESPIMAT in this setting is inappropriate.
- STRIVERDI RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STRIVERDI RESPIMAT has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.
- When beginning STRIVERDI RESPIMAT, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing STRIVERDI RESPIMAT, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
- COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If STRIVERDI RESPIMAT no longer controls symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of STRIVERDI RESPIMAT beyond the recommended dose is not appropriate in this situation.
- Excessive Use of STRIVERDI RESPIMAT and Use with Long-Acting Beta2-Agonists
- As with other inhaled drugs containing beta2-adrenergic agents, STRIVERDI RESPIMAT should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
- Paradoxical Bronchospasm
- As with other inhaled beta2-agonists, STRIVERDI RESPIMAT may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, STRIVERDI RESPIMAT should be discontinued immediately and alternative therapy instituted.
- Cardiovascular Effects
- STRIVERDI RESPIMAT, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms. If such effects occur, STRIVERDI RESPIMAT may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Long acting beta2-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension.
- Co-existing Conditions
- STRIVERDI RESPIMAT, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
- Hypokalemia and Hyperglycemia
- Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.
- In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility for cardiac arrhythmias.
- Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of STRIVERDI RESPIMAT with the rates similar to those for placebo controls. STRIVERDI RESPIMAT has not been investigated in patients whose diabetes mellitus is not well controlled.
- Hypersensitivity Reactions
- Immediate hypersensitivity reactions, including angioedema, may occur after administration of STRIVERDI RESPIMAT. If such a reaction occurs, therapy with STRIVERDI RESPIMAT should be stopped at once and alternative treatment should be considered.
- The STRIVERDI RESPIMAT clinical development program included seven dose-ranging trials and eight confirmatory trials. Four of the confirmatory trials were 6-week cross-over trials and four were 48-week parallel group trials. Adverse reactions observed in the dose-ranging trials and four 6-week cross-over trials were consistent with those observed in the 48-week parallel group trials, which formed the primary safety database.
- The primary safety database consisted of pooled data from the four 48-week double-blind, active and placebo-controlled, parallel group confirmatory clinical trials. These trials included 3104 adult COPD patients (77% males and 23% females) 40 years of age and older. Of these patients, 876 and 883 patients were treated with STRIVERDI RESPIMAT 5 mcg and 10 mcg once-daily, respectively. The STRIVERDI RESPIMAT groups were composed of mostly Caucasians (66%) with a mean age of 64 years and a mean percent predicted FEV1 at baseline of 44% for both the 5 mcg and 10 mcg treatment groups. Control arms for comparison included placebo in all four trials plus formoterol 12 mcg in two trials.
- In these four clinical trials, seventy-two percent (72%) of patients exposed to any dose of STRIVERDI RESPIMAT reported an adverse reaction compared to 71% in the placebo group. The proportion of patients who discontinued due to an adverse reaction was 7.2% for STRIVERDI RESPIMAT treated patients compared to 8.8% for placebo treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD. The most common serious adverse reactions were COPD exacerbation, pneumonia, and atrial fibrillation.
- Table 1 shows all adverse drug reactions reported by at least 2% of patients (and higher than placebo) who received STRIVERDI RESPIMAT 5 mcg during the 48-week trials.
- Additional adverse reactions that occurred in greater than 2% (and higher than placebo) of patients exposed to STRIVERDI RESPIMAT 10 mcg were pneumonia, constipation, and pyrexia.
- Lung cancers were reported in 6 (0.7%), 3 (0.3%), and 2 (0.2%) patients who received STRIVERDI RESPIMAT 10 mcg, 5 mcg, and placebo, respectively.
- If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of STRIVERDI RESPIMAT may be potentiated.
- Xanthine Derivatives, Steroids, or Diuretics
- Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of STRIVERDI RESPIMAT.
- Non-Potassium Sparing Diuretics
- The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium-sparing diuretics.
- Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs
- STRIVERDI RESPIMAT, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
- Beta-Blockers
- Beta-adrenergic receptor antagonists (beta-blockers) and STRIVERDI RESPIMAT may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
- Inhibitors of Cytochrome P450 and P-gp Efflux Transporter
- In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of maximum plasma concentrations and AUC was observed. STRIVERDI RESPIMAT was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment is necessary.
- There are no adequate and well-controlled studies with STRIVERDI RESPIMAT in pregnant women. STRIVERDI RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- STRIVERDI RESPIMAT was not teratogenic in rats at inhalation doses approximately 2,731 times the maximum recommended human daily inhalation dose (MRHDID) on an AUC basis (at a rat maternal inhalation dose of 1,054 mcg/kg/day). Placental transfer of STRIVERDI RESPIMAT was observed in pregnant rats.
- STRIVERDI RESPIMAT has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHDID in adults on an AUC basis (at a rabbit maternal inhalation dose of 2,489 mcg/kg/day). STRIVERDI RESPIMAT exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at an inhalation dose approximately 1,353 times the MRHDID in adults on an AUC basis (at a rabbit maternal inhalation dose of 974 mcg/kg/day).
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olodaterol in women who are pregnant.
- Of the 876 patients who received STRIVERDI RESPIMAT at the recommended dose of 5 mcg once-daily in the clinical studies from the pooled 1-year database, 485 were less than or equal to 65 years of age and 391 (44.6%) were greater than 65 years of age.
- No overall differences in effectiveness were observed, and in the 1-year pooled data, the adverse drug reaction profiles were similar in the older population compared to the patient population overall.
### Signs and Symptoms
- The expected signs and symptoms with overdosage of STRIVERDI RESPIMAT are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of STRIVERDI RESPIMAT.
### Management
- Treatment of overdosage consists of discontinuation of STRIVERDI RESPIMAT together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of STRIVERDI RESPIMAT. Cardiac monitoring is recommended in cases of overdosage.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Olodaterol in the drug label.
- Beta-adrenoceptors are divided into three subtypes: beta1-adrenoceptors predominantly expressed on cardiac smooth muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle, and beta3-adrenoceptors predominantly expressed on adipose tissue. Beta2-agonists cause bronchodilation. Although the beta2-adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle, it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart. The precise function of beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-agonists may have cardiac effects.
- The structural formula is:
- The drug product, STRIVERDI RESPIMAT, is composed of a sterile, aqueous solution of olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STRIVERDI RESPIMAT cartridge) for use with the STRIVERDI RESPIMAT inhaler.
- Excipients include water for injection, benzalkonium chloride, edetate disodium, and anhydrous citric acid. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler. The STRIVERDI RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The STRIVERDI RESPIMAT inhaler has a yellow-colored cap.
- When used with the STRIVERDI RESPIMAT inhaler, each cartridge containing a minimum of 4 grams of a sterile aqueous solution, delivers 60 (or 28) metered actuations after preparation for use, the equivalent of 30 days’ or 14 days’ medication when used as two actuations once a day. Each dose (1 dose equals 2 actuations) from the STRIVERDI RESPIMAT inhaler delivers 5 mcg olodaterol in 22.1 mcL of solution from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).
- Prior to first use, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. When using for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- The major adverse effects of inhaled beta2-adrenergic agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium, and increases in plasma glucose.
- Changes in serum potassium were evaluated in COPD patients in double-blind phase 3 studies. In pooled data, at the recommended 5 mcg dose there was no clinically relevant change compared to placebo in serum potassium.
- Electrophysiology
- The effect of STRIVERDI RESPIMAT on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomized, placebo- and active (moxifloxacin)- controlled study at single doses of 10, 20, 30, and 50 mcg. Dose-dependent QTcI (individual subject corrected QT interval) prolongation was observed. The maximum mean (one-sided 95% upper confidence bound) difference in QTcI from placebo after baseline correction was 2.5 (5.6) ms, 6.1 (9.2) ms, 7.5 (10.7) ms and 8.5 (11.6) ms following doses of 10, 20, 30 and 50 mcg, respectively.
- The effect of 5 mcg and 10 mcg STRIVERDI RESPIMAT on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between STRIVERDI RESPIMAT 5 mcg, 10 mcg, and placebo.
- Absorption
- Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.
- Distribution
- Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.
- Metabolism
- Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose.
- Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.
- Elimination
- Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. However, the effective half-life at daily dose of 5 μg calculated from Cmax from COPD patients is 7.5 hours.
- Following intravenous administration of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5% to 7% of the dose.
- Special Populations
- A pharmacokinetic meta-analysis showed that no dose adjustment is necessary based on the effect of age, gender, and weight on systemic exposure in COPD patients after inhalation of STRIVERDI RESPIMAT.
- Renal Impairment
- Olodaterol levels were increased by approximately 40% in subjects with severe renal impairment. A study in subjects with mild and moderate renal impairment was not performed.
- Hepatic Impairment
- Subjects with mild and moderate hepatic impairment showed no changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. A study in subjects with severe hepatic impairment was not performed.
- Drug-Drug Interactions
- Drug-drug interaction studies were carried out using fluconazole as a model inhibitor of CYP 2C9 and ketoconazole as a potent P-gp (and CYP3A4, 2C8, 2C9) inhibitor.
- Fluconazole: Co-administration of 400 mg fluconazole once a day for 14 days had no relevant effect on systemic exposure to olodaterol.
- Ketoconazole: Co-administration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.
- Tiotropium: Co-administration of tiotropium bromide, delivered as fixed-dose combination with olodaterol, for 21 days had no relevant effect on systemic exposure to olodaterol, and vice versa.
- Olodaterol was not mutagenic in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of micronuclei in rats after intravenous doses. The increased frequency of micronuclei was likely related to drug enhanced (compensatory) erythropoiesis. The mechanism for induction of micronuclei formation is likely not relevant at clinical exposures.
- Olodaterol did not impair male or female fertility in rats at inhalation doses up to 3,068 mcg/kg/day (approximately 2,322 times the MRHDID on an AUC basis).
- Dose-ranging trials
- The first COPD dose-ranging trial was a randomized, double-blind, placebo-controlled, single-dose, 5-way cross-over trial in 36 patients. Results demonstrated dose-related improvements in forced expiratory volume in one second (FEV1) compared to placebo. The difference in trough FEV1 from placebo for the 2, 5, 10, and 20 mcg doses were 0.07L (95% CI 0.03, 0.11), 0.10L (0.06, 0.14), 0.11L (0.07, 0.15), and 0.12L (0.08, 0.16), respectively. The second COPD dose-ranging trial was a 4-week, randomized, double-blind, placebo-controlled, parallel group trial in 405 patients. Dose-related improvements in lung function were also seen, with no added benefit of the 20 mcg dose over the 10 mcg dose (Figure 1). The third COPD dose-ranging trial was a randomized, double-blind, 4-way cross-over, dose-regimen trial in 47 patients. Treatment arms included 2 mcg twice-daily, 5 mcg once-daily, 5 mcg twice-daily, and 10 mcg once-daily. There was no clear difference in treatment effect when comparing twice-daily dosing to once-daily dosing.
- Four randomized, double-blind, placebo-controlled dose-ranging trials were performed in patients with asthma, evaluating doses from 2 to 20 mcg. Results from patients with asthma were consistent with results from dose-ranging trials in patients with COPD.
- STRIVERDI RESPIMAT is not indicated for asthma.
- Based upon the results of the dose-ranging trials, 5 and 10 mcg doses were further evaluated in the confirmatory COPD trials.
- Confirmatory Trials
- The eight confirmatory trials in the STRIVERDI RESPIMAT clinical development program were four pairs of replicate, randomized, double-blind, placebo-controlled trials in 3533 COPD patients (1281 received the 5 mcg dose, 1284 received the 10 mcg dose):
(i) two replicate, placebo-controlled, parallel group, 48 week trials (Trials 1 and 2)
(ii) two replicate, placebo- and active- [[[formoterol]] 12 mcg twice-daily] controlled, parallel group, 48-week trials (Trials 3 and 4)
(iii) two replicate, placebo- and active- [[[formoterol]] 12 mcg twice-daily] controlled, 6-week cross-over trials (Trials 5 and 6)
(iv) two replicate, placebo- and active- [[[tiotropium bromide]] 18 mcg once-daily] controlled, 6-week cross-over trials (Trials 7 and 8).
- These eight trials enrolled patients who were 40 years of age or older with a clinical diagnosis of COPD, a smoking history of at least 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal [GOLD II – IV] and a post-bronchodilator FEV1 to FVC ratio of less than 70%).
- The majority of the 3104 patients in the 48-week trials (Trials 1 and 2, Trials 3 and 4) were male (77%), white (66%) or Asian (32%), with a mean age of 64 years. Mean post-bronchodilator FEV1 was 1.38 L (GOLD II [50%], GOLD III [40%], GOLD IV [10%]). Mean beta2-agonist responsiveness was 15% of baseline (0.16 L). With the exception of other LABAs, all pulmonary medications were allowed as concomitant therapy (e.g., tiotropium [24%], ipratropium [25%], inhaled corticosteroids [45%], xanthines [16%]); patient enrollment was stratified by tiotropium use. In all four trials, the primary efficacy endpoints were change from pre-treatment baseline in FEV1 AUC0-3 and trough (pre-dose) FEV1 (after 12 weeks in Trials 1 and 2; after 24 weeks in Trials 3 and 4).
- In all four 48-week trials, STRIVERDI RESPIMAT 5 mcg demonstrated significant improvements in FEV1 AUC 0-3hr compared to placebo at week 12 (Table 2) and at week 24. In the four 48-week trials, STRIVERDI RESPIMAT 5 mcg demonstrated significant improvements in trough FEV1 compared to placebo at week 12 (Table 2; 3 of 4 trials) and at week 24 (4 trials). STRIVERDI RESPIMAT 5 mcg demonstrated a bronchodilatory treatment effect at 5 minutes after the first dose with a mean increase in FEV1 compared to placebo of 0.11L (range: 0.10L to 0.12L). The 10 mcg dose demonstrated no additional benefit over the 5 mcg dose (data not shown). Patients treated with STRIVERDI RESPIMAT 5 mcg used less rescue albuterol compared to patients treated with placebo.
- In Trials 1 and 2, serial spirometric evaluations were performed pre-dose and up to 12 hours after dosing in a sub-group of 562 patients (201 patients receiving STRIVERDI RESPIMAT 5 mcg, 192 patients receiving 10 mcg, and 169 patients receiving placebo) after 12 weeks of treatment. Dosing occurred at approximately the same time of the day in the morning. The spirometric curves from Trial 1 are displayed in Figure 2.
- The bronchodilatory profile of STRIVERDI RESPIMAT 5 mcg over the 24 hour dosing interval was evaluated in two pairs of replicate, placebo- and active-controlled, 6 week cross-over trials in 199 patients (Trials 5 and 6) and 230 patients (Trials 7 and 8) with moderate to very severe COPD. Mean beta2-agonist responsiveness ranged from 14% -21% of baseline (0.18 to 0.22 L). All pulmonary medications were allowed as concomitant therapy with the exception of other LABAs (all trials) and anti-cholinergics (Trials 7 and 8). In all four trials, the primary endpoints were change from pre-treatment baseline in FEV1 AUC0-12hr and FEV1 AUC12-24hr after 6 weeks; although not a primary endpoint, trough FEV1 was also measured after 6 weeks. Results are shown in Table 3.
- The STRIVERDI RESPIMAT cartridge is an aluminum cylinder with a tamper protection seal on the cap. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler.
- The STRIVERDI RESPIMAT inhaler is a cylindrical-shaped plastic inhalation device with a gray-colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The yellow colored cap and the written information on the label of the gray inhaler body indicates that it is labeled for use with the STRIVERDI RESPIMAT cartridge.
- STRIVERDI RESPIMAT Inhalation Spray is available as:
- STRIVERDI RESPIMAT Inhalation Spray: 60 metered actuations (NDC 0597-0192-61)
- STRIVERDI RESPIMAT Inhalation Spray: 28 metered actuations (NDC 0597-0192-31) (institutional pack)
- The STRIVERDI RESPIMAT cartridge has a net fill weight of at least 4 grams and when used with the STRIVERDI RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations (60 or 28) after preparation for use; which is respectively equivalent to 30 or 14 days of medication when used according to the directions for use (one dose equals two actuations).
- When the labeled number of metered actuations (60 or 28) has been dispensed from the inhaler, the STRIVERDI RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.
- After assembly, the STRIVERDI RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.
- Keep out of reach of children. Do not spray into eyes.
- Storage
- Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). Avoid freezing.
- Inform patients that LABA, such as STRIVERDI RESPIMAT, increase the risk of asthma-related death. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.
- Preparation for Use and Priming
- Instruct patients that priming STRIVERDI RESPIMAT is essential to ensure appropriate content of the medication in each actuation.
- When using the unit for the first time, the STRIVERDI RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. STRIVERDI RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
- Not for Acute Symptoms
- STRIVERDI RESPIMAT is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)
- Instruct patients to notify their physician immediately if they experience any of the following:
Worsening of symptoms
Decreasing effectiveness of inhaled, short-acting beta2-agonists
Need for more inhalations than usual of inhaled, short-acting beta2-agonists
Significant decrease in lung function as outlined by the physician
- Worsening of symptoms
- Decreasing effectiveness of inhaled, short-acting beta2-agonists
- Need for more inhalations than usual of inhaled, short-acting beta2-agonists
- Significant decrease in lung function as outlined by the physician
- Instruct patients not to stop therapy with STRIVERDI RESPIMAT without physician/provider guidance since symptoms may recur after discontinuation.
- Do Not Use Additional Long-Acting Beta2-Agonists
- Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.
- When patients are prescribed STRIVERDI RESPIMAT, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once-daily dose of STRIVERDI RESPIMAT. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
- Risks Associated with Beta2-Agonist Therapy
- Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
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974cf8fb0aa91b2df5b38bcc98e66b63acdd68f5 | wikidoc | Olsalazine | Olsalazine
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# Overview
Olsalazine is a Salicylate that is FDA approved for the treatment of ulcerative colitis. Common adverse reactions include Abdominal pain, Diarrhea, Indigestion, Nausea, Headache, Blurred vision.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Olsalazine is indicated for the maintenance of remission of ulcerative colitis in patients who are intolerant of sulfasalazine.
### Dosage
- The usual dosage in adults for maintenance of remission is 1.0 g/day in two divided doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olsalazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olsalazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Olsalazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olsalazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olsalazine in pediatric patients.
# Contraindications
- Hypersensitivity to olsalazine, other salicylates, or any of the excipients.
# Warnings
### Precautions
- Overall, approximately 17% of subjects receiving olsalazine in clinical studies reported diarrhea sometime during therapy. This diarrhea resulted in withdrawal of treatment in 6% of patients. This diarrhea appears to be dose related, although it may be difficult to distinguish from the underlying symptoms of the disease.
- Exacerbation of the symptoms of colitis thought to have been caused by mesalamine or sulfasalazine has been noted.
- Patients should be instructed to take olsalazine with food. The drug should be taken in evenly divided doses. Patients should be informed that about 17% of subjects receiving olsalazine during clinical studies reported diarrhea sometime during therapy. If diarrhea occurs, patients should contact their physician.
# Adverse Reactions
## Clinical Trials Experience
- Olsalazine has been evaluated in ulcerative colitis patients in remission, as well as those with acute disease. Both sulfasalazine-tolerant and intolerant patients have been studied in controlled clinical trials. Overall, 10.4% of patients discontinued olsalazine because of an adverse experience compared with 6.7% of placebo patients. The most commonly reported adverse reactions leading to treatment withdrawal were diarrhea or loose stools (olsalazine 5.9%; placebo 4.8%), abdominal pain, and rash or itching (slightly more than 1% of patients receiving olsalazine). Other adverse reactions to olsalazine leading to withdrawal occurred in fewer than 1% of patients (TABLE 1).
- For those controlled studies, the comparative incidences of adverse reactions reported in 1% or more patients treated with olsalazine or placebo are provided in Table 2.
- Over 2,500 patients have been treated with olsalazine in various controlled and uncontrolled clinical studies. In these as well as in post-marketing experience, olsalazine was administered mainly to patients intolerant to sulfasalazine. There have been rare reports of the following adverse effects in patients receiving olsalazine. These were often difficult to distinguish from possible symptoms of the underlying disease or from the effects of prior and/or concomitant therapy. A causal relationship to the drug has not been demonstrated for some of these reactions.
- Anemia, Eosinophilia, Hemolytic anemia, Interstitial pulmonary disease, Leukopenia, Lymphopenia, Neutropenia, Reticulocytosis, Thrombocytopenia
- Chest pains, Heart block second degree, Myocarditis, Palpitations, Pericarditis, Peripheral edema, Shortness of breath, Tachycardia
- A patient who developed thyroid disease 9 days after starting DIPENTUM was given propranolol and radioactive iodine and subsequently developed shortness of breath and nausea. The patient died 5 days later with signs and symptoms of acute diffuse myocarditis.
- Tinnitus
- Dry eyes, Vision blurred, Watery eyes
- Abdominal pain (upper), Diarrhea with dehydration, Dry mouth, Epigastric discomfort, Flare in symptoms, Flatulence, Increased blood in stool, Pancreatitis, Rectal bleeding, Rectal discomfort
- In a double-blind, placebo-controlled study, increased frequency and severity of diarrhea were reported in patients randomized to olsalazine 500 mg B.I.D. with concomitant pelvic radiation.
- Rare cases of granulomatous hepatitis and nonspecific, reactive hepatitis have been reported in patients receiving olsalazine. Additionally, a patient developed mild cholestatic hepatitis during treatment with sulfasalazine and experienced the same symptoms two weeks later after the treatment was changed to olsalazine. Withdrawal of olsalazine led to complete recovery in these cases.
- Fever chills, Hot flashes, Irritability, Rigors
- Bronchospasm, Erythema nodosum
- ALT (SGPT) or AST (SGOT) elevated beyond the normal range.
- Muscle cramps
- Insomnia, Paraesthesia, Tremors
- Mood swings
- Dysuria, Hematuria, Interstitial nephritis, Nephrotic syndrome, Proteinuria, Urinary frequency
- Impotence, Menorrhagia
- Alopecia, Erythema, Photosensitivity reaction
- Hypertension, Orthostatic hypotension
## Postmarketing Experience
- The following events have been identified during post-approval use of products that contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:
- Aplastic anemia, Pancytopenia
- Pyrexia
- Hepatic enzyme increased, Hepatitis, Increased bilirubin
- Reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported.
- Myalgia
- Dyspnoea, Interstitial lung disease
- Angioneurotic oedema
- Paraesthesia
- Interstitial nephritis
# Drug Interactions
- The co-administration of salicylates and low molecular weight heparins or heparinoids may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Salicylates should be discontinued prior to the initiation of a low molecular weight heparin or heparinoid. If this is not possible, it is recommended to monitor patients closely for bleeding.
- Increased prothrombin time in patients taking concomitant warfarin has been reported.
- The co-administration of olsalazine and 6-mercaptopurine or thioguanine may result in an increased risk of myelosuppression. If co-administered with 6-mercaptopurine, it is recommended to use the lowest possible doses of each drug and to monitor the patient, especially for leukopenia. In case of co-administration with thioguanine, careful monitoring of blood counts is recommended.
- It is recommended not to give salicylates for six weeks after the varicella vaccine to avoid a possible increased risk of developing Reye’s syndrome.
- None known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Olsalazine has been shown to produce fetal developmental toxicity as indicated by reduced fetal weights, retarded ossifications, and immaturity of the fetal visceral organs when given during organogenesis to pregnant rats in doses 5 to 20 times the human dose (100 to 400 mg/kg).
- There are no adequate and well-controlled studies in pregnant women. Olsalazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olsalazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Olsalazine during labor and delivery.
### Nursing Mothers
- Small amounts of the active metabolite of olsalazine (5-ASA) may pass into breast milk. Harmful infant effects (diarrhea) have been reported when 5-ASA was used during breastfeeding. Unless the benefit of the treatment outweighs the risks, olsalazine should not be taken by breast-feeding women, or patients should be advised to discontinue breastfeeding if using olsalazine.
- Oral administration of olsalazine to lactating rats in doses 5 to 20 times the human dose produced growth retardation in their pups.
### Pediatric Use
- Safety and effectiveness in a pediatric population have not been established.
### Geriatic Use
- Clinical studies of DIPENTUM 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, elderly patients should be treated with caution due to the greater frequency of decreased hepatic, renal, or cardiac function, co-existence of other disease, as well as concomitant drug therapy.
### Gender
There is no FDA guidance on the use of Olsalazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Olsalazine with respect to specific racial populations.
### Renal Impairment
- Patients with impaired renal function should be monitored.
- Although renal abnormalities were not reported in clinical trials with olsalazine, there have been rare reports from post-marketing experience. Therefore, the possibility of renal tubular damage due to absorbed mesalamine or its n-acetylated metabolite, as noted in the ANIMAL TOXICOLOGY section must be kept in mind, particularly for patients with pre-existing renal disease. In these patients, monitoring with urinalysis, BUN, and creatinine determinations is advised.
### Hepatic Impairment
Patients with impaired hepatic function should be monitored
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Olsalazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Olsalazine in patients who are immunocompromised.
### Severe Allergies and/or Asthma
- Patients with severe allergies or asthma should be monitored for signs of worsening symptoms.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- If co-administered with 6-mercaptopurine, it is recommended to use the lowest possible doses of each drug and to monitor the patient, especially for leukopenia. In case of co-administration with thioguanine, careful monitoring of blood counts is recommended.
- Patients with severe allergies or asthma should be monitored for signs of worsening symptoms
- Patients with impaired renal function should be monitored.
- For patients with pre-existing renal disease monitoring with urinalysis, BUN, and creatinine determinations is advised.
- Patients with impaired hepatic function should be monitored
# IV Compatibility
There is limited information regarding IV Compatibility of Olsalazine in the drug label.
# Overdosage
- No overdosage has been reported in humans. The knowledge of overdosage is limited. Possible overdose symptoms include nausea, vomiting and diarrhea. It is recommended to check hematology, acid-base, electrolyte, liver and kidney status, and to provide supportive treatment. There is no specific antidote to DIPENTUM.
- Maximum single oral doses of 5g/kg in mice and rats and 2 g/kg in dogs were not lethal. Symptoms of acute toxicity were decreased motor activity and diarrhea in all species tested. In addition, vomiting was reported in dogs.
### DRUG ABUSE AND DEPENDENCY
- None reported.
- Drug dependence has not been reported with chronic administration of olsalazine.
# Pharmacology
## Mechanism of Action
- The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways (i.e., prostanoids) and through the lipoxygenase pathways (i.e., leukotrienes and hydroxyeicosatetraenoic acids ) is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.
## Structure
- The active ingredient in DIPENTUM Capsules (olsalazine sodium) is the sodium salt of a salicylate, disodium 3,3'-azobis (6-hydroxybenzoate) a compound that is effectively bioconverted to 5-aminosalicylic acid (5-ASA), which has anti-inflammatory activity in ulcerative colitis. Its empirical formula is C14H8N2Na2O6 with a molecular weight of 346.21.
- The structural formula is:
- Olsalazine sodium is a yellow crystalline powder, which melts with decomposition at 240°C. It is the sodium salt of a weak acid, soluble in water and DMSO, and practically insoluble in ethanol, chloroform, and ether. Olsalazine sodium has acceptable stability under acidic or basic conditions.
- DIPENTUM is supplied in hard gelatin capsules for oral administration. The inert ingredient in each 250 mg capsule of olsalazine sodium is magnesium stearate. The capsule shell contains the following inactive ingredients: black iron oxide, caramel, gelatin, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Olsalazine in the drug label.
## Pharmacokinetics
- After oral administration, olsalazine has limited systemic bioavailability. Based on oral and intravenous dosing studies, approximately 2.4% of a single 1.0 g oral dose is absorbed. Less than 1% of olsalazine is recovered in the urine. The remaining 98 to 99% of an oral dose will reach the colon, where each molecule is rapidly converted into two molecules of 5-aminosalicylic acid (5-ASA) by colonic bacteria and the low prevailing redox potential found in this environment. The liberated 5-ASA is absorbed slowly resulting in very high local concentrations in the colon.
- The conversion of olsalazine to mesalamine (5-ASA) in the colon is similar to that of sulfasalazine, which is converted into sulfapyridine and mesalamine. It is thought that the mesalamine component is therapeutically active in ulcerative colitis (A.K. Azad-Kahn et al, LANCET, 2: 892-895, 1977). The usual dose of sulfasalazine for maintenance of remission in patients with ulcerative colitis is 2 grams daily, which would provide approximately 0.8 grams of mesalamine to the colon. More than 0.9 grams of mesalamine would usually be made available in the colon from 1 gram of olsalazine.
- The pharmacokinetics of olsalazine are similar in both healthy volunteers and in patients with ulcerative colitis. Maximum serum concentrations of olsalazine appear after approximately 1 hour and, even after a 1.0 g single dose, are low (e.g., 1.6 to 6.2 µmol/L). Olsalazine has a very short serum half-life, approximately 0.9 hours. Olsalazine is more than 99% bound to plasma proteins. It does not interfere with protein binding of warfarin.The urinary recovery of olsalazine is below 1%. Total recovery of oral 14C-labeled olsalazine in animals and humans ranges from 90 to 97%. Approximately 0.1% of an oral dose of olsalazine is metabolized in the liver to olsalazine-O-sulfate (olsalazine-S). Olsalazine-S, in contrast to olsalazine has a half-life of 7 days. Olsalazine-S accumulates to steady state within 2 to 3 weeks.
- Patients on daily doses of 1.0 g olsalazine for 2 to 4 years show a stable plasma concentration of olsalazine-S (3.3 to 12.4 µmol/L). Olsalazine-S is more than 99% bound to plasma proteins. Its long half-life is mainly due to slow dissociation from the protein binding site. Less than 1% of both olsalazine and olsalazine-S appears undissociated in plasma.
- Serum concentrations of 5-ASA are detected after 4 to 8 hours. The peak levels of 5-ASA after an oral dose of 1.0 g olsalazine are low (i.e., 0 to 4.3 µmol/L). Of the total 5-ASA found in the urine, more than 90% is in the form of N-acetyl-5-ASA (Ac-5-ASA). Only small amounts of 5-ASA are detected.
- N-acetyl-5-ASA (Ac-5-ASA), the major metabolite of 5-ASA found in plasma and urine, is acetylated (deactivated) in at least two sites, the colonic epithelium and the liver. Ac-5-ASA is found in the serum, with peak values of 1.7 to 8.7 µmol/L after a single 1.0 g dose. Approximately 20% of the total 5-ASA is recovered in the urine, where it is found almost exclusively as Ac-5-ASA. The remaining 5-ASA is partially acetylated and is excreted in the feces. From fecal dialysis, the concentration of 5-ASA in the colon following olsalazine has been calculated to be 18 to 49 mmol/L. No accumulation of 5-ASA or Ac-5-ASA in plasma has been detected. 5-ASA and Ac-5-ASA are 74 and 81%, respectively, bound to plasma proteins.
## Nonclinical Toxicology
- In a two year oral rat carcinogenicity study, olsalazine was tested in male and female Wistar rats at daily doses of 200, 400, and 800 mg/kg/day (approximately 10 to 40 times the human maintenance dose, based on a patient weight of 50 kg and a human dose of 1 g). Urinary bladder transitional cell carcinomas were found in three male rats (6%, p=0.022, exact trend test) receiving 40 times the human dose and were not found in untreated male controls. In the same study, urinary bladder transitional cell carcinoma and papilloma occurred in 2 untreated control female rats (2%). No such tumors were found in any of the female rats treated at doses up to 40 times the human dose.
- In an eighteen month oral mouse carcinogenicity study, olsalazine was tested in male and female CD-1 mice at daily doses of 500, 1000, and 2000 mg/kg/day (approximately 25 to 100 times the human maintenance dose). Liver hemangiosarcomata were found in two male mice (4%) receiving olsalazine at 100 times the human dose, while no such tumor occurred in the other treated male mice groups or any of the treated female mice. The observed incidence of this tumor is within the 4% incidence in historical controls.
- Olsalazine was not mutagenic in in vitro Ames tests, mouse lymphoma cell mutation assays, human lymphocyte chromosomal aberration tests, or the in vivo rat bone marrow cell chromosomal aberration test.
- Olsalazine in a dose range of 100 to 400 mg/kg/day (approximately 5 to 20 times the human maintenance dose) did not influence the fertility of male or female rats. The oligospermia and infertility in men associated with sulfasalazine have not been reported with olsalazine.
- Preclinical subacute and chronic toxicity studies in rats have shown the kidney to be the major target organ of olsalazine toxicity. At an oral daily dose of 400 mg/kg or higher, olsalazine treatment produced nephritis and tubular necrosis in a 4-week study; interstitial nephritis and tubular calcinosis in a 6-month study, and renal fibrosis, mineralization, and transitional cell hyperplasia in a 1-year study.
# Clinical Studies
- Two controlled studies have demonstrated the efficacy of olsalazine as maintenance therapy in patients with ulcerative colitis. In the first, ulcerative colitis patients in remission were randomized to olsalazine 500 mg B.I.D. or placebo, and relapse rates for a six month period of time were compared. For the 52 patients randomized to olsalazine, 12 relapses occurred, while for the 49 placebo patients, 22 relapses occurred. This difference in relapse rates was significant (p<0.02).
- In the second study, 164 ulcerative colitis patients in remission were randomized to olsalazine 500 mg B.I.D. or sulfasalazine 1 gram B.I.D., and relapse rates were compared after six months. The relapse rate for olsalazine was 19.5% while that for sulfasalazine was 12.2%, a non-significant difference.
# How Supplied
- Beige colored capsules, containing 250 mg olsalazine sodium imprinted with “DIPENTUM® 250 mg” on the capsule shell, available as:
## Storage
- Store at 20-25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be instructed to take olsalazine with food. The drug should be taken in evenly divided doses. Patients should be informed that about 17% of subjects receiving olsalazine during clinical studies reported diarrhea sometime during therapy. If diarrhea occurs, patients should contact their physician.
# Precautions with Alcohol
- Alcohol-Olsalazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dipentum®
# Look-Alike Drug Names
There is limited information regarding Olsalazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Olsalazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Olsalazine is a Salicylate that is FDA approved for the treatment of ulcerative colitis. Common adverse reactions include Abdominal pain, Diarrhea, Indigestion, Nausea, Headache, Blurred vision.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Olsalazine is indicated for the maintenance of remission of ulcerative colitis in patients who are intolerant of sulfasalazine.
### Dosage
- The usual dosage in adults for maintenance of remission is 1.0 g/day in two divided doses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olsalazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olsalazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Olsalazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olsalazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olsalazine in pediatric patients.
# Contraindications
- Hypersensitivity to olsalazine, other salicylates, or any of the excipients.
# Warnings
### Precautions
- Overall, approximately 17% of subjects receiving olsalazine in clinical studies reported diarrhea sometime during therapy. This diarrhea resulted in withdrawal of treatment in 6% of patients. This diarrhea appears to be dose related, although it may be difficult to distinguish from the underlying symptoms of the disease.
- Exacerbation of the symptoms of colitis thought to have been caused by mesalamine or sulfasalazine has been noted.
- Patients should be instructed to take olsalazine with food. The drug should be taken in evenly divided doses. Patients should be informed that about 17% of subjects receiving olsalazine during clinical studies reported diarrhea sometime during therapy. If diarrhea occurs, patients should contact their physician.
# Adverse Reactions
## Clinical Trials Experience
- Olsalazine has been evaluated in ulcerative colitis patients in remission, as well as those with acute disease. Both sulfasalazine-tolerant and intolerant patients have been studied in controlled clinical trials. Overall, 10.4% of patients discontinued olsalazine because of an adverse experience compared with 6.7% of placebo patients. The most commonly reported adverse reactions leading to treatment withdrawal were diarrhea or loose stools (olsalazine 5.9%; placebo 4.8%), abdominal pain, and rash or itching (slightly more than 1% of patients receiving olsalazine). Other adverse reactions to olsalazine leading to withdrawal occurred in fewer than 1% of patients (TABLE 1).
- For those controlled studies, the comparative incidences of adverse reactions reported in 1% or more patients treated with olsalazine or placebo are provided in Table 2.
- Over 2,500 patients have been treated with olsalazine in various controlled and uncontrolled clinical studies. In these as well as in post-marketing experience, olsalazine was administered mainly to patients intolerant to sulfasalazine. There have been rare reports of the following adverse effects in patients receiving olsalazine. These were often difficult to distinguish from possible symptoms of the underlying disease or from the effects of prior and/or concomitant therapy. A causal relationship to the drug has not been demonstrated for some of these reactions.
- Anemia, Eosinophilia, Hemolytic anemia, Interstitial pulmonary disease, Leukopenia, Lymphopenia, Neutropenia, Reticulocytosis, Thrombocytopenia
- Chest pains, Heart block second degree, Myocarditis, Palpitations, Pericarditis, Peripheral edema, Shortness of breath, Tachycardia
- A patient who developed thyroid disease 9 days after starting DIPENTUM was given propranolol and radioactive iodine and subsequently developed shortness of breath and nausea. The patient died 5 days later with signs and symptoms of acute diffuse myocarditis.
- Tinnitus
- Dry eyes, Vision blurred, Watery eyes
- Abdominal pain (upper), Diarrhea with dehydration, Dry mouth, Epigastric discomfort, Flare in symptoms, Flatulence, Increased blood in stool, Pancreatitis, Rectal bleeding, Rectal discomfort
- In a double-blind, placebo-controlled study, increased frequency and severity of diarrhea were reported in patients randomized to olsalazine 500 mg B.I.D. with concomitant pelvic radiation.
- Rare cases of granulomatous hepatitis and nonspecific, reactive hepatitis have been reported in patients receiving olsalazine. Additionally, a patient developed mild cholestatic hepatitis during treatment with sulfasalazine and experienced the same symptoms two weeks later after the treatment was changed to olsalazine. Withdrawal of olsalazine led to complete recovery in these cases.
- Fever chills, Hot flashes, Irritability, Rigors
- Bronchospasm, Erythema nodosum
- ALT (SGPT) or AST (SGOT) elevated beyond the normal range.
- Muscle cramps
- Insomnia, Paraesthesia, Tremors
- Mood swings
- Dysuria, Hematuria, Interstitial nephritis, Nephrotic syndrome, Proteinuria, Urinary frequency
- Impotence, Menorrhagia
- Alopecia, Erythema, Photosensitivity reaction
- Hypertension, Orthostatic hypotension
## Postmarketing Experience
- The following events have been identified during post-approval use of products that contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:
- Aplastic anemia, Pancytopenia
- Pyrexia
- Hepatic enzyme increased, Hepatitis, Increased bilirubin
- Reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported.
- Myalgia
- Dyspnoea, Interstitial lung disease
- Angioneurotic oedema
- Paraesthesia
- Interstitial nephritis
# Drug Interactions
- The co-administration of salicylates and low molecular weight heparins or heparinoids may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Salicylates should be discontinued prior to the initiation of a low molecular weight heparin or heparinoid. If this is not possible, it is recommended to monitor patients closely for bleeding.
- Increased prothrombin time in patients taking concomitant warfarin has been reported.
- The co-administration of olsalazine and 6-mercaptopurine or thioguanine may result in an increased risk of myelosuppression. If co-administered with 6-mercaptopurine, it is recommended to use the lowest possible doses of each drug and to monitor the patient, especially for leukopenia. In case of co-administration with thioguanine, careful monitoring of blood counts is recommended.
- It is recommended not to give salicylates for six weeks after the varicella vaccine to avoid a possible increased risk of developing Reye’s syndrome.
- None known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Olsalazine has been shown to produce fetal developmental toxicity as indicated by reduced fetal weights, retarded ossifications, and immaturity of the fetal visceral organs when given during organogenesis to pregnant rats in doses 5 to 20 times the human dose (100 to 400 mg/kg).
- There are no adequate and well-controlled studies in pregnant women. Olsalazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olsalazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Olsalazine during labor and delivery.
### Nursing Mothers
- Small amounts of the active metabolite of olsalazine (5-ASA) may pass into breast milk. Harmful infant effects (diarrhea) have been reported when 5-ASA was used during breastfeeding. Unless the benefit of the treatment outweighs the risks, olsalazine should not be taken by breast-feeding women, or patients should be advised to discontinue breastfeeding if using olsalazine.
- Oral administration of olsalazine to lactating rats in doses 5 to 20 times the human dose produced growth retardation in their pups.
### Pediatric Use
- Safety and effectiveness in a pediatric population have not been established.
### Geriatic Use
- Clinical studies of DIPENTUM 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, elderly patients should be treated with caution due to the greater frequency of decreased hepatic, renal, or cardiac function, co-existence of other disease, as well as concomitant drug therapy.
### Gender
There is no FDA guidance on the use of Olsalazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Olsalazine with respect to specific racial populations.
### Renal Impairment
- Patients with impaired renal function should be monitored.
- Although renal abnormalities were not reported in clinical trials with olsalazine, there have been rare reports from post-marketing experience. Therefore, the possibility of renal tubular damage due to absorbed mesalamine or its n-acetylated metabolite, as noted in the ANIMAL TOXICOLOGY section must be kept in mind, particularly for patients with pre-existing renal disease. In these patients, monitoring with urinalysis, BUN, and creatinine determinations is advised.
### Hepatic Impairment
Patients with impaired hepatic function should be monitored
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Olsalazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Olsalazine in patients who are immunocompromised.
### Severe Allergies and/or Asthma
- Patients with severe allergies or asthma should be monitored for signs of worsening symptoms.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- If co-administered with 6-mercaptopurine, it is recommended to use the lowest possible doses of each drug and to monitor the patient, especially for leukopenia. In case of co-administration with thioguanine, careful monitoring of blood counts is recommended.
- Patients with severe allergies or asthma should be monitored for signs of worsening symptoms
- Patients with impaired renal function should be monitored.
- For patients with pre-existing renal disease monitoring with urinalysis, BUN, and creatinine determinations is advised.
- Patients with impaired hepatic function should be monitored
# IV Compatibility
There is limited information regarding IV Compatibility of Olsalazine in the drug label.
# Overdosage
- No overdosage has been reported in humans. The knowledge of overdosage is limited. Possible overdose symptoms include nausea, vomiting and diarrhea. It is recommended to check hematology, acid-base, electrolyte, liver and kidney status, and to provide supportive treatment. There is no specific antidote to DIPENTUM.
- Maximum single oral doses of 5g/kg in mice and rats and 2 g/kg in dogs were not lethal. Symptoms of acute toxicity were decreased motor activity and diarrhea in all species tested. In addition, vomiting was reported in dogs.
### DRUG ABUSE AND DEPENDENCY
- None reported.
- Drug dependence has not been reported with chronic administration of olsalazine.
# Pharmacology
## Mechanism of Action
- The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways (i.e., prostanoids) and through the lipoxygenase pathways (i.e., leukotrienes [LTs] and hydroxyeicosatetraenoic acids [HETEs]) is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.
## Structure
- The active ingredient in DIPENTUM Capsules (olsalazine sodium) is the sodium salt of a salicylate, disodium 3,3'-azobis (6-hydroxybenzoate) a compound that is effectively bioconverted to 5-aminosalicylic acid (5-ASA), which has anti-inflammatory activity in ulcerative colitis. Its empirical formula is C14H8N2Na2O6 with a molecular weight of 346.21.
- The structural formula is:
- Olsalazine sodium is a yellow crystalline powder, which melts with decomposition at 240°C. It is the sodium salt of a weak acid, soluble in water and DMSO, and practically insoluble in ethanol, chloroform, and ether. Olsalazine sodium has acceptable stability under acidic or basic conditions.
- DIPENTUM is supplied in hard gelatin capsules for oral administration. The inert ingredient in each 250 mg capsule of olsalazine sodium is magnesium stearate. The capsule shell contains the following inactive ingredients: black iron oxide, caramel, gelatin, and titanium dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Olsalazine in the drug label.
## Pharmacokinetics
- After oral administration, olsalazine has limited systemic bioavailability. Based on oral and intravenous dosing studies, approximately 2.4% of a single 1.0 g oral dose is absorbed. Less than 1% of olsalazine is recovered in the urine. The remaining 98 to 99% of an oral dose will reach the colon, where each molecule is rapidly converted into two molecules of 5-aminosalicylic acid (5-ASA) by colonic bacteria and the low prevailing redox potential found in this environment. The liberated 5-ASA is absorbed slowly resulting in very high local concentrations in the colon.
- The conversion of olsalazine to mesalamine (5-ASA) in the colon is similar to that of sulfasalazine, which is converted into sulfapyridine and mesalamine. It is thought that the mesalamine component is therapeutically active in ulcerative colitis (A.K. Azad-Kahn et al, LANCET, 2: 892-895, 1977). The usual dose of sulfasalazine for maintenance of remission in patients with ulcerative colitis is 2 grams daily, which would provide approximately 0.8 grams of mesalamine to the colon. More than 0.9 grams of mesalamine would usually be made available in the colon from 1 gram of olsalazine.
- The pharmacokinetics of olsalazine are similar in both healthy volunteers and in patients with ulcerative colitis. Maximum serum concentrations of olsalazine appear after approximately 1 hour and, even after a 1.0 g single dose, are low (e.g., 1.6 to 6.2 µmol/L). Olsalazine has a very short serum half-life, approximately 0.9 hours. Olsalazine is more than 99% bound to plasma proteins. It does not interfere with protein binding of warfarin.The urinary recovery of olsalazine is below 1%. Total recovery of oral 14C-labeled olsalazine in animals and humans ranges from 90 to 97%. Approximately 0.1% of an oral dose of olsalazine is metabolized in the liver to olsalazine-O-sulfate (olsalazine-S). Olsalazine-S, in contrast to olsalazine has a half-life of 7 days. Olsalazine-S accumulates to steady state within 2 to 3 weeks.
- Patients on daily doses of 1.0 g olsalazine for 2 to 4 years show a stable plasma concentration of olsalazine-S (3.3 to 12.4 µmol/L). Olsalazine-S is more than 99% bound to plasma proteins. Its long half-life is mainly due to slow dissociation from the protein binding site. Less than 1% of both olsalazine and olsalazine-S appears undissociated in plasma.
- Serum concentrations of 5-ASA are detected after 4 to 8 hours. The peak levels of 5-ASA after an oral dose of 1.0 g olsalazine are low (i.e., 0 to 4.3 µmol/L). Of the total 5-ASA found in the urine, more than 90% is in the form of N-acetyl-5-ASA (Ac-5-ASA). Only small amounts of 5-ASA are detected.
- N-acetyl-5-ASA (Ac-5-ASA), the major metabolite of 5-ASA found in plasma and urine, is acetylated (deactivated) in at least two sites, the colonic epithelium and the liver. Ac-5-ASA is found in the serum, with peak values of 1.7 to 8.7 µmol/L after a single 1.0 g dose. Approximately 20% of the total 5-ASA is recovered in the urine, where it is found almost exclusively as Ac-5-ASA. The remaining 5-ASA is partially acetylated and is excreted in the feces. From fecal dialysis, the concentration of 5-ASA in the colon following olsalazine has been calculated to be 18 to 49 mmol/L. No accumulation of 5-ASA or Ac-5-ASA in plasma has been detected. 5-ASA and Ac-5-ASA are 74 and 81%, respectively, bound to plasma proteins.
## Nonclinical Toxicology
- In a two year oral rat carcinogenicity study, olsalazine was tested in male and female Wistar rats at daily doses of 200, 400, and 800 mg/kg/day (approximately 10 to 40 times the human maintenance dose, based on a patient weight of 50 kg and a human dose of 1 g). Urinary bladder transitional cell carcinomas were found in three male rats (6%, p=0.022, exact trend test) receiving 40 times the human dose and were not found in untreated male controls. In the same study, urinary bladder transitional cell carcinoma and papilloma occurred in 2 untreated control female rats (2%). No such tumors were found in any of the female rats treated at doses up to 40 times the human dose.
- In an eighteen month oral mouse carcinogenicity study, olsalazine was tested in male and female CD-1 mice at daily doses of 500, 1000, and 2000 mg/kg/day (approximately 25 to 100 times the human maintenance dose). Liver hemangiosarcomata were found in two male mice (4%) receiving olsalazine at 100 times the human dose, while no such tumor occurred in the other treated male mice groups or any of the treated female mice. The observed incidence of this tumor is within the 4% incidence in historical controls.
- Olsalazine was not mutagenic in in vitro Ames tests, mouse lymphoma cell mutation assays, human lymphocyte chromosomal aberration tests, or the in vivo rat bone marrow cell chromosomal aberration test.
- Olsalazine in a dose range of 100 to 400 mg/kg/day (approximately 5 to 20 times the human maintenance dose) did not influence the fertility of male or female rats. The oligospermia and infertility in men associated with sulfasalazine have not been reported with olsalazine.
- Preclinical subacute and chronic toxicity studies in rats have shown the kidney to be the major target organ of olsalazine toxicity. At an oral daily dose of 400 mg/kg or higher, olsalazine treatment produced nephritis and tubular necrosis in a 4-week study; interstitial nephritis and tubular calcinosis in a 6-month study, and renal fibrosis, mineralization, and transitional cell hyperplasia in a 1-year study.
# Clinical Studies
- Two controlled studies have demonstrated the efficacy of olsalazine as maintenance therapy in patients with ulcerative colitis. In the first, ulcerative colitis patients in remission were randomized to olsalazine 500 mg B.I.D. or placebo, and relapse rates for a six month period of time were compared. For the 52 patients randomized to olsalazine, 12 relapses occurred, while for the 49 placebo patients, 22 relapses occurred. This difference in relapse rates was significant (p<0.02).
- In the second study, 164 ulcerative colitis patients in remission were randomized to olsalazine 500 mg B.I.D. or sulfasalazine 1 gram B.I.D., and relapse rates were compared after six months. The relapse rate for olsalazine was 19.5% while that for sulfasalazine was 12.2%, a non-significant difference.
# How Supplied
- Beige colored capsules, containing 250 mg olsalazine sodium imprinted with “DIPENTUM® 250 mg” on the capsule shell, available as:
## Storage
- Store at 20-25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be instructed to take olsalazine with food. The drug should be taken in evenly divided doses. Patients should be informed that about 17% of subjects receiving olsalazine during clinical studies reported diarrhea sometime during therapy. If diarrhea occurs, patients should contact their physician.
# Precautions with Alcohol
- Alcohol-Olsalazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dipentum®[1]
# Look-Alike Drug Names
There is limited information regarding Olsalazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Olsalazine | |
d4491799f58130969654dadde5f890eca372cab6 | wikidoc | Omalizumab | Omalizumab
# Disclaimer
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# Black Box Warning
# Overview
Omalizumab is an anti-allergic and anti-asthmatic agent that is FDA approved for the treatment of allergic asthma and chronic idiopathic urticaria. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia, pain (general), leg pain, fatigue, dizziness, fracture, arm pain, pruritus, dermatitis, earache, nausea, nasopharyngitis, sinusitis, upper respiratory tract infection, viral upper respiratory tract infection, headache, and cough.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Administer Xolair 150 to 375 mg by subcutaneous (SC) injection every 2 or 4 weeks. Determine doses (mg) and dosing frequency by serum total IgE level (IU/mL), measured before the start of treatment, and body weight (kg). See the dose determination charts below (Table 1 and Table 2) for appropriate dose assignment.
- Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control.
### Dosing adjustments for Allergic Asthma
- Adjust doses for significant changes in body weight (see Table 1 and Table 2).
- Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination.
- Interruptions lasting less than one year: Dose based on serum IgE levels obtained at the initial dose determination.
- Interruptions lasting one year or more: Re-test total serum IgE levels for dose determination.
- Dosing Information
- Administer Xolair 150 or 300 mg by subcutaneous injection every 4 weeks.
- Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body weight.
- The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess the need for continued therapy.
- 150 mg of omalizumab as lyophilized, sterile powder in a single-use 5 mL vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omalizumab in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Doses of 150 or 300 mg every 3 to 4 weeks have been effective in adults and children with seasonal allergic rhinitis.
- Dosing Information
- Omalizumab 450 mg significantly increased the threshold of peanut sensitivity following an oral food challenge, compared with placebo in patients (12 to 60 years) with a history of peanut allergy in a randomized study.
- Dosing Information
- In a small randomized trial, omalizumab therapy was effective in reducing clinical symptoms of latex allergy compared with placebo in healthcare workers exposed to latex on a daily basis. Omalizumab was dosed according to body weight and serum IgE levels and ranged from 150 to 750 mg monthly.
- Dosing Information
- The dose of omalizumab is 0.016 mg/kg/IgE (international units/mL)/month subQ every 2 to 4 weeks, depending on weight and baseline IgE levels.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Xolair is not indicated for use in pediatric patients less than 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omalizumab in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Doses of 150 or 300 mg every 3 to 4 weeks have been effective in children with seasonal allergic rhinitis.
- Dosing Information
- Omalizumab 450 mg significantly increased the threshold of peanut sensitivity following an oral food challenge, compared with placebo in patients (12 to 60 years) with a history of peanut allergy in a randomized study.
- There is limited information regarding Off-Label Non-Guideline-Supported use of Omalizumab for Latex Allergy in pediatric patients.
- Dosing Information
- Preseasonal treatment with omalizumab in children and adolescents with seasonal allergic rhinitis decreases symptomatic days and rescue medication use. The dose of omalizumab was 0.016 mg/kg/IgE (international units/mL/month).
# Contraindications
The use of Xolair is contraindicated in the following:
Severe hypersensitivity reaction to Xolair or any ingredient of Xolair.
# Warnings
### Anaphylaxis
Anaphylaxis has been reported to occur after administration of Xolair in premarketing clinical trials and in postmarketing spontaneous reports. Signs and symptoms in these reported cases have included bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Some of these events have been life-threatening. In premarketing clinical trials in allergic asthma, anaphylaxis was reported in 3 of 3507 (0.1%) patients in clinical trials. Anaphylaxis occurred with the first dose of Xolair in two patients and with the fourth dose in one patient. The time to onset of anaphylaxis was 90 minutes after administration in two patients and 2 hours after administration in one patient. In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond one year after beginning regularly scheduled treatment.
Administer Xolair only in a healthcare setting by healthcare providers prepared to manage anaphylaxis that can be life-threatening. Observe patients closely for an appropriate period of time after administration of Xolair, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing spontaneous reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or symptoms occur.
Discontinue Xolair in patients who experience a severe hypersensitivity reaction.
### Malignancy
Malignant neoplasms were observed in 20 of 4127 (0.5%) Xolair-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents (≥ 12 years of age) with asthma and other allergic disorders. The observed malignancies in Xolair-treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types occurring once each. The majority of patients were observed for less than 1 year. The impact of longer exposure to Xolair or use in patients at higher risk for malignancy (e.g., elderly, current smokers) is not known.
### Acute Asthma Symptoms
Xolair has not been shown to alleviate asthma exacerbations acutely. Do not use Xolair to treat acute bronchospasm or status asthmaticus.
### Corticosteroid reduction
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of Xolair therapy for allergic asthma. Decrease corticosteroids gradually under the direct supervision of a physician. In CIU patients, the use of Xolair in combination with corticosteroids has not been evaluated.
### Eosiophilic Conditions
In rare cases, patients with asthma on therapy with Xolair may present with serious systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Xolair and these underlying conditions has not been established.
### Fever, Arthralgia and Rash
In post-approval use, some patients have experienced a constellation of signs and symptoms including arthritis/arthralgia, rash, fever and lymphadenopathy with an onset 1 to 5 days after the first or subsequent injections of Xolair. These signs and symptoms have recurred after additional doses in some patients. Although circulating immune complexes or a skin biopsy consistent with a Type III reaction were not seen with these cases, these signs and symptoms are similar to those seen in patients with serum sickness. Physicians should stop Xolair if a patient develops this constellation of signs and symptoms.
### Parasitic (Helminth) infection
Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment.
In a one-year clinical trial conducted in Brazil in patients at high risk for geohelminthic infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo controls. The point estimate of the odds ratio for infection was 1.96, with a 95% confidence interval (0.88, 4.36) indicating that in this study a patient who had an infection was anywhere from 0.88 to 4.36 times as likely to have received Xolair than a patient who did not have an infection. Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different between treatment groups.
### Laboratory Tests
Serum total IgE levels increase following administration of Xolair due to formation of Xolair:IgE complexes . Elevated serum total IgE levels may persist for up to 1 year following discontinuation of Xolair. Do not use serum total IgE levels obtained less than 1 year following discontinuation to reassess the dosing regimen for allergic asthma patients, because these levels may not reflect steady state free IgE levels.
# Adverse Reactions
## Clinical Trials Experience
### Clinical Trials Experience in Allergic Asthma:
Adult and Adolescent Patients 12 years of Age and Older
The data described below reflect Xolair exposure for 2076 adult and adolescent patients ages 12 and older, including 1687 patients exposed for six months and 555 exposed for one year or more, in either placebo-controlled or other controlled asthma studies. The mean age of patients receiving Xolair was 42 years, with 134 patients 65 years of age or older; 60% were women, and 85% Caucasian. Patients received Xolair 150 to 375 mg every 2 or 4 weeks or, for patients assigned to control groups, standard therapy with or without a placebo.
The adverse events most frequently resulting in clinical intervention (e.g., discontinuation of Xolair, or the need for concomitant medication to treat an adverse event) were injection site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These events were observed at similar rates in Xolair-treated patients and control patients.
Table 4 shows adverse reactions from four placebo-controlled asthma studies that occurred ≥ 1% and more frequently in patients receiving Xolair than in those receiving placebo. Adverse events were classified using preferred terms from the International Medical Nomenclature (IMN) dictionary. Injection site reactions were recorded separately from the reporting of other adverse events and are described following Table 4.
There were no differences in the incidence of adverse reactions based on age (among patients under 65), gender or race.
- Injection Site Reactions
- Injection site reactions of any severity occurred at a rate of 45% in Xolair-treated patients compared with 43% in placebo-treated patients. The types of injection site reactions included: bruising, redness, warmth, burning, stinging, itching, hive formation, pain, indurations, mass, and inflammation.
- Severe injection site reactions occurred more frequently in Xolair-treated patients compared with patients in the placebo group (12% versus 9%).
- The majority of injection site reactions occurred within 1 hour-post injection, lasted less than 8 days, and generally decreased in frequency at subsequent dosing visits.
### Clinical Trials Experience in Chronic Idiopathic Urticaria:
Adult and Adolescent Patients 12 years of Age and Older
The safety of Xolair for the treatment of CIU was assessed in three placebo-controlled, multiple-dose clinical studies of 12 weeks' (CIU Study 2) and 24 weeks' duration (CIU Studies 1 and 3). In CIU Studies 1 and 2, patients received Xolair 75, 150, or 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy throughout the treatment period. In CIU Study 3 patients were randomized to Xolair 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy. The data described below reflect Xolair exposure for 733 patients enrolled and receiving at least one dose of Xolair in the three clinical trials, including 684 patients exposed for 12 weeks and 427 exposed for 24 weeks. The mean age of patients receiving Xolair 300 mg was 43 years, 75% were women, and 89% were white. The demographic profiles for patients receiving Xolair 150 mg and 75 mg were similar.
Table 5 shows adverse events that occurred in ≥ 2% of patients receiving Xolair (150 or 300 mg) and more frequently than those receiving placebo. Adverse events are pooled from Study 2 and the first 12 weeks of Studies 1 and 3.
Additional events reported during the 24 week treatment period in Studies 1 and 3 included: toothache, fungal infection, urinary tract infection, myalgia, pain in extremity, musculoskeletal pain, peripheral edema, pyrexia, migraine, sinus headache, anxiety, oropharyngeal pain, asthma, urticaria, and alopecia.
- Injection Site Reactions
- Injection site reactions of any severity occurred during the studies in more Xolair-treated patients compared with 2 placebo-treated patients (0.8%). The types of injection site reactions included: swelling, erythema, pain, bruising, itching, bleeding and urticaria. None of the events resulted in study discontinuation or treatment interruption.
### Immunogenicity:
Antibodies to Xolair were detected in approximately 1/1723 (< 0.1%) of patients treated with Xolair in the clinical studies for approval of asthma. There were no detectable antibodies in the patients treated in the phase 3 CIU clinical trials, but due to levels of Xolair at the time of anti-therapeutic antibody sampling and missing samples for some patients, antibodies to Xolair could only have been determined in 88% of the 733 patients treated in these clinical studies. The data reflect the percentage of patients whose test results were considered positive for antibodies to Xolair in ELISA assays and are highly dependent on the sensitivity and specificity of the assays.
Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Xolair 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 Xolair in adult and adolescent patients 12 years of age and older. 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.
### Anaphylaxis:
Based on spontaneous reports and an estimated exposure of about 57,300 patients from June 2003 through December 2006, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients. Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to Xolair administration with no other identifiable cause. Signs and symptoms in these reported cases included bronchospasm, hypotension, syncope, urticaria, angioedema of the throat or tongue, dyspnea, cough, chest tightness, and/or cutaneous angioedema. Pulmonary involvement was reported in 89% of the cases. Hypotension or syncope was reported in 14% of cases. Fifteen percent of the reported cases resulted in hospitalization. A previous history of anaphylaxis unrelated to Xolair was reported in 24% of the cases.
Of the reported cases of anaphylaxis attributed to Xolair, 39% occurred with the first dose, 19% occurred with the second dose, 10% occurred with the third dose, and the rest after subsequent doses. One case occurred after 39 doses (after 19 months of continuous therapy, anaphylaxis occurred when treatment was restarted following a 3 month gap). The time to onset of anaphylaxis in these cases was up to 30 minutes in 35%, greater than 30 and up to 60 minutes in 16%, greater than 60 and up to 90 minutes in 2%, greater than 90 and up to 120 minutes in 6%, greater than 2 hours and up to 6 hours in 5%, greater than 6 hours and up to 12 hours in 14%, greater than 12 hours and up to 24 hours in 8%, and greater than 24 hours and up to 4 days in 5%. In 9% of cases the times to onset were unknown.
Twenty-three patients who experienced anaphylaxis were rechallenged with Xolair and 18 patients had a recurrence of similar symptoms of anaphylaxis. In addition, anaphylaxis occurred upon rechallenge with Xolair in 4 patients who previously experienced urticaria only.
### Eosinophilic Conditions:
Eosinophilic conditions have been reported.
### Fever, Arthralgia, and Rash:
A constellation of signs and symptoms including arthritis/arthralgia, rash (urticaria or other forms), fever and lymphadenopathy similar to serum sickness have been reported in post-approval use of Xolair.
Hematologic: Severe thrombocytopenia has been reported.
Skin: Hair loss has been reported.
# Drug Interactions
No formal drug interaction studies have been performed with Xolair.
In patients with allergic asthma the concomitant use of Xolair and allergen immunotherapy has not been evaluated.
In patients with CIU the use of Xolair in combination with immunosuppressive therapies has not been studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
### Pregnancy Category B:
Pregnancy Exposure Registry:
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Xolair during pregnancy. Encourage patients to call 1-866-4XOLAIR (1-866-496-5247) or visit www.xolairpregnancyregistry.com for information about the pregnancy exposure registry and the enrollment procedure.
Risk Summary:
Adequate and well-controlled studies with Xolair have not been conducted in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies, no evidence of fetal harm was observed in Cynomolgus monkeys with subcutaneous doses of omalizumab up to 10 times the maximum recommended human dose (MRHD).
Because animal reproduction studies are not always predictive of human response, Xolair should be used during pregnancy only if clearly needed.
Clinical Considerations:
In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
Data:
Animal Data:
Reproductive studies have been performed in Cynomolgus monkeys at subcutaneous doses of omalizumab up to 75 mg/kg (approximately 10 times the MRHD on a mg/kg basis). No evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when omalizumab was administered throughout organogenesis. Omalizumab did not elicit adverse effects on fetal or neonatal growth when administered throughout late gestation, delivery and nursing. Neonatal serum levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal serum level. Levels of omalizumab in milk were 0.15% of maternal serum concentration.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omalizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Omalizumab during labor and delivery.
### Nursing Mothers
It is not known whether Xolair is present in human breast milk; however, IgG is present in human milk in small amounts. In Cynomolgus monkeys, milk levels of omalizumab were measured at 0.15% of the maternal serum concentration . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Xolair and any potential adverse effects on the breastfed child from Xolair or from the underlying maternal condition. Exercise caution when administering Xolair to a nursing woman.
### Pediatric Use
### Allergic Asthma:
Safety and effectiveness of Xolair for allergic asthma were evaluated in 2 studies in 926 (Xolair 624; placebo 302) asthma patients 6 to <12 years of age. One study was a pivotal study of similar design and conduct to that of adult and adolescent Asthma Studies 1 and 2. The other study was primarily a safety study and included evaluation of efficacy as a secondary outcome. In the pivotal study, Xolair-treated patients had a statistically significant reduction in the rate of exacerbations (exacerbation was defined as worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose), but other efficacy variables such as nocturnal symptom scores, beta-agonist use, and measures of airflow (FEV1) were not significantly different in Xolair-treated patients compared to placebo. Considering the risk of anaphylaxis and malignancy seen in Xolair-treated patients ≥ 12 years old and the modest efficacy of Xolair in the pivotal pediatric study, the risk-benefit assessment does not support the use of Xolair in patients 6 to <12 years of age.
Although patients treated with Xolair in these two studies did not develop anaphylaxis or malignancy, the studies are not adequate to address these concerns because patients with a history of anaphylaxis or malignancy were excluded, and the duration of exposure and sample size were not large enough to exclude these risks in patients 6 to <12 years of age. Furthermore, there is no reason to expect that younger pediatric patients would not be at risk of anaphylaxis and malignancy seen in adult and adolescent patients with Xolair.
Studies in patients 0-5 years of age were not required because of the safety concerns of anaphylaxis and malignancy associated with the use of Xolair in adults and adolescents.
### Chronic Idiopathic Urticaria
The safety and effectiveness of Xolair for adolescent patients with CIU were evaluated in 39 patients 12 to 17 years of age (Xolair 29, placebo 10) included in three randomized, placebo-controlled CIU studies. A numerical decrease in weekly itch score was observed, and adverse reactions were similar to those reported in patients 18 years and older.
Clinical studies with Xolair have not been conducted in CIU patients below the age of 12 years. Considering the risk of anaphylaxis and malignancy seen in Xolair-treated patients ≥ 12 years old, the risk-benefit assessment does not support the use of Xolair in patients <12 years of age. Therefore, the use of Xolair in this patient population is not recommended.
### Geriatic Use
In clinical studies 134 allergic asthma patients and 37 CIU phase 3 study patients 65 years of age or older were treated with Xolair. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Omalizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Omalizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Omalizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Omalizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Omalizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Omalizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
- Prepare Xolair for subcutaneous injection using Sterile Water for Injection (SWFI), USP, ONLY. Each vial of Xolair is for single use only and contains no preservatives.
- Reconstitution
- The lyophilized product takes 15–20 minutes to dissolve. The fully reconstituted product will appear clear or slightly opalescent and it is acceptable if there are a few small bubbles or foam around the edge of the vial. The reconstituted product is somewhat viscous; in order to obtain the full 1.2 mL dose, ALL OF THE PRODUCT MUST BE WITHDRAWN from the vial before expelling any air or excess solution from the syringe.
- Use the solution within 8 hours following reconstitution when stored in the vial at 2–8°C (36–46°F), or within 4 hours of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from sunlight.
Preparation:
STEP 1: Draw 1.4 mL of SWFI, USP into a 3 mL syringe equipped with a 1 inch, 18-gauge needle.
STEP 2: Place the vial upright on a flat surface and using standard aseptic technique, insert the needle and inject the SWFI, USP directly onto the product.
STEP 3: Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to evenly wet the powder. Do not shake.
STEP 4: After completing STEP 3, gently swirl the vial for 5-10 seconds approximately every 5 minutes in order to dissolve any remaining solids. There should be no visible gel like particles in the solution. Do not use if foreign particles are present.
Note: If it takes longer than 20 minutes to dissolve completely, repeat STEP 4 until there are no visible gel-like particles in the solution. Do not use if the contents of the vial do not dissolve completely by 40 minutes.
STEP 5: Invert the vial for 15 seconds in order to allow the solution to drain toward the stopper. Using a new 3 mL syringe equipped with a 1-inch, 18-gauge needle, insert the needle into the inverted vial.
Position the needle tip at the very bottom of the solution in the vial stopper when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
STEP 6: Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection.
STEP 7: Expel air, large bubbles, and any excess solution in order to obtain the required 1.2 mL dose. A thin layer of small bubbles may remain at the top of the solution in the syringe.
- Administration
- Administer Xolair by subcutaneous injection. The injection may take 5-10 seconds to administer because the solution is slightly viscous. Each vial delivers 1.2 mL (150 mg) of Xolair. Do not administer more than 150 mg per injection site. Divide doses of more than 150 mg among two or more injection sites (Table 3).
### Monitoring
- Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment.
# IV Compatibility
There is limited information regarding IV Compatibility of Omalizumab in the drug label.
# Overdosage
The maximum tolerated dose of Xolair has not been determined. Single intravenous doses of up to 4,000 mg have been administered to patients without evidence of dose limiting toxicities. The highest cumulative dose administered to patients was 44,000 mg over a 20 week period, which was not associated with toxicities.
# Pharmacology
There is limited information regarding Omalizumab Pharmacology in the drug label.
## Mechanism of Action
- Allergic Asthma
- Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcεRI receptors on basophils in atopic patients.
- Chronic Idiopathic Urticaria
- Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells down-regulate. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unknown.
## Structure
- Xolair is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody has a molecular weight of approximately 149 kiloDaltons. Xolair is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.
- Xolair is a sterile, white, preservative free, lyophilized powder contained in a single use vial that is reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a subcutaneous (SC) injection. Each 202.5 mg vial of omalizumab also contains L-histidine (1.8 mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 20 (0.5 mg) and sucrose (145.5 mg) and is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.
## Pharmacodynamics
- Allergic Asthma
- In clinical studies, serum free IgE levels were reduced in a dose dependent manner within 1 hour following the first dose and maintained between doses. Mean serum free IgE decrease was greater than 96% using recommended doses. Serum total IgE levels (i.e., bound and unbound) increased after the first dose due to the formation of omalizumab:IgE complexes, which have a slower elimination rate compared with free IgE.
- At 16 weeks after the first dose, average serum total IgE levels were five-fold higher compared with pre-treatment when using standard assays. After discontinuation of Xolair dosing, the Xolair-induced increase in total IgE and decrease in free IgE were reversible, with no observed rebound in IgE levels after drug washout. Total IgE levels did not return to pre-treatment levels for up to one year after discontinuation of Xolair.
- Chronic Idiopathic Urticaria
- In clinical studies in CIU patients, Xolair treatment led to a dose-dependent reduction of serum free IgE and an increase of serum total IgE levels, similar to the observations in allergic asthma patients. Maximum suppression of free IgE was observed 3 days following the first subcutaneous dose. After repeat dosing once every 4 weeks, predose serum free IgE levels remained stable between 12 and 24 weeks of treatment. Total IgE levels in serum increased after the first dose due to the formation of omalizumab-IgE complexes which have a slower elimination rate compared with free IgE. After repeat dosing once every 4 weeks at 75 mg up to 300 mg, average predose serum total IgE levels at Week 12 were two-to three-fold higher compared with pre-treatment levels, and remained stable between 12 and 24 weeks of treatment. After discontinuation of Xolair dosing, free IgE levels increased and total IgE levels decreased towards pre-treatment levels over a 16-week follow-up period.
## Pharmacokinetics
After SC administration, omalizumab was absorbed with an average absolute bioavailability of 62%. Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses greater than 0.5 mg/kg. In patients with asthma, following multiple doses of Xolair, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose. In patients with CIU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as single subcutaneous dose. Following repeat dosing from 75 to 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose levels.
In vitro, omalizumab formed complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million daltons in molecular weight were not observed in vitro or in vivo. Tissue distribution studies in Cynomolgus monkeys showed no specific uptake of 125I-omalizumab by any organ or tissue. The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78 ± 32 mL/kg. In patients with CIU, based on population pharmacokinetics, distribution of omalizumab was similar to that in patients with asthma.
Clearance of omalizumab involved IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG included degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also excreted in bile. In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with Fcγ receptors within the RES at rates that were generally faster than IgG clearance. In asthma patients omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight approximately doubled apparent clearance. In CIU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days and apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).
### Special Populations
### Allergic Asthma
The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics in patients with allergic asthma. Analyses of these data suggested that no dose adjustments are necessary for age (12-76 years), race, ethnicity, or gender.
### Chronic Idiopathic Urticaria
The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure in patients with CIU. Covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (12 to 75 years), race/ethnicity, gender, body weight, body mass index or baseline IgE level.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies have been performed in animals to evaluate the carcinogenic potential of Xolair.
- There were no effects on fertility and reproductive performance in male and female Cynomolgus monkeys that received Xolair at subcutaneous doses up to 75 mg/kg/week (approximately 10 times the maximum recommended human dose on a mg/kg basis).
# Clinical Studies
### Allergic Asthma
Adult and Adolescent Patients 12 Years of Age and Older
The safety and efficacy of Xolair were evaluated in three randomized, double-blind, placebo-controlled, multicenter trials.
The trials enrolled patients 12 to 76 years old, with moderate to severe persistent (NHLBI criteria) asthma for at least one year, and a positive skin test reaction to a perennial aeroallergen. In all trials, Xolair dosing was based on body weight and baseline serum total IgE concentration. All patients were required to have a baseline IgE between 30 and 700 IU/mL and body weight not more than 150 kg. Patients were treated according to a dosing table to administer at least 0.016 mg/kg/IU (IgE/mL) of Xolair or a matching volume of placebo over each 4-week period. The maximum Xolair dose per 4 weeks was 750 mg.
In all three trials an exacerbation was defined as a worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose. Most exacerbations were managed in the out-patient setting and the majority were treated with systemic steroids. Hospitalization rates were not significantly different between Xolair and placebo-treated patients; however, the overall hospitalization rate was small. Among those patients who experienced an exacerbation, the distribution of exacerbation severity was similar between treatment groups.
Asthma Studies 1 and 2:
At screening, patients in Asthma Studies 1 and 2 had a forced expiratory volume in one second (FEV1) between 40% and 80% predicted. All patients had a FEV1 improvement of at least 12% following beta2-agonist administration. All patients were symptomatic and were being treated with inhaled corticosteroids (ICS) and short acting beta2-agonists. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.
Each study was comprised of a run-in period to achieve a stable conversion to a common ICS (beclomethasone dipropionate), followed by randomization to Xolair or placebo. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 12 weeks during which ICS dose reduction was attempted in a step-wise manner.
The distribution of the number of asthma exacerbations per patient in each group during a study was analyzed separately for the stable steroid and steroid-reduction periods.
In both Asthma Studies 1 and 2 the number of exacerbations per patient was reduced in patients treated with Xolair compared with placebo (Table 6).
Measures of airflow (FEV1) and asthma symptoms were also evaluated in these studies. The clinical relevance of the treatment-associated differences is unknown. Results from the stable steroid phase Asthma Study 1 are shown in Table 7. Results from the stable steroid phase of Asthma Study 2 and the steroid reduction phases of both Asthma Studies 1 and 2 were similar to those presented in Table 7.
Asthma Study 3:
In Asthma Study 3, there was no restriction on screening FEV1, and unlike Asthma Studies 1 and 2, long-acting beta2-agonists were allowed. Patients were receiving at least 1000 µg/day fluticasone propionate and a subset was also receiving oral corticosteroids. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.
The study was comprised of a run-in period to achieve a stable conversion to a common ICS (fluticasone propionate), followed by randomization to Xolair or placebo. Patients were stratified by use of ICS-only or ICS with concomitant use of oral steroids. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 16 weeks during which ICS or oral steroid dose reduction was attempted in a step-wise manner.
The number of exacerbations in patients treated with Xolair was similar to that in placebo-treated patients (Table 8). The absence of an observed treatment effect may be related to differences in the patient population compared with Asthma Studies 1 and 2, study sample size, or other factors.
In all three of the studies, a reduction of asthma exacerbations was not observed in the Xolair-treated patients who had FEV1 > 80% at the time of randomization. Reductions in exacerbations were not seen in patients who required oral steroids as maintenance therapy.
- Pediatric Patients 6 to < 12 Years of Age
- Clinical studies with Xolair in pediatric patients 6 to 11 years of age have been conducted.
- Pediatric Patients <6 Years of Age
- Clinical studies with Xolair in pediatric patients less than 6 years of age have not been conducted.
### Chronic Idiopathic Urticaria
Adult and Adolescent Patients 12 Years of Age and Older:
The safety and efficacy of Xolair for the treatment of CIU was assessed in two placebo-controlled, multiple-dose clinical studies of 24 weeks' duration (CIU Study 1; n= 319) and 12 weeks' duration (CIU Study 2; n=322). Patients received Xolair 75, 150, or 300 mg or placebo by SC injection every 4 weeks in addition to their baseline level of H1 antihistamine therapy for 24 or 12 weeks, followed by a 16-week washout observation period. A total of 640 patients (165 males, 475 females) were included for the efficacy analyses. Most patients were white (84%) and the median age was 42 years (range 12–72).
Disease severity was measured by a weekly urticaria activity score (UAS7, range 0–42), which is a composite of the weekly itch severity score (range 0–21) and the weekly hive count score (range 0–21). All patients were required to have a UAS7 of ≥ 16, and a weekly itch severity score of ≥ 8 for the 7 days prior to randomization, despite having used an H1 antihistamine for at least 2 weeks.
The mean weekly itch severity scores at baseline were fairly balanced across treatment groups and ranged between 13.7 and 14.5 despite use of an H1 antihistamine at an approved dose. The reported median durations of CIU at enrollment across treatment groups were between 2.5 and 3.9 years (with an overall subject-level range of 0.5 to 66.4 years).
In both CIU Studies 1 and 2, patients who received Xolair 150 mg or 300 mg had greater decreases from baseline in weekly itch severity scores and weekly hive count scores than placebo at Week 12. Representative results from CIU Study 1 are shown (Table 9); similar results were observed in CIU Study 2. The 75-mg dose did not demonstrate consistent evidence of efficacy and is not approved for use.
The mean weekly itch severity score at each study week by treatment groups is shown in Figure 1. Representative results from CIU Study 1 are shown; similar results were observed in CIU Study 2. The appropriate duration of therapy for CIU with Xolair has not been determined.
In CIU Study 1, a larger proportion of patients treated with Xolair 300 mg (36%) reported no itch and no hives (UAS7=0) at Week 12 compared to patients treated with Xolair 150 mg (15%), Xolair 75 mg (12%), and placebo group (9%). Similar results were observed in CIU Study 2.
# How Supplied
- Xolair is supplied as a lyophilized, sterile powder in a single-use, 5 mL vial without preservatives. Each vial delivers 150 mg of Xolair upon reconstitution with 1.4 mL SWFI, USP. Each carton contains one single-use vial of Xolair® (omalizumab) NDC 50242-040-62.
## Storage
Xolair should be shipped at controlled ambient temperature (≤ 30°C ). Store Xolair under refrigerated conditions 2–8°C (36–46°F). Do not use beyond the expiration date stamped on carton.
Use the solution for subcutaneous administration within 8 hours following reconstitution when stored in the vial at 2–8°C (36–46°F), or within 4 hours of reconstitution when stored at room temperature.
Reconstituted Xolair vials should be protected from direct sunlight.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Information for Patients
- Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment. The complete text of the Medication Guide is reprinted at the end of this document.
- Inform patients of the risk of life-threatening anaphylaxis with Xolair including the following points.
- There have been reports of anaphylaxis occurring up to 4 days after administration of Xolair
- Xolair should only be administered in a healthcare setting by healthcare providers
- Patients should be closely observed following administration
- Patients should be informed of the signs and symptoms of anaphylaxis
- Patients should be instructed to seek immediate medical care should such signs or symptoms occur
- Instruct patients receiving Xolair not to decrease the dose of, or stop taking any other asthma or CIU medications unless otherwise instructed by their physician. Inform patients that they may not see immediate improvement in their asthma or CIU symptoms after beginning Xolair therapy.
- Pregnancy Exposure Registry
- Encourage pregnant women exposed to Xolair to enroll in the Xolair Pregnancy Exposure Registry or visit www.xolairpregnancyregistry.com.
### MEDICATION GUIDE
XOLAIR®(ZOHL-air)
(omalizumab)
Injection
Read this Medication Guide before you start receiving and before each dose of Xolair. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.
- What is the most important information I should know about Xolair?
- A severe allergic reaction called anaphylaxis can happen when you receive Xolair. The reaction can occur after the first dose, or after many doses. It may also occur right after a Xolair injection or days later. Anaphylaxis is a life-threatening condition and can lead to death.
- Go to the nearest emergency room right away if you have any of these symptoms of an allergic reaction:
- wheezing, shortness of breath, cough, chest tightness, or trouble breathing
- low blood pressure, dizziness, fainting, rapid or weak heartbeat, anxiety, or feeling of "impending doom"
- flushing, itching, hives, or feeling warm
- swelling of the throat or tongue, throat tightness, hoarse voice, or trouble swallowing
- Your healthcare provider will monitor you closely for symptoms of an allergic reaction while you are receiving Xolair and for a period of time after your injection. Your healthcare provider should talk to you about getting medical treatment if you have symptoms of an allergic reaction after leaving the healthcare provider's office or treatment center.
- What is Xolair?
- Xolair is an injectable prescription medicine used to treat adults and children 12 years of age and older with:
- moderate to severe persistent allergic asthma who have had a skin or blood test that is positive for allergic asthma and whose asthma symptoms are not controlled by asthma medicines called inhaled corticosteroids.
- chronic idiopathic urticaria (CIU; chronic hives without a known cause) who continue to have hives that are not controlled by H1 antihistamine treatment.
- Xolair is not used to treat other allergic conditions, other forms of urticaria, acute bronchospasm or status asthmaticus.
- Xolair is not for use in children less than 12 years of age.
- Do not receive Xolair if you:
- are allergic to omalizumab or any of the ingredients in Xolair. See the end of this Medication Guide for a complete list of ingredients in Xolair.
- Before receiving Xolair, tell your healthcare provider about all of your medical conditions, including if you:
- have any other allergies (such as food allergy or seasonal allergies)
- have sudden breathing problems (bronchospasm)
- have or have had low white blood cell count (ask your doctor if you are not sure)
- have or have had a parasitic infection
- have or have had cancer
- are pregnant or plan to become pregnant. It is not known if Xolair may harm your unborn baby.
- if you become pregnant while taking Xolair, talk to your healthcare provider about registering with the Xolair Pregnancy Registry. You can get more information and register by calling 1-866-4XOLAIR (1-866-496-5247) or visit www.xolairpregnancyregistry.com. The purpose of this registry is to monitor pregnancy outcomes in women receiving Xolair during pregnancy.
- are breastfeeding or plan to breastfeed. It is not known if Xolair passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you receive Xolair.
- Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.
- How should I receive Xolair?
- Xolair should be given by your healthcare provider, in a healthcare setting.
- Xolair is given in 1 or more injections under the skin (subcutaneous), 1 time every 2 or 4 weeks.
- Your healthcare provider may do certain tests and change your Xolair dose as needed.
- Do not stop taking any of your other asthma or hive medicine unless your healthcare providers tell you to.
- You may not see improvement in your symptoms right away after Xolair treatment.
- What are the possible side effects of Xolair?
- Xolair may cause serious side effects, including:
- See, "What is the most important information I should know about Xolair?"
- Cancer. People who receive treatment with Xolair may have a higher chance for getting certain types of cancer.
- Fever, muscle aches, and rash. Some people who take Xolair get these symptoms 1 to 5 days after receiving a Xolair injection. If you have any of these symptoms, tell your healthcare provider.
- Parasitic infection. Some people who are at a high risk for parasite (worm) infections, get a parasite infection after receiving Xolair. Your healthcare provider can test your stool to check if you have a parasite infection.
- High blood levels of a certain antibody (Serum total IgE)
- The most common side effects of Xolair:
- In people with allergic asthma: pain especially in your arms and legs, dizziness, feeling tired, skin rash, bone fractures, and pain or discomfort of your ears.
- In people with chronic idiopathic urticaria: nausea, headaches, swelling of the inside of your nose, throat or sinuses, cough, joint pain, and upper respiratory tract infection.
- These are not all the possible side effects of Xolair. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- General information about the safe and effective use of Xolair.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about Xolair that is written for health professionals. Do not use Xolair for a condition for which it was not prescribed.
- For more information, go to www.xolair.com or call 1-866-4XOLAIR (1-866-496-5247).
- What are the ingredients in Xolair?
- Active ingredient: omalizumab
- Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20 and sucrose
### PRINCIPAL DISPLAY PANEL
# Precautions with Alcohol
- Alcohol-Omalizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Xolair®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Omalizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
# Disclaimer
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# Black Box Warning
# Overview
Omalizumab is an anti-allergic and anti-asthmatic agent that is FDA approved for the treatment of allergic asthma and chronic idiopathic urticaria. There is a Black Box Warning for this drug as shown here. Common adverse reactions include arthralgia, pain (general), leg pain, fatigue, dizziness, fracture, arm pain, pruritus, dermatitis, earache, nausea, nasopharyngitis, sinusitis, upper respiratory tract infection, viral upper respiratory tract infection, headache, and cough.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Administer Xolair 150 to 375 mg by subcutaneous (SC) injection every 2 or 4 weeks. Determine doses (mg) and dosing frequency by serum total IgE level (IU/mL), measured before the start of treatment, and body weight (kg). See the dose determination charts below (Table 1 and Table 2) for appropriate dose assignment.
- Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control.
### Dosing adjustments for Allergic Asthma
- Adjust doses for significant changes in body weight (see Table 1 and Table 2).
- Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination.
- Interruptions lasting less than one year: Dose based on serum IgE levels obtained at the initial dose determination.
- Interruptions lasting one year or more: Re-test total serum IgE levels for dose determination.
- Dosing Information
- Administer Xolair 150 or 300 mg by subcutaneous injection every 4 weeks.
- Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body weight.
- The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess the need for continued therapy.
- 150 mg of omalizumab as lyophilized, sterile powder in a single-use 5 mL vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omalizumab in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Doses of 150 or 300 mg every 3 to 4 weeks have been effective in adults and children with seasonal allergic rhinitis.
- Dosing Information
- Omalizumab 450 mg significantly increased the threshold of peanut sensitivity following an oral food challenge, compared with placebo in patients (12 to 60 years) with a history of peanut allergy in a randomized study.
- Dosing Information
- In a small randomized trial, omalizumab therapy was effective in reducing clinical symptoms of latex allergy compared with placebo in healthcare workers exposed to latex on a daily basis. Omalizumab was dosed according to body weight and serum IgE levels and ranged from 150 to 750 mg monthly.
- Dosing Information
- The dose of omalizumab is 0.016 mg/kg/IgE (international units/mL)/month subQ every 2 to 4 weeks, depending on weight and baseline IgE levels.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Xolair is not indicated for use in pediatric patients less than 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omalizumab in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Doses of 150 or 300 mg every 3 to 4 weeks have been effective in children with seasonal allergic rhinitis.
- Dosing Information
- Omalizumab 450 mg significantly increased the threshold of peanut sensitivity following an oral food challenge, compared with placebo in patients (12 to 60 years) with a history of peanut allergy in a randomized study.
- There is limited information regarding Off-Label Non-Guideline-Supported use of Omalizumab for Latex Allergy in pediatric patients.
- Dosing Information
- Preseasonal treatment with omalizumab in children and adolescents with seasonal allergic rhinitis decreases symptomatic days and rescue medication use. The dose of omalizumab was 0.016 mg/kg/IgE (international units/mL/month).
# Contraindications
The use of Xolair is contraindicated in the following:
Severe hypersensitivity reaction to Xolair or any ingredient of Xolair.
# Warnings
### Anaphylaxis
Anaphylaxis has been reported to occur after administration of Xolair in premarketing clinical trials and in postmarketing spontaneous reports. Signs and symptoms in these reported cases have included bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Some of these events have been life-threatening. In premarketing clinical trials in allergic asthma, anaphylaxis was reported in 3 of 3507 (0.1%) patients in clinical trials. Anaphylaxis occurred with the first dose of Xolair in two patients and with the fourth dose in one patient. The time to onset of anaphylaxis was 90 minutes after administration in two patients and 2 hours after administration in one patient. In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond one year after beginning regularly scheduled treatment.
Administer Xolair only in a healthcare setting by healthcare providers prepared to manage anaphylaxis that can be life-threatening. Observe patients closely for an appropriate period of time after administration of Xolair, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing spontaneous reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs or symptoms occur.
Discontinue Xolair in patients who experience a severe hypersensitivity reaction.
### Malignancy
Malignant neoplasms were observed in 20 of 4127 (0.5%) Xolair-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents (≥ 12 years of age) with asthma and other allergic disorders. The observed malignancies in Xolair-treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types occurring once each. The majority of patients were observed for less than 1 year. The impact of longer exposure to Xolair or use in patients at higher risk for malignancy (e.g., elderly, current smokers) is not known.
### Acute Asthma Symptoms
Xolair has not been shown to alleviate asthma exacerbations acutely. Do not use Xolair to treat acute bronchospasm or status asthmaticus.
### Corticosteroid reduction
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of Xolair therapy for allergic asthma. Decrease corticosteroids gradually under the direct supervision of a physician. In CIU patients, the use of Xolair in combination with corticosteroids has not been evaluated.
### Eosiophilic Conditions
In rare cases, patients with asthma on therapy with Xolair may present with serious systemic eosinophilia sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Xolair and these underlying conditions has not been established.
### Fever, Arthralgia and Rash
In post-approval use, some patients have experienced a constellation of signs and symptoms including arthritis/arthralgia, rash, fever and lymphadenopathy with an onset 1 to 5 days after the first or subsequent injections of Xolair. These signs and symptoms have recurred after additional doses in some patients. Although circulating immune complexes or a skin biopsy consistent with a Type III reaction were not seen with these cases, these signs and symptoms are similar to those seen in patients with serum sickness. Physicians should stop Xolair if a patient develops this constellation of signs and symptoms.
### Parasitic (Helminth) infection
Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment.
In a one-year clinical trial conducted in Brazil in patients at high risk for geohelminthic infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo controls. The point estimate of the odds ratio for infection was 1.96, with a 95% confidence interval (0.88, 4.36) indicating that in this study a patient who had an infection was anywhere from 0.88 to 4.36 times as likely to have received Xolair than a patient who did not have an infection. Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different between treatment groups.
### Laboratory Tests
Serum total IgE levels increase following administration of Xolair due to formation of Xolair:IgE complexes [see Clinical Pharmacology (12.2)]. Elevated serum total IgE levels may persist for up to 1 year following discontinuation of Xolair. Do not use serum total IgE levels obtained less than 1 year following discontinuation to reassess the dosing regimen for allergic asthma patients, because these levels may not reflect steady state free IgE levels.
# Adverse Reactions
## Clinical Trials Experience
### Clinical Trials Experience in Allergic Asthma:
Adult and Adolescent Patients 12 years of Age and Older
The data described below reflect Xolair exposure for 2076 adult and adolescent patients ages 12 and older, including 1687 patients exposed for six months and 555 exposed for one year or more, in either placebo-controlled or other controlled asthma studies. The mean age of patients receiving Xolair was 42 years, with 134 patients 65 years of age or older; 60% were women, and 85% Caucasian. Patients received Xolair 150 to 375 mg every 2 or 4 weeks or, for patients assigned to control groups, standard therapy with or without a placebo.
The adverse events most frequently resulting in clinical intervention (e.g., discontinuation of Xolair, or the need for concomitant medication to treat an adverse event) were injection site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These events were observed at similar rates in Xolair-treated patients and control patients.
Table 4 shows adverse reactions from four placebo-controlled asthma studies that occurred ≥ 1% and more frequently in patients receiving Xolair than in those receiving placebo. Adverse events were classified using preferred terms from the International Medical Nomenclature (IMN) dictionary. Injection site reactions were recorded separately from the reporting of other adverse events and are described following Table 4.
There were no differences in the incidence of adverse reactions based on age (among patients under 65), gender or race.
- Injection Site Reactions
- Injection site reactions of any severity occurred at a rate of 45% in Xolair-treated patients compared with 43% in placebo-treated patients. The types of injection site reactions included: bruising, redness, warmth, burning, stinging, itching, hive formation, pain, indurations, mass, and inflammation.
- Severe injection site reactions occurred more frequently in Xolair-treated patients compared with patients in the placebo group (12% versus 9%).
- The majority of injection site reactions occurred within 1 hour-post injection, lasted less than 8 days, and generally decreased in frequency at subsequent dosing visits.
### Clinical Trials Experience in Chronic Idiopathic Urticaria:
Adult and Adolescent Patients 12 years of Age and Older
The safety of Xolair for the treatment of CIU was assessed in three placebo-controlled, multiple-dose clinical studies of 12 weeks' (CIU Study 2) and 24 weeks' duration (CIU Studies 1 and 3). In CIU Studies 1 and 2, patients received Xolair 75, 150, or 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy throughout the treatment period. In CIU Study 3 patients were randomized to Xolair 300 mg or placebo every 4 weeks in addition to their baseline level of H1 antihistamine therapy. The data described below reflect Xolair exposure for 733 patients enrolled and receiving at least one dose of Xolair in the three clinical trials, including 684 patients exposed for 12 weeks and 427 exposed for 24 weeks. The mean age of patients receiving Xolair 300 mg was 43 years, 75% were women, and 89% were white. The demographic profiles for patients receiving Xolair 150 mg and 75 mg were similar.
Table 5 shows adverse events that occurred in ≥ 2% of patients receiving Xolair (150 or 300 mg) and more frequently than those receiving placebo. Adverse events are pooled from Study 2 and the first 12 weeks of Studies 1 and 3.
Additional events reported during the 24 week treatment period in Studies 1 and 3 [≥2% of patients receiving Xolair (150 or 300 mg) and more frequently than those receiving placebo] included: toothache, fungal infection, urinary tract infection, myalgia, pain in extremity, musculoskeletal pain, peripheral edema, pyrexia, migraine, sinus headache, anxiety, oropharyngeal pain, asthma, urticaria, and alopecia.
- Injection Site Reactions
- Injection site reactions of any severity occurred during the studies in more Xolair-treated patients [11 patients (2.7%) at 300 mg, 1 patient (0.6%) at 150 mg] compared with 2 placebo-treated patients (0.8%). The types of injection site reactions included: swelling, erythema, pain, bruising, itching, bleeding and urticaria. None of the events resulted in study discontinuation or treatment interruption.
### Immunogenicity:
Antibodies to Xolair were detected in approximately 1/1723 (< 0.1%) of patients treated with Xolair in the clinical studies for approval of asthma. There were no detectable antibodies in the patients treated in the phase 3 CIU clinical trials, but due to levels of Xolair at the time of anti-therapeutic antibody sampling and missing samples for some patients, antibodies to Xolair could only have been determined in 88% of the 733 patients treated in these clinical studies. The data reflect the percentage of patients whose test results were considered positive for antibodies to Xolair in ELISA assays and are highly dependent on the sensitivity and specificity of the assays.
Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Xolair 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 Xolair in adult and adolescent patients 12 years of age and older. 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.
### Anaphylaxis:
Based on spontaneous reports and an estimated exposure of about 57,300 patients from June 2003 through December 2006, the frequency of anaphylaxis attributed to Xolair use was estimated to be at least 0.2% of patients. Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to Xolair administration with no other identifiable cause. Signs and symptoms in these reported cases included bronchospasm, hypotension, syncope, urticaria, angioedema of the throat or tongue, dyspnea, cough, chest tightness, and/or cutaneous angioedema. Pulmonary involvement was reported in 89% of the cases. Hypotension or syncope was reported in 14% of cases. Fifteen percent of the reported cases resulted in hospitalization. A previous history of anaphylaxis unrelated to Xolair was reported in 24% of the cases.
Of the reported cases of anaphylaxis attributed to Xolair, 39% occurred with the first dose, 19% occurred with the second dose, 10% occurred with the third dose, and the rest after subsequent doses. One case occurred after 39 doses (after 19 months of continuous therapy, anaphylaxis occurred when treatment was restarted following a 3 month gap). The time to onset of anaphylaxis in these cases was up to 30 minutes in 35%, greater than 30 and up to 60 minutes in 16%, greater than 60 and up to 90 minutes in 2%, greater than 90 and up to 120 minutes in 6%, greater than 2 hours and up to 6 hours in 5%, greater than 6 hours and up to 12 hours in 14%, greater than 12 hours and up to 24 hours in 8%, and greater than 24 hours and up to 4 days in 5%. In 9% of cases the times to onset were unknown.
Twenty-three patients who experienced anaphylaxis were rechallenged with Xolair and 18 patients had a recurrence of similar symptoms of anaphylaxis. In addition, anaphylaxis occurred upon rechallenge with Xolair in 4 patients who previously experienced urticaria only.
### Eosinophilic Conditions:
Eosinophilic conditions have been reported.
### Fever, Arthralgia, and Rash:
A constellation of signs and symptoms including arthritis/arthralgia, rash (urticaria or other forms), fever and lymphadenopathy similar to serum sickness have been reported in post-approval use of Xolair.
Hematologic: Severe thrombocytopenia has been reported.
Skin: Hair loss has been reported.
# Drug Interactions
No formal drug interaction studies have been performed with Xolair.
In patients with allergic asthma the concomitant use of Xolair and allergen immunotherapy has not been evaluated.
In patients with CIU the use of Xolair in combination with immunosuppressive therapies has not been studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
### Pregnancy Category B:
Pregnancy Exposure Registry:
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Xolair during pregnancy. Encourage patients to call 1-866-4XOLAIR (1-866-496-5247) or visit www.xolairpregnancyregistry.com for information about the pregnancy exposure registry and the enrollment procedure.
Risk Summary:
Adequate and well-controlled studies with Xolair have not been conducted in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies, no evidence of fetal harm was observed in Cynomolgus monkeys with subcutaneous doses of omalizumab up to 10 times the maximum recommended human dose (MRHD).
Because animal reproduction studies are not always predictive of human response, Xolair should be used during pregnancy only if clearly needed.
Clinical Considerations:
In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
Data:
Animal Data:
Reproductive studies have been performed in Cynomolgus monkeys at subcutaneous doses of omalizumab up to 75 mg/kg (approximately 10 times the MRHD on a mg/kg basis). No evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when omalizumab was administered throughout organogenesis. Omalizumab did not elicit adverse effects on fetal or neonatal growth when administered throughout late gestation, delivery and nursing. Neonatal serum levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal serum level. Levels of omalizumab in milk were 0.15% of maternal serum concentration.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omalizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Omalizumab during labor and delivery.
### Nursing Mothers
It is not known whether Xolair is present in human breast milk; however, IgG is present in human milk in small amounts. In Cynomolgus monkeys, milk levels of omalizumab were measured at 0.15% of the maternal serum concentration [see Use in Specific Populations (8.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Xolair and any potential adverse effects on the breastfed child from Xolair or from the underlying maternal condition. Exercise caution when administering Xolair to a nursing woman.
### Pediatric Use
### Allergic Asthma:
Safety and effectiveness of Xolair for allergic asthma were evaluated in 2 studies in 926 (Xolair 624; placebo 302) asthma patients 6 to <12 years of age. One study was a pivotal study of similar design and conduct to that of adult and adolescent Asthma Studies 1 and 2. The other study was primarily a safety study and included evaluation of efficacy as a secondary outcome. In the pivotal study, Xolair-treated patients had a statistically significant reduction in the rate of exacerbations (exacerbation was defined as worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose), but other efficacy variables such as nocturnal symptom scores, beta-agonist use, and measures of airflow (FEV1) were not significantly different in Xolair-treated patients compared to placebo. Considering the risk of anaphylaxis and malignancy seen in Xolair-treated patients ≥ 12 years old and the modest efficacy of Xolair in the pivotal pediatric study, the risk-benefit assessment does not support the use of Xolair in patients 6 to <12 years of age.
Although patients treated with Xolair in these two studies did not develop anaphylaxis or malignancy, the studies are not adequate to address these concerns because patients with a history of anaphylaxis or malignancy were excluded, and the duration of exposure and sample size were not large enough to exclude these risks in patients 6 to <12 years of age. Furthermore, there is no reason to expect that younger pediatric patients would not be at risk of anaphylaxis and malignancy seen in adult and adolescent patients with Xolair.
Studies in patients 0-5 years of age were not required because of the safety concerns of anaphylaxis and malignancy associated with the use of Xolair in adults and adolescents.
### Chronic Idiopathic Urticaria
The safety and effectiveness of Xolair for adolescent patients with CIU were evaluated in 39 patients 12 to 17 years of age (Xolair 29, placebo 10) included in three randomized, placebo-controlled CIU studies. A numerical decrease in weekly itch score was observed, and adverse reactions were similar to those reported in patients 18 years and older.
Clinical studies with Xolair have not been conducted in CIU patients below the age of 12 years. Considering the risk of anaphylaxis and malignancy seen in Xolair-treated patients ≥ 12 years old, the risk-benefit assessment does not support the use of Xolair in patients <12 years of age. Therefore, the use of Xolair in this patient population is not recommended.
### Geriatic Use
In clinical studies 134 allergic asthma patients and 37 CIU phase 3 study patients 65 years of age or older were treated with Xolair. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Omalizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Omalizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Omalizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Omalizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Omalizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Omalizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
- Prepare Xolair for subcutaneous injection using Sterile Water for Injection (SWFI), USP, ONLY. Each vial of Xolair is for single use only and contains no preservatives.
- Reconstitution
- The lyophilized product takes 15–20 minutes to dissolve. The fully reconstituted product will appear clear or slightly opalescent and it is acceptable if there are a few small bubbles or foam around the edge of the vial. The reconstituted product is somewhat viscous; in order to obtain the full 1.2 mL dose, ALL OF THE PRODUCT MUST BE WITHDRAWN from the vial before expelling any air or excess solution from the syringe.
- Use the solution within 8 hours following reconstitution when stored in the vial at 2–8°C (36–46°F), or within 4 hours of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from sunlight.
Preparation:
STEP 1: Draw 1.4 mL of SWFI, USP into a 3 mL syringe equipped with a 1 inch, 18-gauge needle.
STEP 2: Place the vial upright on a flat surface and using standard aseptic technique, insert the needle and inject the SWFI, USP directly onto the product.
STEP 3: Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to evenly wet the powder. Do not shake.
STEP 4: After completing STEP 3, gently swirl the vial for 5-10 seconds approximately every 5 minutes in order to dissolve any remaining solids. There should be no visible gel like particles in the solution. Do not use if foreign particles are present.
Note: If it takes longer than 20 minutes to dissolve completely, repeat STEP 4 until there are no visible gel-like particles in the solution. Do not use if the contents of the vial do not dissolve completely by 40 minutes.
STEP 5: Invert the vial for 15 seconds in order to allow the solution to drain toward the stopper. Using a new 3 mL syringe equipped with a 1-inch, 18-gauge needle, insert the needle into the inverted vial.
Position the needle tip at the very bottom of the solution in the vial stopper when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
STEP 6: Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection.
STEP 7: Expel air, large bubbles, and any excess solution in order to obtain the required 1.2 mL dose. A thin layer of small bubbles may remain at the top of the solution in the syringe.
- Administration
- Administer Xolair by subcutaneous injection. The injection may take 5-10 seconds to administer because the solution is slightly viscous. Each vial delivers 1.2 mL (150 mg) of Xolair. Do not administer more than 150 mg per injection site. Divide doses of more than 150 mg among two or more injection sites (Table 3).
### Monitoring
- Monitor patients at high risk of geohelminth infection while on Xolair therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment.
# IV Compatibility
There is limited information regarding IV Compatibility of Omalizumab in the drug label.
# Overdosage
The maximum tolerated dose of Xolair has not been determined. Single intravenous doses of up to 4,000 mg have been administered to patients without evidence of dose limiting toxicities. The highest cumulative dose administered to patients was 44,000 mg over a 20 week period, which was not associated with toxicities.
# Pharmacology
There is limited information regarding Omalizumab Pharmacology in the drug label.
## Mechanism of Action
- Allergic Asthma
- Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcεRI receptors on basophils in atopic patients.
- Chronic Idiopathic Urticaria
- Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells down-regulate. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unknown.
## Structure
- Xolair is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody has a molecular weight of approximately 149 kiloDaltons. Xolair is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.
- Xolair is a sterile, white, preservative free, lyophilized powder contained in a single use vial that is reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a subcutaneous (SC) injection. Each 202.5 mg vial of omalizumab also contains L-histidine (1.8 mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 20 (0.5 mg) and sucrose (145.5 mg) and is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.
## Pharmacodynamics
- Allergic Asthma
- In clinical studies, serum free IgE levels were reduced in a dose dependent manner within 1 hour following the first dose and maintained between doses. Mean serum free IgE decrease was greater than 96% using recommended doses. Serum total IgE levels (i.e., bound and unbound) increased after the first dose due to the formation of omalizumab:IgE complexes, which have a slower elimination rate compared with free IgE.
- At 16 weeks after the first dose, average serum total IgE levels were five-fold higher compared with pre-treatment when using standard assays. After discontinuation of Xolair dosing, the Xolair-induced increase in total IgE and decrease in free IgE were reversible, with no observed rebound in IgE levels after drug washout. Total IgE levels did not return to pre-treatment levels for up to one year after discontinuation of Xolair.
- Chronic Idiopathic Urticaria
- In clinical studies in CIU patients, Xolair treatment led to a dose-dependent reduction of serum free IgE and an increase of serum total IgE levels, similar to the observations in allergic asthma patients. Maximum suppression of free IgE was observed 3 days following the first subcutaneous dose. After repeat dosing once every 4 weeks, predose serum free IgE levels remained stable between 12 and 24 weeks of treatment. Total IgE levels in serum increased after the first dose due to the formation of omalizumab-IgE complexes which have a slower elimination rate compared with free IgE. After repeat dosing once every 4 weeks at 75 mg up to 300 mg, average predose serum total IgE levels at Week 12 were two-to three-fold higher compared with pre-treatment levels, and remained stable between 12 and 24 weeks of treatment. After discontinuation of Xolair dosing, free IgE levels increased and total IgE levels decreased towards pre-treatment levels over a 16-week follow-up period.
## Pharmacokinetics
After SC administration, omalizumab was absorbed with an average absolute bioavailability of 62%. Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses greater than 0.5 mg/kg. In patients with asthma, following multiple doses of Xolair, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose. In patients with CIU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as single subcutaneous dose. Following repeat dosing from 75 to 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose levels.
In vitro, omalizumab formed complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million daltons in molecular weight were not observed in vitro or in vivo. Tissue distribution studies in Cynomolgus monkeys showed no specific uptake of 125I-omalizumab by any organ or tissue. The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78 ± 32 mL/kg. In patients with CIU, based on population pharmacokinetics, distribution of omalizumab was similar to that in patients with asthma.
Clearance of omalizumab involved IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG included degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also excreted in bile. In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with Fcγ receptors within the RES at rates that were generally faster than IgG clearance. In asthma patients omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight approximately doubled apparent clearance. In CIU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days and apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).
### Special Populations
### Allergic Asthma
The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics in patients with allergic asthma. Analyses of these data suggested that no dose adjustments are necessary for age (12-76 years), race, ethnicity, or gender.
### Chronic Idiopathic Urticaria
The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure in patients with CIU. Covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (12 to 75 years), race/ethnicity, gender, body weight, body mass index or baseline IgE level.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies have been performed in animals to evaluate the carcinogenic potential of Xolair.
- There were no effects on fertility and reproductive performance in male and female Cynomolgus monkeys that received Xolair at subcutaneous doses up to 75 mg/kg/week (approximately 10 times the maximum recommended human dose on a mg/kg basis).
# Clinical Studies
### Allergic Asthma
Adult and Adolescent Patients 12 Years of Age and Older
The safety and efficacy of Xolair were evaluated in three randomized, double-blind, placebo-controlled, multicenter trials.
The trials enrolled patients 12 to 76 years old, with moderate to severe persistent (NHLBI criteria) asthma for at least one year, and a positive skin test reaction to a perennial aeroallergen. In all trials, Xolair dosing was based on body weight and baseline serum total IgE concentration. All patients were required to have a baseline IgE between 30 and 700 IU/mL and body weight not more than 150 kg. Patients were treated according to a dosing table to administer at least 0.016 mg/kg/IU (IgE/mL) of Xolair or a matching volume of placebo over each 4-week period. The maximum Xolair dose per 4 weeks was 750 mg.
In all three trials an exacerbation was defined as a worsening of asthma that required treatment with systemic corticosteroids or a doubling of the baseline ICS dose. Most exacerbations were managed in the out-patient setting and the majority were treated with systemic steroids. Hospitalization rates were not significantly different between Xolair and placebo-treated patients; however, the overall hospitalization rate was small. Among those patients who experienced an exacerbation, the distribution of exacerbation severity was similar between treatment groups.
Asthma Studies 1 and 2:
At screening, patients in Asthma Studies 1 and 2 had a forced expiratory volume in one second (FEV1) between 40% and 80% predicted. All patients had a FEV1 improvement of at least 12% following beta2-agonist administration. All patients were symptomatic and were being treated with inhaled corticosteroids (ICS) and short acting beta2-agonists. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.
Each study was comprised of a run-in period to achieve a stable conversion to a common ICS (beclomethasone dipropionate), followed by randomization to Xolair or placebo. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 12 weeks during which ICS dose reduction was attempted in a step-wise manner.
The distribution of the number of asthma exacerbations per patient in each group during a study was analyzed separately for the stable steroid and steroid-reduction periods.
In both Asthma Studies 1 and 2 the number of exacerbations per patient was reduced in patients treated with Xolair compared with placebo (Table 6).
Measures of airflow (FEV1) and asthma symptoms were also evaluated in these studies. The clinical relevance of the treatment-associated differences is unknown. Results from the stable steroid phase Asthma Study 1 are shown in Table 7. Results from the stable steroid phase of Asthma Study 2 and the steroid reduction phases of both Asthma Studies 1 and 2 were similar to those presented in Table 7.
Asthma Study 3:
In Asthma Study 3, there was no restriction on screening FEV1, and unlike Asthma Studies 1 and 2, long-acting beta2-agonists were allowed. Patients were receiving at least 1000 µg/day fluticasone propionate and a subset was also receiving oral corticosteroids. Patients receiving other concomitant controller medications were excluded, and initiation of additional controller medications while on study was prohibited. Patients currently smoking were excluded.
The study was comprised of a run-in period to achieve a stable conversion to a common ICS (fluticasone propionate), followed by randomization to Xolair or placebo. Patients were stratified by use of ICS-only or ICS with concomitant use of oral steroids. Patients received Xolair for 16 weeks with an unchanged corticosteroid dose unless an acute exacerbation necessitated an increase. Patients then entered an ICS reduction phase of 16 weeks during which ICS or oral steroid dose reduction was attempted in a step-wise manner.
The number of exacerbations in patients treated with Xolair was similar to that in placebo-treated patients (Table 8). The absence of an observed treatment effect may be related to differences in the patient population compared with Asthma Studies 1 and 2, study sample size, or other factors.
In all three of the studies, a reduction of asthma exacerbations was not observed in the Xolair-treated patients who had FEV1 > 80% at the time of randomization. Reductions in exacerbations were not seen in patients who required oral steroids as maintenance therapy.
- Pediatric Patients 6 to < 12 Years of Age
- Clinical studies with Xolair in pediatric patients 6 to 11 years of age have been conducted.
- Pediatric Patients <6 Years of Age
- Clinical studies with Xolair in pediatric patients less than 6 years of age have not been conducted.
### Chronic Idiopathic Urticaria
Adult and Adolescent Patients 12 Years of Age and Older:
The safety and efficacy of Xolair for the treatment of CIU was assessed in two placebo-controlled, multiple-dose clinical studies of 24 weeks' duration (CIU Study 1; n= 319) and 12 weeks' duration (CIU Study 2; n=322). Patients received Xolair 75, 150, or 300 mg or placebo by SC injection every 4 weeks in addition to their baseline level of H1 antihistamine therapy for 24 or 12 weeks, followed by a 16-week washout observation period. A total of 640 patients (165 males, 475 females) were included for the efficacy analyses. Most patients were white (84%) and the median age was 42 years (range 12–72).
Disease severity was measured by a weekly urticaria activity score (UAS7, range 0–42), which is a composite of the weekly itch severity score (range 0–21) and the weekly hive count score (range 0–21). All patients were required to have a UAS7 of ≥ 16, and a weekly itch severity score of ≥ 8 for the 7 days prior to randomization, despite having used an H1 antihistamine for at least 2 weeks.
The mean weekly itch severity scores at baseline were fairly balanced across treatment groups and ranged between 13.7 and 14.5 despite use of an H1 antihistamine at an approved dose. The reported median durations of CIU at enrollment across treatment groups were between 2.5 and 3.9 years (with an overall subject-level range of 0.5 to 66.4 years).
In both CIU Studies 1 and 2, patients who received Xolair 150 mg or 300 mg had greater decreases from baseline in weekly itch severity scores and weekly hive count scores than placebo at Week 12. Representative results from CIU Study 1 are shown (Table 9); similar results were observed in CIU Study 2. The 75-mg dose did not demonstrate consistent evidence of efficacy and is not approved for use.
The mean weekly itch severity score at each study week by treatment groups is shown in Figure 1. Representative results from CIU Study 1 are shown; similar results were observed in CIU Study 2. The appropriate duration of therapy for CIU with Xolair has not been determined.
In CIU Study 1, a larger proportion of patients treated with Xolair 300 mg (36%) reported no itch and no hives (UAS7=0) at Week 12 compared to patients treated with Xolair 150 mg (15%), Xolair 75 mg (12%), and placebo group (9%). Similar results were observed in CIU Study 2.
# How Supplied
- Xolair is supplied as a lyophilized, sterile powder in a single-use, 5 mL vial without preservatives. Each vial delivers 150 mg of Xolair upon reconstitution with 1.4 mL SWFI, USP. Each carton contains one single-use vial of Xolair® (omalizumab) NDC 50242-040-62.
## Storage
Xolair should be shipped at controlled ambient temperature (≤ 30°C [ ≤ 86°F]). Store Xolair under refrigerated conditions 2–8°C (36–46°F). Do not use beyond the expiration date stamped on carton.
Use the solution for subcutaneous administration within 8 hours following reconstitution when stored in the vial at 2–8°C (36–46°F), or within 4 hours of reconstitution when stored at room temperature.
Reconstituted Xolair vials should be protected from direct sunlight.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Information for Patients
- Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment. The complete text of the Medication Guide is reprinted at the end of this document.
- Inform patients of the risk of life-threatening anaphylaxis with Xolair including the following points.
- There have been reports of anaphylaxis occurring up to 4 days after administration of Xolair
- Xolair should only be administered in a healthcare setting by healthcare providers
- Patients should be closely observed following administration
- Patients should be informed of the signs and symptoms of anaphylaxis
- Patients should be instructed to seek immediate medical care should such signs or symptoms occur
- Instruct patients receiving Xolair not to decrease the dose of, or stop taking any other asthma or CIU medications unless otherwise instructed by their physician. Inform patients that they may not see immediate improvement in their asthma or CIU symptoms after beginning Xolair therapy.
- Pregnancy Exposure Registry
- Encourage pregnant women exposed to Xolair to enroll in the Xolair Pregnancy Exposure Registry [1-866-4XOLAIR (1-866-496-5247)] or visit www.xolairpregnancyregistry.com.
### MEDICATION GUIDE
XOLAIR®(ZOHL-air)
(omalizumab)
Injection
Read this Medication Guide before you start receiving and before each dose of Xolair. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.
- What is the most important information I should know about Xolair?
- A severe allergic reaction called anaphylaxis can happen when you receive Xolair. The reaction can occur after the first dose, or after many doses. It may also occur right after a Xolair injection or days later. Anaphylaxis is a life-threatening condition and can lead to death.
- Go to the nearest emergency room right away if you have any of these symptoms of an allergic reaction:
- wheezing, shortness of breath, cough, chest tightness, or trouble breathing
- low blood pressure, dizziness, fainting, rapid or weak heartbeat, anxiety, or feeling of "impending doom"
- flushing, itching, hives, or feeling warm
- swelling of the throat or tongue, throat tightness, hoarse voice, or trouble swallowing
- Your healthcare provider will monitor you closely for symptoms of an allergic reaction while you are receiving Xolair and for a period of time after your injection. Your healthcare provider should talk to you about getting medical treatment if you have symptoms of an allergic reaction after leaving the healthcare provider's office or treatment center.
- What is Xolair?
- Xolair is an injectable prescription medicine used to treat adults and children 12 years of age and older with:
- moderate to severe persistent allergic asthma who have had a skin or blood test that is positive for allergic asthma and whose asthma symptoms are not controlled by asthma medicines called inhaled corticosteroids.
- chronic idiopathic urticaria (CIU; chronic hives without a known cause) who continue to have hives that are not controlled by H1 antihistamine treatment.
- Xolair is not used to treat other allergic conditions, other forms of urticaria, acute bronchospasm or status asthmaticus.
- Xolair is not for use in children less than 12 years of age.
- Do not receive Xolair if you:
- are allergic to omalizumab or any of the ingredients in Xolair. See the end of this Medication Guide for a complete list of ingredients in Xolair.
- Before receiving Xolair, tell your healthcare provider about all of your medical conditions, including if you:
- have any other allergies (such as food allergy or seasonal allergies)
- have sudden breathing problems (bronchospasm)
- have or have had low white blood cell count (ask your doctor if you are not sure)
- have or have had a parasitic infection
- have or have had cancer
- are pregnant or plan to become pregnant. It is not known if Xolair may harm your unborn baby.
- if you become pregnant while taking Xolair, talk to your healthcare provider about registering with the Xolair Pregnancy Registry. You can get more information and register by calling 1-866-4XOLAIR (1-866-496-5247) or visit www.xolairpregnancyregistry.com. The purpose of this registry is to monitor pregnancy outcomes in women receiving Xolair during pregnancy.
- are breastfeeding or plan to breastfeed. It is not known if Xolair passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you receive Xolair.
- Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.
- How should I receive Xolair?
- Xolair should be given by your healthcare provider, in a healthcare setting.
- Xolair is given in 1 or more injections under the skin (subcutaneous), 1 time every 2 or 4 weeks.
- Your healthcare provider may do certain tests and change your Xolair dose as needed.
- Do not stop taking any of your other asthma or hive medicine unless your healthcare providers tell you to.
- You may not see improvement in your symptoms right away after Xolair treatment.
- What are the possible side effects of Xolair?
- Xolair may cause serious side effects, including:
- See, "What is the most important information I should know about Xolair?"
- Cancer. People who receive treatment with Xolair may have a higher chance for getting certain types of cancer.
- Fever, muscle aches, and rash. Some people who take Xolair get these symptoms 1 to 5 days after receiving a Xolair injection. If you have any of these symptoms, tell your healthcare provider.
- Parasitic infection. Some people who are at a high risk for parasite (worm) infections, get a parasite infection after receiving Xolair. Your healthcare provider can test your stool to check if you have a parasite infection.
- High blood levels of a certain antibody (Serum total IgE)
- The most common side effects of Xolair:
- In people with allergic asthma: pain especially in your arms and legs, dizziness, feeling tired, skin rash, bone fractures, and pain or discomfort of your ears.
- In people with chronic idiopathic urticaria: nausea, headaches, swelling of the inside of your nose, throat or sinuses, cough, joint pain, and upper respiratory tract infection.
- These are not all the possible side effects of Xolair. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- General information about the safe and effective use of Xolair.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about Xolair that is written for health professionals. Do not use Xolair for a condition for which it was not prescribed.
- For more information, go to www.xolair.com or call 1-866-4XOLAIR (1-866-496-5247).
- What are the ingredients in Xolair?
- Active ingredient: omalizumab
- Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20 and sucrose
### PRINCIPAL DISPLAY PANEL
# Precautions with Alcohol
- Alcohol-Omalizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Xolair®
# Look-Alike Drug Names
- N/A[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Omalizumab | |
5dc769c7be2a7b41cfbe62eb91ba4a5db4d062cc | wikidoc | Ophiovirus | Ophiovirus
# Overview
The viral genus Ophiovirus is characterized by an elongated and highly filamentous and flexible nucleocapsid with helical symmetry.
Virus capsid is not enveloped and have a constant diameter of 1500-2500 nm and a width of 3 nm, or 9 nm. They form kinked circles, which can collapse to form linear duplex structures, much like a spring. The entire genome is 1100-1200 nucleotides long.
The best studied species under this genus is the Citrus psorosis virus. | Ophiovirus
# Overview
The viral genus Ophiovirus is characterized by an elongated and highly filamentous and flexible nucleocapsid with helical symmetry.
Virus capsid is not enveloped and have a constant diameter of 1500-2500 nm and a width of 3 nm, or 9 nm. They form kinked circles, which can collapse to form linear duplex structures, much like a spring. The entire genome is 1100-1200 nucleotides long[1].
The best studied species under this genus is the Citrus psorosis virus. | https://www.wikidoc.org/index.php/Ophiovirus | |
9f767e4db71181a3375cacb9e932c0e30540d38b | wikidoc | Opsophagos | Opsophagos
# Background
Opsophagos was an ancient Greek term used to describe one who exhibited a seemingly uncontrollable desire for fish. This term had extremely negative connotations, as it was a criticism not of one's tastes, but rather of one's character.
To be labeled an opsophagos was to be accused of obsessive and over-indulgent behavior, and this was no small charge in ancient Greek society, since such behavior was understood to imply the corruption of the soul. Proper humans were expected to be rational and exercise moderation, so those who could not control their desires were seen as barbaric and uncivilized.
Tales of infamous opsophogoi (plural form) depicted men who took their obsession and greed to unbelievable levels, training their bodies in various ways to be able to consume massive quantities of fish immediately after they had been prepared, ensuring that they would have the fish to themselves, since they would be too hot for others to even touch, let alone eat. These tales of men with heat-resistant throats and padded fingertips were likely fictional, but they served as reminders to all who heard them that letting the pleasure-driven body overcome the rational soul was not the way to become an ideal human. One could enjoy fish, but one had to be careful not to take this enjoyment too far and become an opsophagos.
Source: Davidson, James (1997). Courtesans and Fishcakes: The Consuming Passions of Classical Athens. Great Britain: Harper Collins. Retrieved 2007-02-10..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} | Opsophagos
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Opsophagos was an ancient Greek term used to describe one who exhibited a seemingly uncontrollable desire for fish. This term had extremely negative connotations, as it was a criticism not of one's tastes, but rather of one's character.
To be labeled an opsophagos was to be accused of obsessive and over-indulgent behavior, and this was no small charge in ancient Greek society, since such behavior was understood to imply the corruption of the soul. Proper humans were expected to be rational and exercise moderation, so those who could not control their desires were seen as barbaric and uncivilized.
Tales of infamous opsophogoi (plural form) depicted men who took their obsession and greed to unbelievable levels, training their bodies in various ways to be able to consume massive quantities of fish immediately after they had been prepared, ensuring that they would have the fish to themselves, since they would be too hot for others to even touch, let alone eat. These tales of men with heat-resistant throats and padded fingertips were likely fictional, but they served as reminders to all who heard them that letting the pleasure-driven body overcome the rational soul was not the way to become an ideal human. One could enjoy fish, but one had to be careful not to take this enjoyment too far and become an opsophagos.
Source: Davidson, James (1997). Courtesans and Fishcakes: The Consuming Passions of Classical Athens. Great Britain: Harper Collins. Retrieved 2007-02-10..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Template:Food-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Opsophagos | |
767b41a7bd9e415df244c4ae12956fb75f89377a | wikidoc | Optineurin | Optineurin
Optineurin is a protein that in humans is encoded by the OPTN gene.
# Function
This gene encodes the coiled-coil containing protein optineurin. Optineurin may play a role in normal-tension glaucoma and adult-onset primary open angle glaucoma. Optineurin interacts with adenovirus E3-14.7K protein and may utilize tumor necrosis factor-alpha or Fas-ligand pathways to mediate apoptosis, inflammation or vasoconstriction. Optineurin may also function in cellular morphogenesis and membrane trafficking, vesicle trafficking, and transcription activation through its interactions with the RAB8, huntingtin, and transcription factor IIIA proteins. Alternative splicing results in multiple transcript variants encoding the same protein.
# Model organisms
Model organisms have been used in the study of OPTN function. A conditional knockout mouse line, called Optntm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program – a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists – at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty one tests were carried out on mutant mice, however no significant abnormalities were observed.
# Interactions
Optineurin has been shown to interact with Huntingtin and RAB8A. | Optineurin
Optineurin is a protein that in humans is encoded by the OPTN gene.[1][2][3]
# Function
This gene encodes the coiled-coil containing protein optineurin. Optineurin may play a role in normal-tension glaucoma and adult-onset primary open angle glaucoma. Optineurin interacts with adenovirus E3-14.7K protein and may utilize tumor necrosis factor-alpha or Fas-ligand pathways to mediate apoptosis, inflammation or vasoconstriction. Optineurin may also function in cellular morphogenesis and membrane trafficking, vesicle trafficking, and transcription activation through its interactions with the RAB8, huntingtin, and transcription factor IIIA proteins. Alternative splicing results in multiple transcript variants encoding the same protein.[3]
# Model organisms
Model organisms have been used in the study of OPTN function. A conditional knockout mouse line, called Optntm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program – a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists – at the Wellcome Trust Sanger Institute.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty one tests were carried out on mutant mice, however no significant abnormalities were observed.[6]
# Interactions
Optineurin has been shown to interact with Huntingtin[14][15] and RAB8A.[15] | https://www.wikidoc.org/index.php/Optineurin | |
84cb74acd30846467c0d9d969469aea8a5bdea73 | wikidoc | Oral torus | Oral torus
# Overview
Oral Torus is a legion made of compact bone and occurs along the palate or the mandible inside the mouth. The palatal torus or torus palatinus occurs along the palate, close to the midline, where as the mandibular torus or torus mandibularis occur along the lingual side of the mandible.
Occurrences of tori are more frequent in women then they are in men. Tori are associated with adulthood and rarely appear before the age of 15. The palatal version of tori have a higher occurrence in Native American and Inuit populations.
Treatment is not necessary unless they become an obstruction to chewing or prosthetic appliances. | Oral torus
# Overview
Oral Torus is a legion made of compact bone and occurs along the palate or the mandible inside the mouth. The palatal torus or torus palatinus occurs along the palate, close to the midline, where as the mandibular torus or torus mandibularis occur along the lingual side of the mandible.
Occurrences of tori are more frequent in women then they are in men. Tori are associated with adulthood and rarely appear before the age of 15. The palatal version of tori have a higher occurrence in Native American and Inuit populations.
Treatment is not necessary unless they become an obstruction to chewing or prosthetic appliances. | https://www.wikidoc.org/index.php/Oral_torus | |
0289a8efb9eba9f6d478ea4548651c20aa1ad902 | wikidoc | Orange oil | Orange oil
Orange oil is an essential oil produced by glands inside the rind of an orange fruit. It is extracted or steam distilled as a by-product of orange juice production. It is composed mostly of d-limonene, and is therefore often used in place of pure lemon, which can be further extracted from the oil by distillation.
# Limonene
Limonene is what gives citrus fruit their familiar aroma, and is therefore used in perfume and household cleaners for its fragrance. It is also an effective, environmentally friendly, and relatively safe solvent, which makes it an active ingredient of choice in many applications, such as, but not limited to, adhesive and stain removers, cleaners of various sorts, and strippers.
# Safety
The limonene which is the main component of the oil is a mild hand irritant, by virtue of dissolving the protective oils in the skin. It is wise to wear solvent-resistant gloves when handling limonene solutions.
Limonene is also combustible. If you squeeze an orange peel in front of a flame, the glands will burst with an aerosol that will ignite on contact with the flame.
Limonene has been observed to cause cancer in male rats, by reacting with α2U-globulin, which is not produced by female rats. There is no evidence for carcinogenicity or genotoxicity in humans. The IARC classifies d-limonene under Class 3: not classifiable as to its carcinogenicity to humans.
For more details of the regulatory status and toxicity, see limonene.
# Insecticide
d-Limonene serves as a natural insect repellent for citrus fruits. Direct contact with d-Limonene can act as an organic insecticide. Experiments with fruit flies have shown that they by-pass this problem by laying eggs between the oil-producing glands.
Also effective on Drywood Termites | Orange oil
Orange oil is an essential oil produced by glands inside the rind of an orange fruit. It is extracted or steam distilled as a by-product of orange juice production. It is composed mostly of d-limonene, and is therefore often used in place of pure lemon, which can be further extracted from the oil by distillation.
# Limonene
Limonene is what gives citrus fruit their familiar aroma, and is therefore used in perfume and household cleaners for its fragrance. It is also an effective, environmentally friendly, and relatively safe solvent, which makes it an active ingredient of choice in many applications, such as, but not limited to, adhesive and stain removers, cleaners of various sorts, and strippers.
# Safety
The limonene which is the main component of the oil is a mild hand irritant, by virtue of dissolving the protective oils in the skin. It is wise to wear solvent-resistant gloves when handling limonene solutions.
Limonene is also combustible. If you squeeze an orange peel in front of a flame, the glands will burst with an aerosol that will ignite on contact with the flame.
Limonene has been observed to cause cancer in male rats, by reacting with α2U-globulin, which is not produced by female rats. There is no evidence for carcinogenicity or genotoxicity in humans. The IARC classifies d-limonene under Class 3: not classifiable as to its carcinogenicity to humans. [1]
For more details of the regulatory status and toxicity, see limonene.
# Insecticide
d-Limonene serves as a natural insect repellent for citrus fruits. Direct contact with d-Limonene can act as an organic insecticide. Experiments with fruit flies have shown that they by-pass this problem by laying eggs between the oil-producing glands.
Also effective on Drywood Termites
# External links
- The Effect of Citrus Oils on Fruit Flies
de:Orangenöl
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Orange_oil | |
592ab8c656012f4dc9e1a68d4b13adc660b1119b | wikidoc | Orchialgia | Orchialgia
Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing.
# Overview
Orchialgia is chronic pain of the testicles or scrotum that typically lasts for more than three months.
# Causes
## Common Causes
- Cancer
- Injury
- Orchialgia is a possible complication after vasectomy.
- Surgery
- Testicular torsion
# Diagnosis
## History and Symptoms
Patient usually complaints of deep aching pain in the testes. Following history has to be taken from a patient presenting with complaints of testicular pain:
- Onset can be sudden or gradual
- Site location: Unilateral or bilateral (bilateral testicular pain is more commonly seen)
- Intermittent or constant: Pain is usually intermittent and can shift from one side to the other.
- Type of pain: Patients usually have deep aching pain.
- Associated symptoms:
Local area redness, warmth and swelling can be seen in case of testicular torsion or infections.
Associated back pain and pain in inguinal area may be seen.
Epididymitis is often accompanied by symptoms of a urinary tract infection, fever, and in over half of cases it presents in combination with orchitis.
- Local area redness, warmth and swelling can be seen in case of testicular torsion or infections.
- Associated back pain and pain in inguinal area may be seen.
- Epididymitis is often accompanied by symptoms of a urinary tract infection, fever, and in over half of cases it presents in combination with orchitis.
- Recent history of surgery and trauma to the local area needs to be elicited to know the cause of the pain.
## Laboratory Findings
Testing for gonorrhea and chlamydia should be routinely performed.
# Treatment
## Medical Therapy
Treatment is often with NSAIDs and antibiotics. However, this is not always effective.
# Related Chapters
- Post-vasectomy pain syndrome | Orchialgia
Template:Search infobox
Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Orchialgia is chronic pain of the testicles or scrotum that typically lasts for more than three months.
# Causes
## Common Causes
- Cancer
- Injury
- Orchialgia is a possible complication after vasectomy.
- Surgery
- Testicular torsion
# Diagnosis
## History and Symptoms
Patient usually complaints of deep aching pain in the testes. Following history has to be taken from a patient presenting with complaints of testicular pain:
- Onset can be sudden or gradual
- Site location: Unilateral or bilateral (bilateral testicular pain is more commonly seen)
- Intermittent or constant: Pain is usually intermittent and can shift from one side to the other.
- Type of pain: Patients usually have deep aching pain.
- Associated symptoms:
Local area redness, warmth and swelling can be seen in case of testicular torsion or infections.
Associated back pain and pain in inguinal area may be seen.
Epididymitis is often accompanied by symptoms of a urinary tract infection, fever, and in over half of cases it presents in combination with orchitis.
- Local area redness, warmth and swelling can be seen in case of testicular torsion or infections.
- Associated back pain and pain in inguinal area may be seen.
- Epididymitis is often accompanied by symptoms of a urinary tract infection, fever, and in over half of cases it presents in combination with orchitis.
- Recent history of surgery and trauma to the local area needs to be elicited to know the cause of the pain.
## Laboratory Findings
Testing for gonorrhea and chlamydia should be routinely performed.[1]
# Treatment
## Medical Therapy
Treatment is often with NSAIDs and antibiotics. However, this is not always effective.[1]
# Related Chapters
- Post-vasectomy pain syndrome | https://www.wikidoc.org/index.php/Orchalgia | |
ae4890ad74e40b5085294f1f24b29ec0e800ae4f | wikidoc | Orellanine | Orellanine
Orellanine or Orellanin is a pyridine N-oxide and a crystalline alkaloid that is found naturally in some lifeforms, specifically certain fungi.
It has been found in at least 34 Cortinariaceae.
# History
In Poland during the 1950s there was a small epidemic where over 100 people became ill. What caused the illness remained a mystery until 1952 when Polish physician Dr. S. Grzymała discovered that everyone suffering from the illness, which had by now claimed several lives, had eaten the mushroom Cortinarius orellanus.
In 1955 he isolated a substance from the fungus. He named it orellanine after the Latin name of the toadstool. Given orally to research animals, he produced the same reaction as in humans.
In 1973 orellanine was discovered in the toadstool Cortinarius rubellus.
# Chemistry
The chemical constitution of orellanine remained unknown until the Polish chemists Antkowiak and Gessner in the last half of the 1970s discovered that it belongs to a group of compounds called bipyridines, a double ring structure where both rings are principally a pyridine ring (a heterocyclic ring with one nitrogen atom). In the most stable form of orellanine, the nitrogen atoms are positively charged.
An interesting feature of orellanine is its ability to bind aluminium ions to organic complexes.
# Toxicity
Bipyridines with positively charged nitrogen atoms were already known to be poisonous before the structure of orellanine was elucidated. The herbicides paraquat and diquat are toxic not only to plants, but also to animals including humans. Bipyridines with charged nitrogen atoms confound important redox reactions in organisms, ‘stealing’ one or two electrons and sometimes bypass the electrons into other and often undesirable redox reactions. The terminal product can be peroxide or superoxide ions, the latter of which is harmful to the cells. It is likely that orellanine works in the same way, although the process from disturbed redox reactions to the serious clinical kidney damage has not been properly resolved.
In humans, a characteristic of poisoning by the nephrotoxin orellanine is the long latency; the first symptoms usually do not appear until 2-3 days after ingestion and can in some cases take as long as 3 weeks. The first symptoms of orellanine poisoning are similar to the common flu (nausea, vomiting, stomach pains, headaches, myalgia, etc), these symptoms are followed by early stages of renal failure (immense thirst, frequent urination, pain on and around the kidneys) and eventually decreased or nonexistent urine output and other symptoms of renal failure occur. If left untreated death will follow.
The lethal dose of orellanine in mice is 12 to 20 mg per kg body weight, where it must be noted that this is the dose which leads to death within two weeks. From cases of orellanine-related mushroom poisoning in humans it seems that the lethal dose for humans is considerably lower.
# Treatment
Although there is no known antidote against orellanine poisoning, early hospitalization can sometimes prevent serious injury and usually prevent death. Research is ongoing. Some treatments make use of anti-oxidant therapy and corticosteroids to help victims recover from their renal failure. | Orellanine
Orellanine or Orellanin is a pyridine N-oxide and a crystalline alkaloid that is found naturally in some lifeforms, specifically certain fungi.
It has been found in at least 34 Cortinariaceae. [1]
# History
In Poland during the 1950s there was a small epidemic where over 100 people became ill. What caused the illness remained a mystery until 1952 when Polish physician Dr. S. Grzymała discovered that everyone suffering from the illness, which had by now claimed several lives, had eaten the mushroom Cortinarius orellanus.[1]
In 1955 he isolated a substance from the fungus. He named it orellanine after the Latin name of the toadstool. Given orally to research animals, he produced the same reaction as in humans. [2]
In 1973 orellanine was discovered in the toadstool Cortinarius rubellus.
# Chemistry
The chemical constitution of orellanine remained unknown until the Polish chemists Antkowiak and Gessner in the last half of the 1970s discovered that it belongs to a group of compounds called bipyridines, a double ring structure where both rings are principally a pyridine ring (a heterocyclic ring with one nitrogen atom). In the most stable form of orellanine, the nitrogen atoms are positively charged.[3]
An interesting feature of orellanine is its ability to bind aluminium ions to organic complexes.[4]
# Toxicity
Bipyridines with positively charged nitrogen atoms were already known to be poisonous before the structure of orellanine was elucidated. The herbicides paraquat and diquat are toxic not only to plants, but also to animals including humans. Bipyridines with charged nitrogen atoms confound important redox reactions in organisms, ‘stealing’ one or two electrons and sometimes bypass the electrons into other and often undesirable redox reactions. The terminal product can be peroxide or superoxide ions, the latter of which is harmful to the cells. It is likely that orellanine works in the same way, although the process from disturbed redox reactions to the serious clinical kidney damage has not been properly resolved.
In humans, a characteristic of poisoning by the nephrotoxin orellanine is the long latency; the first symptoms usually do not appear until 2-3 days after ingestion and can in some cases take as long as 3 weeks. The first symptoms of orellanine poisoning are similar to the common flu (nausea, vomiting, stomach pains, headaches, myalgia, etc), these symptoms are followed by early stages of renal failure (immense thirst, frequent urination, pain on and around the kidneys) and eventually decreased or nonexistent urine output and other symptoms of renal failure occur. If left untreated death will follow.
The lethal dose of orellanine in mice is 12 to 20 mg per kg body weight,[2][3] where it must be noted that this is the dose which leads to death within two weeks. From cases of orellanine-related mushroom poisoning in humans it seems that the lethal dose for humans is considerably lower.
# Treatment
Although there is no known antidote against orellanine poisoning, early hospitalization can sometimes prevent serious injury and usually prevent death. Research is ongoing. Some treatments make use of anti-oxidant therapy and corticosteroids to help victims recover from their renal failure.[4] | https://www.wikidoc.org/index.php/Orellanine | |
67b0ee449317c6c271ea69dfb068334f003733c6 | wikidoc | Oscillator | Oscillator
Oscillation is the repetitive variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples include a swinging pendulum and AC power. The term vibration is sometimes used more narrowly to mean a mechanical oscillation but sometimes is used to be synonymous with "oscillation." Oscillations occur not only in physical systems but also in biological systems and in human society.
# Simplicity
The simplest mechanical oscillating system is a mass attached to a linear spring, subject to no other forces; except for the point of equilibrium, this system is equivalent to the same one subject to a constant force such as gravity. Such a system may be approximated on an air table or ice surface. The system is in an equilibrium state when the spring is unstretched. If the system is displaced from the equilibrium, there is a net restoring force on the mass, tending to bring it back to equilibrium. However, in moving the mass back to the equilibrium position, it has acquired momentum which keeps it moving beyond that position, establishing a new restoring force in the opposite sense. The time taken for an oscillation to occur is often referred to as the oscillatory period.
The specific dynamics of this spring-mass system are described mathematically by the simple harmonic oscillator and the regular periodic motion is known as simple harmonic motion. In the spring-mass system, oscillations occur because, at the static equilibrium displacement, the mass has kinetic energy which is converted into potential energy stored in the spring at the extremes of its path. The spring-mass system illustrates some common features of oscillation, namely the existence of an equilibrium and the presence of a restoring force which grows stronger the further the system deviates from equilibrium.
The harmonic oscillator offers a model of many more complicated types of oscillation and can be extended by the use of Fourier analysis.
# Damped, driven and self-induced oscillations
In real-world systems, the second law of thermodynamics dictates that there is some continual and inevitable conversion of energy into the thermal energy of the environment. Thus, damped oscillations tend to decay with time unless there is some net source of energy in the system. The simplest description of this decay process can be illustrated by the harmonic oscillator. In addition, an oscillating system may be subject to some external force (often sinusoidal), as when an AC circuit is connected to an outside power source. In this case the oscillation is said to be driven.
Some systems can be excited by energy transfer from the environment. This transfer typically occurs where systems are embedded in some fluid flow. For example, the phenomenon of flutter in aerodynamics occurs when an arbitrarily small displacement of an aircraft wing (from its equilibrium) results in an increase in the angle of attack of the wing on the air flow and a consequential increase in lift coefficient, leading to a still greater displacement. At sufficiently large displacements, the stiffness of the wing dominates to provide the restoring force that enables an oscillation.
# Coupled oscillations
The harmonic oscillator and the systems it models have a single degree of freedom. More complicated systems have more degrees of freedom, for example two masses and three springs (each mass being attached to fixed points and to each other). In such cases, the behavior of each variable influences that of the others. This leads to a coupling of the oscillations of the individual degrees of freedom. For example, two pendulum clocks mounted on a common wall will tend to synchronise. The apparent motions of the individual oscillations typically appears very complicated but a more economic, computationally simpler and conceptually deeper description is given by resolving the motion into normal modes.
# Continuous systems - waves
As the number of degrees of freedom becomes arbitrarily large, a system approaches continuity; examples include a string or the surface of a body of water. Such systems have (in the classical limit) an infinite number of normal modes and their oscillations occur in the form of waves that can characteristically propagate.
# Examples
See also: list of wave topics
## Mechanical
- Double pendulum
- Quantum harmonic oscillator
- Foucault pendulum
- Helmholtz resonator
- Playground swing
- String instruments
- Tuning fork
- Vibrating string
- Oscillations in the Sun (helioseismology) and stars (asteroseismology)
## Electrical
- Alternating current
- Armstrong oscillator
- Astable multivibrator
- Blocking oscillator
- Clapp oscillator
- Colpitts oscillator
- Delay line oscillator
- Electronic oscillator
- Hartley oscillator
- Oscillistor
- Pierce oscillator
- Relaxation oscillator
- RLC circuit
- Royer oscillator
- Vačkář oscillator
- Wien bridge oscillator
- Oscillators and Multivibrators
- Virtual Cathode Oscillator
## Electro-mechanical
- Crystal oscillator
- Loudspeaker
- Microphone
## Optical
- Laser (oscillation of electromagnetic field with frequency of order 10^{15}Hz)
- Oscillator Toda or self-pulsation (pulsation of output power of laser at frequencies 10^{4}Hz -- 10^{6}Hz in the transient regime)
- Quantum oscillator may refer to an optical local oscillator, as well as to a usual model in quantum optics.
## Biological
- Circadian rhythm
- Prey-predator systems
- Neural oscillations
## Human
- Brain waves
- Pilot-induced oscillation
- Voice production
- Insulin release oscillations
## Economic and social
- Business cycle
- Generation gap
- Malthusian economics
- News cycle
## Climate and geophysics
- Chandler wobble
- El Niño-Southern Oscillation
- Quasi-biennial oscillation
- Tides in the Earth's oceans
## Chemical
- Belousov-Zhabotinsky reaction
- Mercury beating heart | Oscillator
Oscillation is the repetitive variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples include a swinging pendulum and AC power. The term vibration is sometimes used more narrowly to mean a mechanical oscillation but sometimes is used to be synonymous with "oscillation." Oscillations occur not only in physical systems but also in biological systems and in human society.
# Simplicity
The simplest mechanical oscillating system is a mass attached to a linear spring, subject to no other forces; except for the point of equilibrium, this system is equivalent to the same one subject to a constant force such as gravity. Such a system may be approximated on an air table or ice surface. The system is in an equilibrium state when the spring is unstretched. If the system is displaced from the equilibrium, there is a net restoring force on the mass, tending to bring it back to equilibrium. However, in moving the mass back to the equilibrium position, it has acquired momentum which keeps it moving beyond that position, establishing a new restoring force in the opposite sense. The time taken for an oscillation to occur is often referred to as the oscillatory period.
The specific dynamics of this spring-mass system are described mathematically by the simple harmonic oscillator and the regular periodic motion is known as simple harmonic motion. In the spring-mass system, oscillations occur because, at the static equilibrium displacement, the mass has kinetic energy which is converted into potential energy stored in the spring at the extremes of its path. The spring-mass system illustrates some common features of oscillation, namely the existence of an equilibrium and the presence of a restoring force which grows stronger the further the system deviates from equilibrium.
The harmonic oscillator offers a model of many more complicated types of oscillation and can be extended by the use of Fourier analysis.
# Damped, driven and self-induced oscillations
In real-world systems, the second law of thermodynamics dictates that there is some continual and inevitable conversion of energy into the thermal energy of the environment. Thus, damped oscillations tend to decay with time unless there is some net source of energy in the system. The simplest description of this decay process can be illustrated by the harmonic oscillator. In addition, an oscillating system may be subject to some external force (often sinusoidal), as when an AC circuit is connected to an outside power source. In this case the oscillation is said to be driven.
Some systems can be excited by energy transfer from the environment. This transfer typically occurs where systems are embedded in some fluid flow. For example, the phenomenon of flutter in aerodynamics occurs when an arbitrarily small displacement of an aircraft wing (from its equilibrium) results in an increase in the angle of attack of the wing on the air flow and a consequential increase in lift coefficient, leading to a still greater displacement. At sufficiently large displacements, the stiffness of the wing dominates to provide the restoring force that enables an oscillation.
# Coupled oscillations
The harmonic oscillator and the systems it models have a single degree of freedom. More complicated systems have more degrees of freedom, for example two masses and three springs (each mass being attached to fixed points and to each other). In such cases, the behavior of each variable influences that of the others. This leads to a coupling of the oscillations of the individual degrees of freedom. For example, two pendulum clocks mounted on a common wall will tend to synchronise. The apparent motions of the individual oscillations typically appears very complicated but a more economic, computationally simpler and conceptually deeper description is given by resolving the motion into normal modes.
# Continuous systems - waves
As the number of degrees of freedom becomes arbitrarily large, a system approaches continuity; examples include a string or the surface of a body of water. Such systems have (in the classical limit) an infinite number of normal modes and their oscillations occur in the form of waves that can characteristically propagate.
# Examples
See also: list of wave topics
## Mechanical
- Double pendulum
- Quantum harmonic oscillator
- Foucault pendulum
- Helmholtz resonator
- Playground swing
- String instruments
- Tuning fork
- Vibrating string
- Oscillations in the Sun (helioseismology) and stars (asteroseismology)
## Electrical
- Alternating current
- Armstrong oscillator
- Astable multivibrator
- Blocking oscillator
- Clapp oscillator
- Colpitts oscillator
- Delay line oscillator
- Electronic oscillator
- Hartley oscillator
- Oscillistor
- Pierce oscillator
- Relaxation oscillator
- RLC circuit
- Royer oscillator
- Vačkář oscillator
- Wien bridge oscillator
- Oscillators and Multivibrators
- Virtual Cathode Oscillator
## Electro-mechanical
- Crystal oscillator
- Loudspeaker
- Microphone
## Optical
- Laser (oscillation of electromagnetic field with frequency of order <math>10^{15}</math>Hz)
- Oscillator Toda or self-pulsation (pulsation of output power of laser at frequencies <math>10^{4}</math>Hz -- <math>10^{6}</math>Hz in the transient regime)
- Quantum oscillator may refer to an optical local oscillator, as well as to a usual model in quantum optics.
## Biological
- Circadian rhythm
- Prey-predator systems
- Neural oscillations
## Human
- Brain waves
- Pilot-induced oscillation
- Voice production
- Insulin release oscillations
## Economic and social
- Business cycle
- Generation gap
- Malthusian economics
- News cycle
## Climate and geophysics
- Chandler wobble
- El Niño-Southern Oscillation
- Quasi-biennial oscillation
- Tides in the Earth's oceans
## Chemical
- Belousov-Zhabotinsky reaction
- Mercury beating heart | https://www.wikidoc.org/index.php/Oscillator | |
ab4b6c8c3bc7629b72cb2c764c52ecd1961ddf78 | wikidoc | Ospemifene | Ospemifene
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# Black Box Warning
# Overview
Ospemifene is a Selective Estrogen Receptor Modulator that is FDA approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- OSPHENA is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.
### Dosage
- OSPHENA is an estrogen agonist/antagonist which has agonistic effects on the endometrium. Generally, when a product with estrogen agonistic effects on the endometrium is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin .
- Use of OSPHENA should be for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.
- Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause
- Take one 60 mg tablet with food once daily.
### DOSAGE FORMS AND STRENGTHS
- OSPHENA tablets are white to off-white, oval, biconvex, film coated tablets containing 60 mg of ospemifene and engraved with "60" on one side.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Ospemifene in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Ospemifene in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Ospemifene in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Ospemifene in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Ospemifene in pediatric patients.
# Contraindications
- OSPHENA is contraindicated in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding
- Known or suspected estrogen-dependent neoplasia
- Active DVT, pulmonary embolism (PE), or a history of these conditions
- Active arterial thromboembolic disease , or a history of these conditions
- OSPHENA is contraindicated in women who are or may become pregnant. OSPHENA may cause fetal harm when administered to a pregnant woman.
- Ospemifene was embryo-fetal lethal with labor difficulties and increased pup deaths in rats at doses below clinical exposures, and embryo-fetal lethal in rabbits at 10 times the clinical exposure based on mg/m2. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus.
# Warnings
- Risk factors for cardiovascular disorders, arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus), should be managed appropriately.
- In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per ten thousand women-years). The increase in risk was demonstrated in year 1 and persisted.
- In the clinical trials for OSPHENA (duration of treatment up to 15 months), the incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per thousand women, respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women in placebo.
- Should thromboembolic or hemorrhagic stroke occur or be suspected, OSPHENA should be discontinued immediately.
- In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. In the OSPHENA clinical trials, a single MI occurred in a woman receiving 60 mg of ospemifene.
- In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per ten thousand women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per ten thousand women-years). The increase in VTE risk was demonstrated during the first 2 years.
- In the OSPHENA clinical trials, the incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo. Should a VTE occur or be suspected, OSPHENA should be discontinued immediately.
- If feasible, OSPHENA should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
- Endometrial Cancer
- OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has agonistic effects. In the OSPHENA clinical trials (60 mg treatment group), no cases of endometrial cancer were seen with exposure up to 52 weeks. There was a single case of simple hyperplasia without atypia. Endometrial thickening equal to 5 mm or greater was seen in the OSPHENA treatment groups at a rate of 60.1 per thousand women vs. 21.2 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 86.1 per thousand women in OSPHENA vs. 13.3 per thousand women for placebo. Uterine polyps occurred at an incidence of 5.9 per thousand women vs. 1.8 per thousand women for placebo.
- An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. The use of progestins with OSPHENA therapy was not evaluated in the clinical trials.
- Clinical surveillance of all women using OSPHENA is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
- OSPHENA 60 mg has not been adequately studied in women with breast cancer; therefore it should not be used in women with known or suspected breast cancer or with a history of breast cancer.
- OSPHENA should not be used in women with severe hepatic impairment
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders
- Malignant Neoplasms
- 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 OSPHENA has been assessed in nine phase 2/3 trials (N=1892) with doses ranging from 5 to 90 mg per day. The duration of treatment in these studies ranged from 6 weeks to 15 months. Most women (N=1370) had a treatment period of at least 12 weeks, 409 had at least 52 weeks (1 year) of exposure.
- The incidence rates of thromboembolic and hemorrhagic stroke were 0.72 per thousand women (1 reported case of thromboembolic stroke) and 1.45 per thousand women (2 reported cases of hemorrhagic stroke), respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women, respectively in placebo. The incidence of deep vein thrombosis (DVT) was 1.45 per thousand women in OSPHENA 60 mg treatment group (2 reported cases of DVT) and 1.04 (1 case of DVT) in placebo.
- Table 1 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency ≥1%.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ospemifene in the drug label.
# Drug Interactions
- OSPHENA is primarily metabolized by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene.
- OSPHENA should not be used concomitantly with estrogens and estrogen agonists/antagonists. The safety of concomitant use of OSPHENA with estrogens and estrogen agonists/antagonists has not been studied.
- Fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor, should not be used with OSPHENA. Fluconazole increases the systemic exposure of ospemifene by 2.7-fold. Administration of fluconazole with ospemifene may increase the risk of OSPHENA-related adverse events .
- Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, co-administration of OSPHENA with drugs such as rifampin which induce CYP3A4, CYP2C9 and/or CYP2C19 activity would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect.
- Ketoconazole, a strong CYP3A4 inhibitor increases the systemic exposure of ospemifene by 1.4-fold. Administration of ketoconazole chronically with ospemifene may increase the risk of OSPHENA-related adverse reactions.
- Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. No study was conducted with multiple doses of warfarin. The effect of ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) was not studied.
- Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other drugs. Use of OSPHENA with other drug products that are highly protein bound may lead to increased exposure of either that drug or ospemifene.
- Co-administration of OSPHENA with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of OSPHENA-related adverse reactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Based on animal data, OSPHENA is likely to increase the risk of adverse outcomes during pregnancy and labor. Adverse findings at maternally toxic doses included embryofetal lethality in rats and rabbits, and neonatal mortality and difficult labor in rats. The reproductive effects observed are consistent with and are considered to be related to estrogen receptor activity of OSPHENA.
- The effects of OSPHENA on embryo-fetal development were studied in rats (0.1, 1 or 4 mg/kg/day) and rabbits (3, 10, or 30 mg/kg/day) when treated from implantation through organogenesis. In rabbits, there was an increase in the incidence of total resorptions at 30 mg/kg/day (10 times the human exposure based on surface area mg/m2). Drug-induced malformations were not observed in either rats or rabbits.
- The effects of OSPHENA on pre-and postnatal development were studied in pregnant rats (0.01, 0.05, and 0.25 mg/kg/day) treated from implantation through lactation. Pregnant rats given 0.05 or 0.25 mg/kg/day OSPHENA (0.8% to 4% the human exposure based on surface area mg/m2), had a significantly prolonged and difficult gestation, increased post-implantation loss, increased number of dead pups at birth, and an increased incidence of postnatal loss. OSPHENA did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures up to 4% the human exposure.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ospemifene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ospemifene during labor and delivery.
### Nursing Mothers
- It is not known whether OSPHENA is excreted in human breast milk.
- In a nonclinical study, ospemifene was excreted in rat milk and detected at concentrations higher than that in maternal plasma.
### Pediatric Use
- OSPHENA is not indicated in children. Clinical studies have not been conducted in the pediatric population.
### Geriatic Use
- Of the 1892 OSPHENA-treated women enrolled in the nine phase 2/3 trials of OSPHENA, >19 percent were 65 years of age or older. No clinically meaningful differences in safety or effectiveness were observed between these women and younger women less than 65 years of age.
### Gender
There is no FDA guidance on the use of Ospemifene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ospemifene with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of ospemifene in women with severe renal impairment (CrCL <30 mL/min) was similar to those in women with normal renal function .
- No dose adjustment of OSPHENA is required in women with renal impairment.
### Hepatic Impairment
- The pharmacokinetics of ospemifene has not been studied in women with severe hepatic impairment (Child-Pugh Class C); therefore, OSPHENA should not be used in women with severe hepatic impairment .
- No clinically important pharmacokinetic differences with OSPHENA were observed between women with mild to moderate hepatic impairment and healthy women .
- No dose adjustment of OSPHENA is required in women with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ospemifene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ospemifene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ospemifene in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ospemifene in the drug label.
# Overdosage
- There is no specific antidote for OSPHENA.
# Pharmacology
## Mechanism of Action
- OSPHENA is an estrogen agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).
## Structure
- OSPHENA is an estrogen agonist/antagonist. The chemical structure of ospemifene is shown in Figure 1.
- The chemical designation is Z-2-ethanol, and has the empirical formula C24H23ClO2, which corresponds to a molecular weight of 378.9. Ospemifene is a white to off-white crystalline powder that is insoluble in water and soluble in ethanol.
- Each OSPHENA tablet contains 60 mg of ospemifene. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ospemifene in the drug label.
## Pharmacokinetics
- Following a single oral administration of OSPHENA 60 mg tablet in postmenopausal women under fasted condition, peak median serum concentrations was reached at approximately 2 hours (range: 1 to 8 hours) post-dose (see Figure 2). Mean ospemifene Cmax and AUC0-inf were 533 ng/mL and 4165 nghr/mL, respectively. After a single oral administration of OSPHENA 60 mg tablet in postmenopausal women with a high fat/high calorie (860 kcal) meal, Cmax was reached at approximately 2.5 hours (range: 1 to 6 hours) post-dose. Mean ospemifene Cmax and AUC0-inf were 1198 ng/mL and 7521 nghr/mL, respectively. The absolute bioavailability of ospemifene was not evaluated. Ospemifene exhibits less than dose-proportional pharmacokinetics from 25 to 200 mg with ospemifene capsule formulation. Accumulation of ospemifene with respect to AUC0-inf was approximately 2 after twelve weeks of daily administration. Steady-state was reached after nine days of ospemifene administration.
- In general, food increased the bioavailability of ospemifene by approximately 2-3 fold. In a cross-study comparison, single dose OSPHENA 60 mg tablet administered with a high fat/high calorie meal (860 kcal) in postmenopausal women increased Cmax and AUC0-inf by 2.3- and 1.7-fold, respectively, compared to fasted condition. Elimination half-life and time to maximum concentration (Tmax) were unchanged in the presence of food. In two food effect studies in healthy males using different ospemifene tablet formulations Cmax and AUC0-inf increased by 2.3- and 1.8-fold, respectively, with a low fat/low calorie meal (300 kcal) and increased by 3.6- and 2.7-fold, respectively, with a high fat/high calorie meal (860 kcal), compared to fasted condition. OSPHENA should be taken with food .
- OSPHENA is highly (>99 percent) bound to serum proteins. The apparent volume of distribution is 448 L.
- In vitro experiments with human liver microsomes indicated that ospemifene primarily undergoes metabolism via CYP3A4, CYP2C9 and CYP2C19. The major metabolite was 4-hydroxyospemifene. The apparent total body clearance is 9.16 L/hr using a population approach.
- The apparent terminal half-life of ospemifene in postmenopausal women is approximately 26 hours. Following an oral administration of ospemifene, approximately 75% and 7% of the dose was excreted in feces and urine, respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine.
- The pharmacokinetics of ospemifene in pediatric patients has not been evaluated .
- No differences in ospemifene pharmacokinetics were detected with regard to age (range 40 to 80 years) .
- Race did not have clinically relevant effect on ospemifene pharmacokinetics.
- In women with severe renal impairment (CrCL <30 mL/min), the Cmax and AUC0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and higher by 20%, respectively .
- In women with mild hepatic impairment (Child-Pugh Class A), the Cmax and AUC0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and 9.1%, respectively, compared to women with normal hepatic function. In women with moderate hepatic impairment (Child-Pugh Class B), the Cmax and AUC0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were higher by 1% and 29%, respectively, compared to women with normal hepatic function. The effect of severe hepatic impairment on the pharmacokinetics of ospemifene has not been evaluated.
- Ospemifene is metabolized primarily by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene. In order of decreasing potency, ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6 and CYP3A4 in in vitro studies. Ospemifene is not a significant P-glycoprotein substrate in vitro; no in vivo transporter study was conducted.
- Effect of Co-Administered Drugs on the Pharmacokinetics of Ospemifene
- Fluconazole (CYP3A4/CYP2C9/CYP2C19 Inhibitor)
- Fluconazole (a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor) 400 mg was given on Day 1 followed by 200 mg on Days 2 to 5 under fasted condition. On Day 5 approximately one hour after fluconazole administration, ospemifene 60 mg was administered after breakfast (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Fluconazole 200 mg was taken for three additional days under fasted condition. Multiple doses of fluconazole in fourteen postmenopausal women increased the Cmax and AUC0-inf of ospemifene by 1.7- and 2.7-fold, respectively .
- Rifampin (CYP3A4/CYP2C9/CYP2C19 Inducer)
- Rifampin 600 mg was given once daily for 5 consecutive days (given at least one hour before or two hours after a meal) in the late afternoon. On Day 6 after an overnight fast, ospemifene 60 mg was administered in the morning after under fed condition (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Multiple doses of rifampin 600 mg in twelve postmenopausal women reduced Cmax and AUC0-inf of ospemifene by 51% and 58%, respectively. Rifampin and other inducers of CYP3A4 are expected to decrease the systemic exposure of ospemifene .
- Ketoconazole (CYP3A4 Inhibitor)
- Ketoconazole 400 mg was given once daily for 4 consecutive days after breakfast. On Day 5 after an overnight fast, ketoconazole 400 mg and ospemifene 60 mg were co-administered under fed condition (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Ketoconazole administration once daily continued for an additional 3 days (Days 6 to 8). Co-administration of a single 60 mg dose of ospemifene and multiple doses of ketoconazole in twelve postmenopausal women increased Cmax and AUC0-inf by 1.5- and 1.4-fold, respectively.
- Omeprazole (CYP2C19 Inhibitor)
- Omeprazole (a moderate CYP2C19 inhibitor) 40 mg was given for 5 days. On Day 5, approximately one hour after omeprazole administration, ospemifene 60 mg was administered after breakfast (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Multiple doses of omeprazole in fourteen postmenopausal women increased Cmax and AUC0-inf by 1.20- and 1.17-fold, respectively.
- Effect of Ospemifene on the Pharmacokinetics of the Co-Administered Drug
- Warfarin
- Ospemifene 60 mg was given after a light breakfast (two slices of bread with ham and cheese and juice) once daily for 12 days in sixteen postmenopausal women who were determined to be rapid metabolizers of CYP2C9 (CYP2C9*1/*1 or CYP2C9*1/*2). On Day 8, a single dose of warfarin 10 mg and vitamin K 10 mg were administered one hour after a light breakfast. The geometric mean ratio (90% CI) for S-warfarin with and without ospemifene for Cmax and AUC0-inf were 0.97 (0.92-1.02) and 0.96 (0.91-1.02), respectively. Multiple doses of ospemifene did not significantly affect the pharmacokinetics of a single dose of warfarin. No study was conducted with multiple doses of warfarin.
- Omeprazole
- Ospemifene 60 mg was administered once daily for 7 days after a light meal in the late afternoon in fourteen postmenopausal women. On Day 8 after an overnight fast, a single 20 mg dose of omeprazole was administered in the morning of at least 10 hrs; ospemifene was not given on Day 8. The geometric mean ratios for the metabolic index (omeprazole/5-hydroxyomeprazole) at the concentration at the 3 hr time point and for AUC0-8hr was 0.97 with and without ospemifene. It is unclear if ospemifene will affect the pharmacokinetics of drugs metabolized by CYP2C19 due to the significant time gap between ospemifene and omeprazole administration.
- Bupropion
- Ospemifene 60 mg was administered once daily for seven consecutive days after the evening meal in sixteen postmenopausal women (not homozygous for CYP2B6*6). On the Day 8 after overnight fast, a single 150 mg dose of sustained release bupropion was administered in morning under fasted condition. The geometric mean ratio (90% CI) for bupropion with and without ospemifene for Cmax and AUC0-inf were 0.82 (0.75-0.91) and 0.81 (0.77-0.86), respectively. The geometric mean ratio (90% CI) for hydroxybupropion, an active metabolite formed via CYP2B6, with and without ospemifene for Cmax and AUC0-inf were 1.16 (1.09-1.24) and 0.98 (0.92-1.04), respectively.
## Nonclinical Toxicology
- In a 2-year carcinogenicity study in female mice, ospemifene administration of 100, 400 or 1500 mg/kg/day was well tolerated. No evaluation for carcinogenicity was conducted in male mice. There was significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the human exposure based on AUC, and adrenal cortical tumors at 5 times the human exposure. In the ovary, an increase in sex cord/stromal tumors, tubulostromal tumors, granulosa cell tumors, and luteomas were also seen. These findings occurred at doses 2 to 5 times the human exposure based on AUC, and are probably related to estrogenic/antiestrogenic effect of ospemifene in mice.
- In a 2-year carcinogenicity study in rats, ospemifene administration of 10, 50, or 300 mg/kg/day was well tolerated. A significant increase in thymomas was recorded for males and thymomas for females at all ospemifene dose levels, or 0.3 to 1.2 times the human exposure based on AUC. In the liver, an increase in hepatocellular tumors were recorded at for females at all ospemifene dose levels.
- Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system. In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of DNA adducts in the liver of rats.
- The effect of ospemifene on fertility was not directly evaluated. In female rats and monkeys, decreases in ovarian and uterine weights, decreased corpora lutea number, increased ovarian cysts, uterine atrophy, and disrupted cycles were observed when given repeated daily oral doses. In male rats, atrophy of the prostate and seminal vesicles was noted. The effects on reproductive organs observed in animals are consistent with the estrogen receptor activity of ospemifene and potential for impairment of fertility.
# Clinical Studies
- The effectiveness and safety of OSPHENA on moderate to severe symptoms of vulvar and vaginal atrophy in postmenopausal women were examined in three placebo-controlled clinical trials (two 12-week efficacy trials and one 52-week long-term safety trial). In the three placebo-controlled trials, a total of 787 women received placebo and 1102 women received 60 mg OSPHENA.
- The first clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 826 generally healthy postmenopausal women between 41 to 81 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified at least one moderate to severe vaginal symptom that was considered the most bothersome to her (vaginal dryness, pain during intercourse , or vaginal irritation/itching). Treatment groups included 30 mg OSPHENA (n=282), 60 mg OSPHENA (n=276), and placebo (n=268). All women were assessed for improvement in the mean change from Baseline to Week 12 for the co-primary efficacy variables of: most bothersome symptom (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that was identified by the woman as most bothersome at baseline), percentage of vaginal superficial and vaginal parabasal cells on a vaginal smear, and vaginal pH. Following completion of 12-weeks, women with an intact uterus were allowed to enroll in a 40-week double-blind extension study, and women without an intact uterus were allowed to enroll in a 52-week open-label extension study.
- The second clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 919 generally healthy postmenopausal women between 41 to 79 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified either moderate to severe vaginal dryness (dryness cohort) or moderate to severe dyspareunia (dyspareunia cohort) as most bothersome to her at baseline. Treatment groups included 60 mg OSPHENA (n=463) and placebo (n=456). Primary endpoints and study conduct were similar to those in Trial 1.
- The third clinical trial was a 52-week, randomized, double-blind, placebo-controlled, long-term safety study that enrolled 426 generally healthy postmenopausal women between 49 to 79 years of age (mean 62 years of age) with an intact uterus. Treatment groups included 60 mg OSPHENA (n=363) and placebo (n=63).
- Effects on Dyspareunia
- In the 1st and 2nd clinical trial, the modified intent-to-treat population of women treated with OSPHENA when compared to placebo, demonstrated a statistically significant improvement (least square mean change from Baseline to Week 12) in the moderate to severe most bothersome symptom (MBS) of dyspareunia (1st trial p=0.0012, 2nd trial p<0.0001). See Table 2. A statistically significant increase in the proportion of superficial cells and a corresponding statistically significant decrease in the proportion of parabasal cells on a vaginal smear was also demonstrated (p<0.0001 for both). The mean reduction in vaginal pH between baseline and Week 12 was also statistically significant (p<0.0001).
# How Supplied
- OSPHENA tablets are white to off-white, oval, biconvex, film coated tablets containing 60 mg of ospemifene and engraved with "60" on one side. They are available as follows:
## Storage
- Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) .
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 60 mg Tablet Blister Pack Package
NDC 59630-580-30
Rx only
30 tablets
(Two blister cards of 15 tablets each)
Osphena™
(ospemifene) tablets
60 mg
For oral use only
Each tablet contains 60 mg ospemifene.
USUAL ADULT DOSAGE: See package insert.
Keep this and all drugs out of the reach of children.
SHIONOGI INC.
### Ingredients and Appearance
# Patient Counseling Information
- Hot Flashes or Flushes
- OSPHENA may initiate or increase the occurrence of hot flashes in some women.
- Inform postmenopausal women of the importance of reporting unusual vaginal bleeding to their healthcare providers as soon as possible
# Precautions with Alcohol
- Alcohol-Ospemifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Osphena®
# Look-Alike Drug Names
There is limited information regarding Ospemifene Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ospemifene
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
Ospemifene is a Selective Estrogen Receptor Modulator that is FDA approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- OSPHENA is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.
### Dosage
- OSPHENA is an estrogen agonist/antagonist which has agonistic effects on the endometrium. Generally, when a product with estrogen agonistic effects on the endometrium is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin .
- Use of OSPHENA should be for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.
- Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause
- Take one 60 mg tablet with food once daily.
### DOSAGE FORMS AND STRENGTHS
- OSPHENA tablets are white to off-white, oval, biconvex, film coated tablets containing 60 mg of ospemifene and engraved with "60" on one side.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Ospemifene in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Ospemifene in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Ospemifene in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Ospemifene in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Ospemifene in pediatric patients.
# Contraindications
- OSPHENA is contraindicated in women with any of the following conditions:
- Undiagnosed abnormal genital bleeding
- Known or suspected estrogen-dependent neoplasia
- Active DVT, pulmonary embolism (PE), or a history of these conditions
- Active arterial thromboembolic disease [for example, stroke and myocardial infarctions (MI)], or a history of these conditions
- OSPHENA is contraindicated in women who are or may become pregnant. OSPHENA may cause fetal harm when administered to a pregnant woman.
- Ospemifene was embryo-fetal lethal with labor difficulties and increased pup deaths in rats at doses below clinical exposures, and embryo-fetal lethal in rabbits at 10 times the clinical exposure based on mg/m2. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus.
# Warnings
- Risk factors for cardiovascular disorders, arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus), should be managed appropriately.
- In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per ten thousand women-years). The increase in risk was demonstrated in year 1 and persisted.
- In the clinical trials for OSPHENA (duration of treatment up to 15 months), the incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per thousand women, respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women in placebo.
- Should thromboembolic or hemorrhagic stroke occur or be suspected, OSPHENA should be discontinued immediately.
- In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. In the OSPHENA clinical trials, a single MI occurred in a woman receiving 60 mg of ospemifene.
- In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per ten thousand women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per ten thousand women-years). The increase in VTE risk was demonstrated during the first 2 years.
- In the OSPHENA clinical trials, the incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo. Should a VTE occur or be suspected, OSPHENA should be discontinued immediately.
- If feasible, OSPHENA should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
- Endometrial Cancer
- OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has agonistic effects. In the OSPHENA clinical trials (60 mg treatment group), no cases of endometrial cancer were seen with exposure up to 52 weeks. There was a single case of simple hyperplasia without atypia. Endometrial thickening equal to 5 mm or greater was seen in the OSPHENA treatment groups at a rate of 60.1 per thousand women vs. 21.2 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 86.1 per thousand women in OSPHENA vs. 13.3 per thousand women for placebo. Uterine polyps occurred at an incidence of 5.9 per thousand women vs. 1.8 per thousand women for placebo.
- An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. The use of progestins with OSPHENA therapy was not evaluated in the clinical trials.
- Clinical surveillance of all women using OSPHENA is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
- OSPHENA 60 mg has not been adequately studied in women with breast cancer; therefore it should not be used in women with known or suspected breast cancer or with a history of breast cancer.
- OSPHENA should not be used in women with severe hepatic impairment
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular Disorders
- Malignant Neoplasms
- 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 OSPHENA has been assessed in nine phase 2/3 trials (N=1892) with doses ranging from 5 to 90 mg per day. The duration of treatment in these studies ranged from 6 weeks to 15 months. Most women (N=1370) had a treatment period of at least 12 weeks, 409 had at least 52 weeks (1 year) of exposure.
- The incidence rates of thromboembolic and hemorrhagic stroke were 0.72 per thousand women (1 reported case of thromboembolic stroke) and 1.45 per thousand women (2 reported cases of hemorrhagic stroke), respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women, respectively in placebo. The incidence of deep vein thrombosis (DVT) was 1.45 per thousand women in OSPHENA 60 mg treatment group (2 reported cases of DVT) and 1.04 (1 case of DVT) in placebo.
- Table 1 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency ≥1%.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ospemifene in the drug label.
# Drug Interactions
- OSPHENA is primarily metabolized by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene.
- OSPHENA should not be used concomitantly with estrogens and estrogen agonists/antagonists. The safety of concomitant use of OSPHENA with estrogens and estrogen agonists/antagonists has not been studied.
- Fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor, should not be used with OSPHENA. Fluconazole increases the systemic exposure of ospemifene by 2.7-fold. Administration of fluconazole with ospemifene may increase the risk of OSPHENA-related adverse events .
- Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, co-administration of OSPHENA with drugs such as rifampin which induce CYP3A4, CYP2C9 and/or CYP2C19 activity would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect.
- Ketoconazole, a strong CYP3A4 inhibitor increases the systemic exposure of ospemifene by 1.4-fold. Administration of ketoconazole chronically with ospemifene may increase the risk of OSPHENA-related adverse reactions.
- Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. No study was conducted with multiple doses of warfarin. The effect of ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) was not studied.
- Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other drugs. Use of OSPHENA with other drug products that are highly protein bound may lead to increased exposure of either that drug or ospemifene.
- Co-administration of OSPHENA with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of OSPHENA-related adverse reactions.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Based on animal data, OSPHENA is likely to increase the risk of adverse outcomes during pregnancy and labor. Adverse findings at maternally toxic doses included embryofetal lethality in rats and rabbits, and neonatal mortality and difficult labor in rats. The reproductive effects observed are consistent with and are considered to be related to estrogen receptor activity of OSPHENA.
- The effects of OSPHENA on embryo-fetal development were studied in rats (0.1, 1 or 4 mg/kg/day) and rabbits (3, 10, or 30 mg/kg/day) when treated from implantation through organogenesis. In rabbits, there was an increase in the incidence of total resorptions at 30 mg/kg/day (10 times the human exposure based on surface area mg/m2). Drug-induced malformations were not observed in either rats or rabbits.
- The effects of OSPHENA on pre-and postnatal development were studied in pregnant rats (0.01, 0.05, and 0.25 mg/kg/day) treated from implantation through lactation. Pregnant rats given 0.05 or 0.25 mg/kg/day OSPHENA (0.8% to 4% the human exposure based on surface area mg/m2), had a significantly prolonged and difficult gestation, increased post-implantation loss, increased number of dead pups at birth, and an increased incidence of postnatal loss. OSPHENA did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures up to 4% the human exposure.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ospemifene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ospemifene during labor and delivery.
### Nursing Mothers
- It is not known whether OSPHENA is excreted in human breast milk.
- In a nonclinical study, ospemifene was excreted in rat milk and detected at concentrations higher than that in maternal plasma.
### Pediatric Use
- OSPHENA is not indicated in children. Clinical studies have not been conducted in the pediatric population.
### Geriatic Use
- Of the 1892 OSPHENA-treated women enrolled in the nine phase 2/3 trials of OSPHENA, >19 percent were 65 years of age or older. No clinically meaningful differences in safety or effectiveness were observed between these women and younger women less than 65 years of age.
### Gender
There is no FDA guidance on the use of Ospemifene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ospemifene with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of ospemifene in women with severe renal impairment (CrCL <30 mL/min) was similar to those in women with normal renal function .
- No dose adjustment of OSPHENA is required in women with renal impairment.
### Hepatic Impairment
- The pharmacokinetics of ospemifene has not been studied in women with severe hepatic impairment (Child-Pugh Class C); therefore, OSPHENA should not be used in women with severe hepatic impairment .
- No clinically important pharmacokinetic differences with OSPHENA were observed between women with mild to moderate hepatic impairment and healthy women .
- No dose adjustment of OSPHENA is required in women with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ospemifene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ospemifene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ospemifene in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ospemifene in the drug label.
# Overdosage
- There is no specific antidote for OSPHENA.
# Pharmacology
## Mechanism of Action
- OSPHENA is an estrogen agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).
## Structure
- OSPHENA is an estrogen agonist/antagonist. The chemical structure of ospemifene is shown in Figure 1.
- The chemical designation is Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol, and has the empirical formula C24H23ClO2, which corresponds to a molecular weight of 378.9. Ospemifene is a white to off-white crystalline powder that is insoluble in water and soluble in ethanol.
- Each OSPHENA tablet contains 60 mg of ospemifene. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ospemifene in the drug label.
## Pharmacokinetics
- Following a single oral administration of OSPHENA 60 mg tablet in postmenopausal women under fasted condition, peak median serum concentrations was reached at approximately 2 hours (range: 1 to 8 hours) post-dose (see Figure 2). Mean ospemifene Cmax and AUC0-inf were 533 ng/mL and 4165 ng•hr/mL, respectively. After a single oral administration of OSPHENA 60 mg tablet in postmenopausal women with a high fat/high calorie (860 kcal) meal, Cmax was reached at approximately 2.5 hours (range: 1 to 6 hours) post-dose. Mean ospemifene Cmax and AUC0-inf were 1198 ng/mL and 7521 ng•hr/mL, respectively. The absolute bioavailability of ospemifene was not evaluated. Ospemifene exhibits less than dose-proportional pharmacokinetics from 25 to 200 mg with ospemifene capsule formulation. Accumulation of ospemifene with respect to AUC0-inf was approximately 2 after twelve weeks of daily administration. Steady-state was reached after nine days of ospemifene administration.
- In general, food increased the bioavailability of ospemifene by approximately 2-3 fold. In a cross-study comparison, single dose OSPHENA 60 mg tablet administered with a high fat/high calorie meal (860 kcal) in postmenopausal women increased Cmax and AUC0-inf by 2.3- and 1.7-fold, respectively, compared to fasted condition. Elimination half-life and time to maximum concentration (Tmax) were unchanged in the presence of food. In two food effect studies in healthy males using different ospemifene tablet formulations Cmax and AUC0-inf increased by 2.3- and 1.8-fold, respectively, with a low fat/low calorie meal (300 kcal) and increased by 3.6- and 2.7-fold, respectively, with a high fat/high calorie meal (860 kcal), compared to fasted condition. OSPHENA should be taken with food [see Dosage and Administration (2.1)].
- OSPHENA is highly (>99 percent) bound to serum proteins. The apparent volume of distribution is 448 L.
- In vitro experiments with human liver microsomes indicated that ospemifene primarily undergoes metabolism via CYP3A4, CYP2C9 and CYP2C19. The major metabolite was 4-hydroxyospemifene. The apparent total body clearance is 9.16 L/hr using a population approach.
- The apparent terminal half-life of ospemifene in postmenopausal women is approximately 26 hours. Following an oral administration of ospemifene, approximately 75% and 7% of the dose was excreted in feces and urine, respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine.
- The pharmacokinetics of ospemifene in pediatric patients has not been evaluated .
- No differences in ospemifene pharmacokinetics were detected with regard to age (range 40 to 80 years) [see Use in Specific Populations (8.5)].
- Race did not have clinically relevant effect on ospemifene pharmacokinetics.
- In women with severe renal impairment (CrCL <30 mL/min), the Cmax and AUC0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and higher by 20%, respectively [see Use in Specific Populations (8.6)].
- In women with mild hepatic impairment (Child-Pugh Class A), the Cmax and AUC0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and 9.1%, respectively, compared to women with normal hepatic function. In women with moderate hepatic impairment (Child-Pugh Class B), the Cmax and AUC0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were higher by 1% and 29%, respectively, compared to women with normal hepatic function. The effect of severe hepatic impairment on the pharmacokinetics of ospemifene has not been evaluated.
- Ospemifene is metabolized primarily by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene. In order of decreasing potency, ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6 and CYP3A4 in in vitro studies. Ospemifene is not a significant P-glycoprotein substrate in vitro; no in vivo transporter study was conducted.
- Effect of Co-Administered Drugs on the Pharmacokinetics of Ospemifene
- Fluconazole (CYP3A4/CYP2C9/CYP2C19 Inhibitor)
- Fluconazole (a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor) 400 mg was given on Day 1 followed by 200 mg on Days 2 to 5 under fasted condition. On Day 5 approximately one hour after fluconazole administration, ospemifene 60 mg was administered after breakfast (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Fluconazole 200 mg was taken for three additional days under fasted condition. Multiple doses of fluconazole in fourteen postmenopausal women increased the Cmax and AUC0-inf of ospemifene by 1.7- and 2.7-fold, respectively .
- Rifampin (CYP3A4/CYP2C9/CYP2C19 Inducer)
- Rifampin 600 mg was given once daily for 5 consecutive days (given at least one hour before or two hours after a meal) in the late afternoon. On Day 6 after an overnight fast, ospemifene 60 mg was administered in the morning after under fed condition (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Multiple doses of rifampin 600 mg in twelve postmenopausal women reduced Cmax and AUC0-inf of ospemifene by 51% and 58%, respectively. Rifampin and other inducers of CYP3A4 are expected to decrease the systemic exposure of ospemifene .
- Ketoconazole (CYP3A4 Inhibitor)
- Ketoconazole 400 mg was given once daily for 4 consecutive days after breakfast. On Day 5 after an overnight fast, ketoconazole 400 mg and ospemifene 60 mg were co-administered under fed condition (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Ketoconazole administration once daily continued for an additional 3 days (Days 6 to 8). Co-administration of a single 60 mg dose of ospemifene and multiple doses of ketoconazole in twelve postmenopausal women increased Cmax and AUC0-inf by 1.5- and 1.4-fold, respectively.
- Omeprazole (CYP2C19 Inhibitor)
- Omeprazole (a moderate CYP2C19 inhibitor) 40 mg was given for 5 days. On Day 5, approximately one hour after omeprazole administration, ospemifene 60 mg was administered after breakfast (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Multiple doses of omeprazole in fourteen postmenopausal women increased Cmax and AUC0-inf by 1.20- and 1.17-fold, respectively.
- Effect of Ospemifene on the Pharmacokinetics of the Co-Administered Drug
- Warfarin
- Ospemifene 60 mg was given after a light breakfast (two slices of bread with ham and cheese and juice) once daily for 12 days in sixteen postmenopausal women who were determined to be rapid metabolizers of CYP2C9 (CYP2C9*1/*1 or CYP2C9*1/*2). On Day 8, a single dose of warfarin 10 mg and vitamin K 10 mg were administered one hour after a light breakfast. The geometric mean ratio (90% CI) for S-warfarin with and without ospemifene for Cmax and AUC0-inf were 0.97 (0.92-1.02) and 0.96 (0.91-1.02), respectively. Multiple doses of ospemifene did not significantly affect the pharmacokinetics of a single dose of warfarin. No study was conducted with multiple doses of warfarin.
- Omeprazole
- Ospemifene 60 mg was administered once daily for 7 days after a light meal in the late afternoon in fourteen postmenopausal women. On Day 8 after an overnight fast, a single 20 mg dose of omeprazole was administered in the morning of at least 10 hrs; ospemifene was not given on Day 8. The geometric mean ratios for the metabolic index (omeprazole/5-hydroxyomeprazole) at the concentration at the 3 hr time point and for AUC0-8hr was 0.97 with and without ospemifene. It is unclear if ospemifene will affect the pharmacokinetics of drugs metabolized by CYP2C19 due to the significant time gap between ospemifene and omeprazole administration.
- Bupropion
- Ospemifene 60 mg was administered once daily for seven consecutive days after the evening meal in sixteen postmenopausal women (not homozygous for CYP2B6*6). On the Day 8 after overnight fast, a single 150 mg dose of sustained release bupropion was administered in morning under fasted condition. The geometric mean ratio (90% CI) for bupropion with and without ospemifene for Cmax and AUC0-inf were 0.82 (0.75-0.91) and 0.81 (0.77-0.86), respectively. The geometric mean ratio (90% CI) for hydroxybupropion, an active metabolite formed via CYP2B6, with and without ospemifene for Cmax and AUC0-inf were 1.16 (1.09-1.24) and 0.98 (0.92-1.04), respectively.
## Nonclinical Toxicology
- In a 2-year carcinogenicity study in female mice, ospemifene administration of 100, 400 or 1500 mg/kg/day was well tolerated. No evaluation for carcinogenicity was conducted in male mice. There was significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the human exposure based on AUC, and adrenal cortical tumors at 5 times the human exposure. In the ovary, an increase in sex cord/stromal tumors, tubulostromal tumors, granulosa cell tumors, and luteomas were also seen. These findings occurred at doses 2 to 5 times the human exposure based on AUC, and are probably related to estrogenic/antiestrogenic effect of ospemifene in mice.
- In a 2-year carcinogenicity study in rats, ospemifene administration of 10, 50, or 300 mg/kg/day was well tolerated. A significant increase in thymomas was recorded for males and thymomas for females at all ospemifene dose levels, or 0.3 to 1.2 times the human exposure based on AUC. In the liver, an increase in hepatocellular tumors were recorded at for females at all ospemifene dose levels.
- Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system. In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of DNA adducts in the liver of rats.
- The effect of ospemifene on fertility was not directly evaluated. In female rats and monkeys, decreases in ovarian and uterine weights, decreased corpora lutea number, increased ovarian cysts, uterine atrophy, and disrupted cycles were observed when given repeated daily oral doses. In male rats, atrophy of the prostate and seminal vesicles was noted. The effects on reproductive organs observed in animals are consistent with the estrogen receptor activity of ospemifene and potential for impairment of fertility.
# Clinical Studies
- The effectiveness and safety of OSPHENA on moderate to severe symptoms of vulvar and vaginal atrophy in postmenopausal women were examined in three placebo-controlled clinical trials (two 12-week efficacy trials and one 52-week long-term safety trial). In the three placebo-controlled trials, a total of 787 women received placebo and 1102 women received 60 mg OSPHENA.
- The first clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 826 generally healthy postmenopausal women between 41 to 81 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified at least one moderate to severe vaginal symptom that was considered the most bothersome to her (vaginal dryness, pain during intercourse [dyspareunia], or vaginal irritation/itching). Treatment groups included 30 mg OSPHENA (n=282), 60 mg OSPHENA (n=276), and placebo (n=268). All women were assessed for improvement in the mean change from Baseline to Week 12 for the co-primary efficacy variables of: most bothersome symptom (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that was identified by the woman as most bothersome at baseline), percentage of vaginal superficial and vaginal parabasal cells on a vaginal smear, and vaginal pH. Following completion of 12-weeks, women with an intact uterus were allowed to enroll in a 40-week double-blind extension study, and women without an intact uterus were allowed to enroll in a 52-week open-label extension study.
- The second clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 919 generally healthy postmenopausal women between 41 to 79 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified either moderate to severe vaginal dryness (dryness cohort) or moderate to severe dyspareunia (dyspareunia cohort) as most bothersome to her at baseline. Treatment groups included 60 mg OSPHENA (n=463) and placebo (n=456). Primary endpoints and study conduct were similar to those in Trial 1.
- The third clinical trial was a 52-week, randomized, double-blind, placebo-controlled, long-term safety study that enrolled 426 generally healthy postmenopausal women between 49 to 79 years of age (mean 62 years of age) with an intact uterus. Treatment groups included 60 mg OSPHENA (n=363) and placebo (n=63).
- Effects on Dyspareunia
- In the 1st and 2nd clinical trial, the modified intent-to-treat population of women treated with OSPHENA when compared to placebo, demonstrated a statistically significant improvement (least square mean change from Baseline to Week 12) in the moderate to severe most bothersome symptom (MBS) of dyspareunia (1st trial p=0.0012, 2nd trial p<0.0001). See Table 2. A statistically significant increase in the proportion of superficial cells and a corresponding statistically significant decrease in the proportion of parabasal cells on a vaginal smear was also demonstrated (p<0.0001 for both). The mean reduction in vaginal pH between baseline and Week 12 was also statistically significant (p<0.0001).
# How Supplied
- OSPHENA tablets are white to off-white, oval, biconvex, film coated tablets containing 60 mg of ospemifene and engraved with "60" on one side. They are available as follows:
## Storage
- Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 60 mg Tablet Blister Pack Package
NDC 59630-580-30
Rx only
30 tablets
(Two blister cards of 15 tablets each)
Osphena™
(ospemifene) tablets
60 mg
For oral use only
Each tablet contains 60 mg ospemifene.
USUAL ADULT DOSAGE: See package insert.
Keep this and all drugs out of the reach of children.
SHIONOGI INC.
### Ingredients and Appearance
# Patient Counseling Information
- Hot Flashes or Flushes
- OSPHENA may initiate or increase the occurrence of hot flashes in some women.
- Inform postmenopausal women of the importance of reporting unusual vaginal bleeding to their healthcare providers as soon as possible
# Precautions with Alcohol
- Alcohol-Ospemifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Osphena®[1]
# Look-Alike Drug Names
There is limited information regarding Ospemifene Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ospemifene | |
cd0f6564a2ffb3600cad7d4984b5194d84f32883 | wikidoc | Osteoblast | Osteoblast
# Overview
An osteoblast (from the Greek words for "bone" and "germ" or embryonic) is a mononucleate cell that is responsible for bone formation. Osteoblasts produce osteoid, which is composed mainly of Type I collagen. Osteoblasts are also responsible for mineralization of the osteoid matrix. Bone is a dynamic tissue that is constantly being reshaped by osteoblasts, which build bone, and osteoclasts, which resorb bone.
# Osteogenesis
Osteoblasts arise from osteoprogenitor cells located in the periosteum and the bone marrow. Osteoprogenitors are immature progenitor cells that express the master regulatory transcription factor Cbfa1/Runx2.
Osteoprogenitors are induced to differentiate under the influence of growth factors, in particular the bone morphogenetic proteins (BMPs). Aside from BMPs, other growth factors including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β) may promote the division of osteoprogenitors and potentially increase osteogenesis.
Once osteoprogenitors start to differentiate into osteoblasts, they begin to express a range of genetic markers including Osterix, Col1, ALP, osteocalcin, osteopontin, and osteonectin. Although the term osteoblast implies an immature cell type, osteoblasts are in fact the mature bone cells entirely responsible for generating bone tissue in animals and humans.
# Morphology and histological staining
The cytoplasm of osteoblasts appears to be basophilic via normal H&E stain due to presence of large amount of rough endoplasmic reticulum. A large Golgi apparatus is also present in the centre. The nucleus is spherical and large. Osteoblasts can be stained for type 1 collagen or for the production of alkaline phosphatase.
# Osteoblasts and osteocytes
Osteoblasts that become trapped in the bone matrix become osteocytes. They cease to generate osteoid and mineralized matrix, and instead act in a paracrine manner on active osteoblasts. They are believed to act in a mechanosensory manner. | Osteoblast
Template:Infobox Anatomy
# Overview
An osteoblast (from the Greek words for "bone" and "germ" or embryonic) is a mononucleate cell that is responsible for bone formation. Osteoblasts produce osteoid, which is composed mainly of Type I collagen. Osteoblasts are also responsible for mineralization of the osteoid matrix. Bone is a dynamic tissue that is constantly being reshaped by osteoblasts, which build bone, and osteoclasts, which resorb bone.
# Osteogenesis
Osteoblasts arise from osteoprogenitor cells located in the periosteum and the bone marrow. Osteoprogenitors are immature progenitor cells that express the master regulatory transcription factor Cbfa1/Runx2.
Osteoprogenitors are induced to differentiate under the influence of growth factors, in particular the bone morphogenetic proteins (BMPs). Aside from BMPs, other growth factors including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β) may promote the division of osteoprogenitors and potentially increase osteogenesis.
Once osteoprogenitors start to differentiate into osteoblasts, they begin to express a range of genetic markers including Osterix, Col1, ALP, osteocalcin, osteopontin, and osteonectin. Although the term osteoblast implies an immature cell type, osteoblasts are in fact the mature bone cells entirely responsible for generating bone tissue in animals and humans.
# Morphology and histological staining
The cytoplasm of osteoblasts appears to be basophilic via normal H&E stain due to presence of large amount of rough endoplasmic reticulum. A large Golgi apparatus is also present in the centre. The nucleus is spherical and large. Osteoblasts can be stained for type 1 collagen or for the production of alkaline phosphatase.
# Osteoblasts and osteocytes
Osteoblasts that become trapped in the bone matrix become osteocytes. They cease to generate osteoid and mineralized matrix, and instead act in a paracrine manner on active osteoblasts. They are believed to act in a mechanosensory manner.
# External links
- Template:LoyolaMedEd
Template:Bone and cartilage
ca:Osteoblast
de:Osteoblast
it:Osteoblasto
he:אוסטאובלסט
nl:Osteoblast
sk:Osteoblast
sv:Osteoblast
Template:Jb1
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Osteoblast | |
263b7edf0426ad1f1fad40af5d1af64781a05e30 | wikidoc | Osteoclast | Osteoclast
# Overview
An osteoclast (from the Greek words for "bone" and "broken") is a type of bone cell that removes bone tissue by removing the bone's mineralized matrix. This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue. Osteoblasts form bone; osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line. Osteoclasts are characterized by high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K.
# Morphology
An osteoclast is a large cell that is characterized by multiple nuclei and a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration of vesicles and vacuoles. At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border", which touches the surface of the bone tissue. The ruffled border, which facilitates removal of the bony matrix, is a morphologic characteristic of an osteoclast that is actively resorbing bone. The ruffled border increases surface area interface for bone resorption. The mineral portion of the matrix (called hydroxyapatite) includes calcium and phosphate ions. These ions are absorbed into small vesicles (see endocytosis) which move across the cell and eventually are released into the extracellular fluid, thus increasing levels of the ions in the blood.
# Formation
Osteoclasts formation requires the presence of RANK ligand (receptor activator of nuclear factor κβ) and M-CSF (Macrophage colony-stimulating factor). These membrane bound proteins are produced by neighbouring stromal cells and osteoblasts; thus requiring direct contact between these cells and osteoclast precursors.
M-CSF acts through its receptor on the osteoclast, c-fms (colony stimulating factor 1 receptor), a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells.
RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. NF-κβ activation is stimulated almost immediately after RANKL-RANK interaction occurs, and is not upregulated. NFATc1 stimulation, however, begins ~24-48 hours after binding occurs and its expression has been shown to be RANKL dependent.
Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which binds to RANKL thereby preventing interaction with RANK.
# Function
Once activated, they move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship's lacuna, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast's plasmalemma to the underlying bone. Sealing zones are bounded by belts of specilized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The osteoclast releases hydrogen ions (H2O + CO2 → HCO3- + H+) through the ruffled border into the cavity, acidifying and dissolving the mineralized bone matrix into Ca2+, H3PO4, H2CO3 and water. Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease(MMP) groups , are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.
## Cathepsin K and other cathepsins
Cathepsin K is a collagenolytic, papain-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by lack of functional cathepsin K expression. Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced osteoclastogenesis.
Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa.
In the osteoclast, cathepsin K functions in the resorptive process. Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Here, it is the major protease involved in the degradation of type I collagen and other noncollagenous proteins, which have been demineralized by the acidic environment of the resorptive pit. From the resorptive pit, cathepsin K transmigrates across the ruffled border, through the osteoclast via intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with ROS generation by TRAP further degrades bone resorption products.
Numerous other cathepsins are expressed in osteoclasts. These include cathepsin B, C, D, E, G, and L. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels that cathepsin K.
Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities.
## Matrix metalloproteinases
The matrix metalloproteinases (MMPs) comprise a family of more that 20 zinc-dependent endopeptidases. The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis.
MMP-9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair.
MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption.
MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is know about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.
# Regulation
Osteoclasts are regulated by several hormones, including parathyroid hormone (PTH) from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). This last hormone, IL-6, is one of the factors in the disease osteoporosis, which is an imbalance between bone resorption and bone formation. Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Note that these molecules also regulate differentiation of the osteoclast.
# Alternate use of term
An osteoclast can also be an instrument used to fracture and reset bones (the origin is Greek osteon:bone and klastos:broken). To avoid confusion, the cell was originally termed osotoclast. When the surgical instrument went out of use, the cell became known by its present name. | Osteoclast
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An osteoclast (from the Greek words for "bone" and "broken") is a type of bone cell that removes bone tissue by removing the bone's mineralized matrix. This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue. Osteoblasts form bone; osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line.[1] Osteoclasts are characterized by high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K.
# Morphology
An osteoclast is a large cell that is characterized by multiple nuclei and a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration of vesicles and vacuoles.[2][3] At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border", which touches the surface of the bone tissue.[1] The ruffled border, which facilitates removal of the bony matrix, is a morphologic characteristic of an osteoclast that is actively resorbing bone. The ruffled border increases surface area interface for bone resorption. The mineral portion of the matrix (called hydroxyapatite) includes calcium and phosphate ions. These ions are absorbed into small vesicles (see endocytosis) which move across the cell and eventually are released into the extracellular fluid, thus increasing levels of the ions in the blood.
# Formation
Osteoclasts formation requires the presence of RANK ligand (receptor activator of nuclear factor κβ) and M-CSF (Macrophage colony-stimulating factor). These membrane bound proteins are produced by neighbouring stromal cells and osteoblasts; thus requiring direct contact between these cells and osteoclast precursors.
M-CSF acts through its receptor on the osteoclast, c-fms (colony stimulating factor 1 receptor), a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells.
RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. NF-κβ activation is stimulated almost immediately after RANKL-RANK interaction occurs, and is not upregulated. NFATc1 stimulation, however, begins ~24-48 hours after binding occurs and its expression has been shown to be RANKL dependent.
Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which binds to RANKL thereby preventing interaction with RANK.
# Function
Once activated, they move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship's lacuna, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast's plasmalemma to the underlying bone. Sealing zones are bounded by belts of specilized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The osteoclast releases hydrogen ions (H2O + CO2 → HCO3- + H+) through the ruffled border into the cavity, acidifying and dissolving the mineralized bone matrix into Ca2+, H3PO4, H2CO3 and water. Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease(MMP) groups , are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.
## Cathepsin K and other cathepsins
Cathepsin K is a collagenolytic, papain-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by lack of functional cathepsin K expression. Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced osteoclastogenesis.
Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa.
In the osteoclast, cathepsin K functions in the resorptive process. Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Here, it is the major protease involved in the degradation of type I collagen and other noncollagenous proteins, which have been demineralized by the acidic environment of the resorptive pit. From the resorptive pit, cathepsin K transmigrates across the ruffled border, through the osteoclast via intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with ROS generation by TRAP further degrades bone resorption products.
Numerous other cathepsins are expressed in osteoclasts. These include cathepsin B, C, D, E, G, and L. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels that cathepsin K.
Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities.
## Matrix metalloproteinases
The matrix metalloproteinases (MMPs) comprise a family of more that 20 zinc-dependent endopeptidases. The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis.
MMP-9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair.
MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption.
MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is know about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.
# Regulation
Osteoclasts are regulated by several hormones, including parathyroid hormone (PTH) from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). This last hormone, IL-6, is one of the factors in the disease osteoporosis, which is an imbalance between bone resorption and bone formation. Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Note that these molecules also regulate differentiation of the osteoclast.[4]
# Alternate use of term
An osteoclast can also be an instrument used to fracture and reset bones (the origin is Greek osteon:bone and klastos:broken). To avoid confusion, the cell was originally termed osotoclast. When the surgical instrument went out of use, the cell became known by its present name. | https://www.wikidoc.org/index.php/Osteoclast | |
dd4678d218d1bcf6924cfa21ae2c5acee9203373 | wikidoc | Osteopathy | Osteopathy
Osteopathy is an approach to healthcare that emphasizes the role of the musculoskeletal system in health and disease. In most countries osteopathy is a form of complementary medicine, emphasizing a holistic approach and the skilled use of a range of manual and physical treatment interventions (Osteopathic Manipulative Medicine, or OMM in the United States) in the prevention and treatment of disease. In practice, this most commonly relates to musculoskeletal problems such as back and neck pain.
Many osteopaths see their role as facilitating the body's own recuperative powers by treating musculoskeletal or somatic dysfunction. According to the American Osteopathic Association, the difference between an osteopath and an osteopathic physician is often confused. In the United States, Doctors of Osteopathic Medicine (D.O.s) are fully licensed medical physicians and surgeons, practicing in all clinical specialties along with their M.D. colleagues . Just like M.D.s, D.O.s practice the full scope of medicine, but with an emphasis on the role of the neuromusculoskeletal system. D.O.s practicing in primary care, pediatrics, family, or internal medicine, are trained to have a more empathetic approach to patient care which has awarded them some level of distinction from M.D.s Outside the United States. The practice rights of U.S.-trained Doctors of Osteopathic medicine varies.
# History
The practice of osteopathic medicine began in the United States in 1874. The term "osteopathy" was coined by Andrew Taylor Still, M.D., an allopathically-trained physician who was born in 1828 in Virginia. Still was a free state leader who lived near Baldwin City, Kansas at the time of the American Civil War, and it was here he developed the practice of osteopathy. Still was trained by apprenticeship, as were most physicians of the day, and was employed as an army doctor during the American Civil War in the U.S. Army. The horrors of battlefield injury and the subsequent death of his wife and several children from infectious diseases left him totally disillusioned with the traditional practice of medicine. Still perceived the medical practices of his day to be ineffective, even barbaric. Troubled by what he saw as problems in the medical profession, Still founded osteopathic practice. Using an alternative philosophical approach, he opposed the use of drugs and surgery as remedial agents, reserving their use for such cases as being the cure for the condition, such as an antidote for a poison or amputation for gangrene. He saw the human body as being capable of curing itself, and the duty of the physician to remove any impediments to the healthy function of each person. He promoted healthy lifestyle, nutrition, abstinence from alcohol and drugs, and used manipulative techniques to improve physiological function.
Still named his new school of medicine "osteopathy," reasoning that "the bone, osteon, was the starting point from which was to ascertain the cause of pathological conditions." The object of osteopathy was to "improve upon the present systems of surgery, midwifery, and the treatment of general diseases." Its scientific foundation was the discipline of anatomy. Its philosophy was based on the understanding of the integration between body, mind and spirit, the interrelatedness of structure and function, and the ability of the body to heal itself when mechanically sound. Osteopathic treatment must be a rational application of these principles in comprehensive patient care with a focus on the neuromusculoskeletal system as an integral part of health and disease processes. Over time he and his students and faculty developed a complete medical school curriculum which included a series of specialized physical treatments, now called Osteopathic Manipulative Treatment (OMT). Still founded the American School of Osteopathy (now the Andrew Taylor Still University, Kirksville College of Osteopathic Medicine) in Kirksville, Missouri, for the teaching of osteopathic medicine on May 10, 1892. While the state of Missouri, recognizing the equivalency of the curriculum, was willing to grant him a charter for awarding the M.D. degree, he remained dissatisfied with the limitations of allopathic medicine and instead chose to retain the distinction of the D.O. degree.
In the late 1800s Still taught that "dis-ease" was caused when bones were out of place and disrupted the flow of blood or the flow of nervous impulses; he therefore concluded that one could cure diseases by manipulating bones to restore the interrupted flow. Still stimulated his students to investigate these postulates. Research began in the 1890s at Kirksville and has continued there and at other osteopathic institutions ever since. The A.T. Still Research Institute was founded in 1913 and Louisa Burns, D.O. and others developed a rigorous series of scientific investigations of the relationships between musculoskeletal dysfunctions and health and disease. Still's critics point out that he never personally ran any controlled experiments to test his hypothesis; his supporters point out that many of Still's writings are philosophical rather than scientific in nature. He questioned the drug practices of his day and regarded surgery as a last resort. As medical science developed, osteopathic medicine gradually incorporated all its proven theories and practices.
By the 1960s, osteopathic medicine had become integrated into the American mainstream, and the reliance on manipulative therapies had fallen into less common usage. The osteopathic profession has evolved independently outside the US, where it has remained essentially a drug-free system based on manipulative techniques - a scope of practice similar to chiropractors. Chiropractic is a distinct manipulative profession that originated around 1895 in the US. The ancient Greek "father of medicine," Hippocrates, is said to have spoken highly of manual and manipulative therapies for a range of conditions.
# Osteopathic principles
These are the eight major principles of osteopathy and are widely accepted throughout the osteopathic community.
- The body is a unit.
- Structure and function are reciprocally inter-related.
- The body possesses self-regulatory mechanisms.
- The body has the inherent capacity to defend and repair itself.
- When the normal adaptability is disrupted, or when environmental changes overcome the body’s capacity for self maintenance, disease may ensue.
- The movement of body fluids is essential to the maintenance of health.
- The nerves play a crucial part in controlling the fluids of the body.
- There are somatic components to disease that are not only manifestations of disease, but also are factors that contribute to maintenance of the disease state.
These principles are not held by osteopathic physicians to be empirical laws, nor contradictions to medical principles; they are thought to be the underpinnings of the osteopathic philosophy on health and disease.
# Techniques of Osteopathic Manual Medicine
In the United States, physical or manual treatment carried out by D.O.s is referred to as Osteopathic Manual Medicine or Osteopathic Manipulative Medicine (both abbreviated OMM). In other countries, manual treatment by osteopathic physicians is simply referred to as osteopathic treatment.
The goal of OMM is the resolution of somatic dysfunction to reestablish the self-regulatory mechanisms of the body. There are various techniques applied to the musculoskeletal system as OMM. These are normally employed together with dietary, postural, and occupational advice, as well as counseling to help patients recover from illness and injury, and to minimize pain and disease. Most osteopathic physicians view manual therapies as a complement to physiotherapy, and use more invasive therapies (pharmaceuticals and surgery) where necessary.
## Scope of manual therapies
There is now a well-established body of scientific literature that makes a strong case for the use of manual therapies in the treatment of many neuromusculoskeletal pain syndromes, such as low back pain and tension headache, alongside exercise and other rehabilitative techniques. In recent years, mainstream medicine has begun to accept the use of manual therapies to treat spinal pain of mechanical origin.
More controversial is the use of manual therapies in the treatment of seemingly organic conditions, such as asthma, middle ear infections in children, menstrual pain, and pulmonary infection. While research is beginning to shed some light in this area, exploration of the relationship between the NMS system and organic disease and the scope of manual therapies are in their infancy. Nevertheless, the sum of research and clinical experience to date suggests that osteopathic treatment can be a safe and cost-effective means of managing (or co-managing) certain diseases.
## Cranial osteopathy
Cranial osteopathy, although well-established,
is a contested issue within the profession; it is not known what proportion of osteopathic physicians are practitioners.
Cranial osteopathic physicians are trained to feel a very subtle, rhythmic shape change that is present throughout the head and body. This is known as the involuntary mechanism or the cranial rhythm. The movement is said to be very subtle, and it takes practitioners with a very finely developed sense of touch (palpation) to feel it. This rhythm was first described in the early 1900s by Dr. William G. Sutherland.
The theory underlying cranial osteopathy is rejected by many physicians because it was previously understood that cranial bones fuse by the end of adolescence. However, histological studies have demonstrated the presence of Sharpey's fibres between the adjacent bones forming the sutural margins, and it is known that these specialized fibers form only at areas where tissue movement is allowed. It is, of course, accepted by most modern osteopathic physicians working within the cranial field, that the spheno-basilar symphysis (a large joint in the skull base) does indeed ossify (turn to bone) and the original principles of cranial osteopathy have thus evolved alongside increasing knowledge. Cranial osteopathic teaching refers to movement remaining within the thin bone of the sutures, and that flexibility within living bone occurs, in contrast to dried specimen bones. The brain does pulsate, but some research suggests this is related to the cardiovascular system.
The same study looked at inter-operator reliability of palpating the 'cranial rhythm' and found there to be little agreement, although modern understandings in the cranial field describe a number of simultaneous rhythms with differing rates, relating to different aspects of function.
How this mechanism is related to health/disease has not been scientifically established. Some osteopathic physicians believe that healing dysfunctional cranial rhythmic impulses enhances cerebral spinal fluid flow to peripheral nerves, thereby enhancing metabolic outflow and nutrition inflow. Many without direct experience of the benefits of treatment dismiss cranial osteopathy as merely theoretical. However, patients of cranial osteopathic physicians have reported emotional releases, lightness and buoyancy, and visualizations. This technique is increasingly being recognised as especially suitable for newborn babies and young children, with particularly good results in the treatment of colic and crying. It is claimed that as their bones have not fully fused and hardened, they are more susceptible to the treatment. All in all, this practice appears to be popular with patients with an increasing demand for experienced practitioners.
Craniosacral therapy is based on the same principles but the practitioners have not attended medical school and are therefore not osteopathic medical physicians. Chiropractor & osteopathic physician, M.B. Dejarnette further developed craniopathic techniques inside of a complete Chiropractic system known as Sacro-Occipital Technique or simply "S.O.T."
## Visceral osteopathy
Proponents of visceral osteopathy state that the visceral systems (the internal organs: digestive tract, respiratory system, etc.) rely on the interconnected synchronicity between the motion of all the organs and structures of the body, that at optimal health this harmonious relationship remains stable despite the body's endless varieties of motion. The theory is that both somato-visceral and viscero-somatic connections exist, and manipulation of the somatic system can affect the visceral system (and vice-versa).
Visceral osteopathy is said to relieve imbalances and restrictions in the interconnections between the motion of all the organs and structures of the body--namely, nerves, blood vessels, and fascial compartments. During the 1940s, osteopaths like H.V. Hoover and M.D. Young built on the pioneering work of Andrew Taylor Still to create this method of detailed assessment and highly specific manipulation. The efficacy and basis of this treatment remains controversial even within the osteopathic profession. Visceral manipulation was further promoted within osteopathic treatment by Jean-Pierre Barral in his recent series of books on the subject.
While neither cranial osteopathy nor visceral manipulation are the mainstay of most osteopathic medical practices, there is increasing interest in both of these areas from patients and practitioners alike. Training in cranial osteopathy in the UK has now reached validated MSc level, which aims to improve standards and contribute to the body of evidence with research-based studies carried out from within the profession.
# Osteopathy around the world
There are two main schools of thought within the osteopathic world. They are so different in practice as to be separate professions, but there have been attempts in the last few years to enhance exchange and dialogue between them.
Osteopathic physicians in the United States are licensed medical practitioners. In other countries, osteopaths continue to rely on non-surgical, non-pharmaceutical approaches, and see themselves as a complete school of manual medicine or NMS specialists, complementary to most mainstream medical practices. Commonwealth osteopathic students may spend up to ten times as many hours training in osteopathic diagnosis and technique as their American counterparts. Because of this specialization, they have traditionally remained as an alternative to mainstream healthcare alongside naturopaths and chiropractors. In Commonwealth countries, osteopaths have also had to compete with physiotherapists, many of whom have integrated manipulative therapy into their practice. Nevertheless, osteopathic medicine is growing in size and mainstream acceptance in many countries of the Commonwealth and Europe. Osteopathic and allopathic physicians now work side by side in academic, hospital, and clinical settings, and osteopathic medical departments are now well-established in many public universities.
## Osteopathy in the United States
In the United States, osteopathy is only practiced by medical doctors. Graduates of osteopathic medical schools are awarded the Doctor of Osteopathic Medicine degree, and can become licensed to practice medicine as a physician or surgeon.
## Osteopathy in the United Kingdom
In the United Kingdom osteopathy developed as a distinct profession. The first osteopathic college was established in the UK in 1917 by Littlejohn, a Scot who had studied under Dr Andrew Taylor Still. Littlejohn altered the osteopathic curriculum to include the study of physiology. The UK school he founded, the British School of Osteopathy, was the first osteopathic education institution outside the USA, and it still exists today. British osteopaths use manipulative techniques based on the philosophy of Dr Andrew Taylor Still, but are not medical doctors. Some medical doctors do undertake osteopathic training as a postgraduate interest. The profession is subject to statutory regulation following the passing of the Osteopathy Act in 1993. The General Osteopathic Council (GOsC) was established by the act to regulate the profession. There are currently seven approved training institutions in the UK. There are approximately 5000 registered osteopaths in the UK, a small but growing profession. For the sake of comparison there are approximately 36,000 physiotherapists. Most medical services in the UK are delivered through the state funded National Health Service, osteopathy is largely excluded from this with most osteopaths working in private practice. Several large studies in the UK have produced evidence of the cost-effectiveness and clinical effectiveness of manipulation in the management of low back pain, the latest being the UK Back pain Exercise And Manipulation (UK BEAM) trial.
There is an increasing interest in osteopathic medicine amongst patients, but barriers remain to osteopathic provision within the state system, among them opposition from the allopathic medical profession and physiotherapists. Many UK osteopaths are also naturopaths, with one osteopathic college offering a dual training in osteopathy & naturopathy (the British College of Osteopathic Medicine) and another offering a post-graduate programme (the College of Osteopaths).
In 2005 the General Medical Council of Great Britain announced that U.S.-trained D.O.s would be accepted for full medical practice rights in the United Kingdom. This decision was an important departure from the United Kingdom's long-standing tradition of exclusively manual, or "traditional" osteopathy.
## Osteopathy in Australia & New Zealand
In Australia the profession has developed along the same lines, and Osteopathy celebrates 100 years in Australia in 2007. The peak body representing Osteopaths in Australia is the Australian Osteopathic Association (#REDIRECT AOA), and in New Zealand the Osteopathic Society of New Zealand (OSNZ). Since the 1970's Australia has formally trained practitioners although many were trained less formally prior to that time. Both Australia and New Zealand require registration, and thus disallow osteopathic practice except by government registered practitioners. Workers' compensation, the various motor accident authorities, Medicare and private health insurancers all recognise and reimburse osteopathic treatment. Four publicly-funded Universities now offer osteopathic medical courses in Australia - RMIT, VU, SCU and UWS. It is offered at UNITEC in New Zealand. Australian courses consist of a bachelor's degree in clinical science (Osteopathy) followed by a Master's degree. Integration into the university system has given Australian osteopaths the opportunity to access public research funding, has raised the credibility of the profession, and focused attention on refining the scope of practice through clinical trials and basic research.
Australia now recognises the USA D.O. degree for full medical practice rights within Australia. Australia and the UK now recognise the USA medical educational model as the equivalent to its own.
## Osteopathy in Canada
In Canada osteopathic physicians are trained along similar lines to those in Britain and other Commonwealth countries. However, when US-trained osteopathic physicians visit or relocate to Canada or Great Britain, their parity with allopathic physicians is recognized and they have an unlimited scope of medical practice.
Note: with the exception of the Provice of Quebec, D.O.M.P. is no longer recognized by the Insurance industry as a covered practitioner, only a fully-fledged D.O.
In some countries, osteopathic medicine straddles the boundary between Allopathic medicine and alternative medicine, with a variety of approaches and philosophies being brought to the practice. Osteopathic physicians are trained in standard medical differential diagnosis and have diagnostic competences similar to primary care physicians, but with a scope of practice focused mainly on musculoskeletal conditions and treatment of some other conditions by manual means. Osteopathic physicians in these countries, except Canada, do not have prescribing rights, although the British Government has included osteopathic medicine in the list of Allied health professions that may be granted prescribing rights in the future..
## Osteopathy in the European Union
Within the EU there is no standardized training or regulatory framework for osteopaths but attempts are being made to coordinate the profession within the union. There is a conflict between the principle of free movement of labour - a cornerstone of the EU - and the right to practice osteopathic medicine in different member states as there is cross-border equivalence in training and regulation of the profession. The UK's General Osteopathic Council, a regulatory body set up under the country's 1993 Osteopaths Act has issued a position paper on European regulation of osteopathy. The teaching of osteopathy in the UK, France and (European Economic Area member) Switzerland is well established - but not all European nations have yet embraced this form of medicine.
In the UK, since the Osteopaths Act, osteopathy has been a recognised profession. Doctors within the country's National Health Service recognise osteopathy as a therapy and refer patients to its practitioners when other forms of treatment are not successful or are considered inappropriate - but the NHS will not usually pay for any treatment. Final year students following the B. Ost. degree course offered by the
British School of Osteopathy gain hands-on experience under the supervision of tutors, who are practicing osteopaths, in the school's Borough, south London, building in Europe's largest osteopathic clinic. The fees that patients, who do not need a doctor's referral, at the school's clinics are greatly subsidised - and people who qualify for pensions or some benefits get a 50 percent discount on them. Some people qualify for free treatment. The school, founded in 1917, also offers postgraduate qualifications, an M.Sc. postgraduate degree in pediatric osteopathy and a professional diploma in cranial osteopathy.
# Criticism
Osteopathic medicine is subject to criticisms from those outside of the field, similar to those levelled at other types of alternative medicine, namely that evidence for the efficacy of the treatment is testimonial-based and not experiment based. Placebo-controlled trials show that osteopathy is no better than sham treatment for lower back pain or for pain after knee/hip surgery.
The practice of osteopathy in the cranial field is considered even by some within the field as lacking scientific evidence.
As with all medical treatments, manipulative and manual therapies carry inherent risks of injury. Direct, forceful techniques are more likely than indirect techniques to cause injury, but - in general - the risk is small when performed by skilled practitioners. The skill of the practitioner also determines the relative safety of the technique. 'Neck cracking', i.e. cervical high-velocity low-amplitude thrusting, has received particular attention in the popular media because of a risk of arterial occlusion and consequently of stroke. However, the causal relationship between stroke and neck manipulation has never been established sufficiently to resolve the debate, with osteopaths and other manipulative therapists contending that the risk of injury is very small in any case. | Osteopathy
Template:Otheruses4
Template:Alternative medical systems
Template:Osteopathic medicine
Osteopathy is an approach to healthcare that emphasizes the role of the musculoskeletal system in health and disease. In most countries osteopathy is a form of complementary medicine, emphasizing a holistic approach and the skilled use of a range of manual and physical treatment interventions (Osteopathic Manipulative Medicine, or OMM in the United States) in the prevention and treatment of disease. In practice, this most commonly relates to musculoskeletal problems such as back and neck pain.
Many osteopaths see their role as facilitating the body's own recuperative powers by treating musculoskeletal or somatic dysfunction. According to the American Osteopathic Association, the difference between an osteopath and an osteopathic physician is often confused.[1] In the United States, Doctors of Osteopathic Medicine (D.O.s) are fully licensed medical physicians and surgeons, practicing in all clinical specialties along with their M.D. colleagues . Just like M.D.s, D.O.s practice the full scope of medicine, but with an emphasis on the role of the neuromusculoskeletal system. D.O.s practicing in primary care, pediatrics, family, or internal medicine, are trained to have a more empathetic approach to patient care which has awarded them some level of distinction from M.D.s Outside the United States. The practice rights of U.S.-trained Doctors of Osteopathic medicine varies.
# History
The practice of osteopathic medicine began in the United States in 1874. The term "osteopathy" was coined by Andrew Taylor Still, M.D., an allopathically-trained physician who was born in 1828 in Virginia. Still was a free state leader who lived near Baldwin City, Kansas at the time of the American Civil War, and it was here he developed the practice of osteopathy.[2] Still was trained by apprenticeship, as were most physicians of the day, and was employed as an army doctor during the American Civil War in the U.S. Army. The horrors of battlefield injury and the subsequent death of his wife and several children from infectious diseases left him totally disillusioned with the traditional practice of medicine. Still perceived the medical practices of his day to be ineffective, even barbaric. Troubled by what he saw as problems in the medical profession, Still founded osteopathic practice. Using an alternative philosophical approach, he opposed the use of drugs and surgery as remedial agents, reserving their use for such cases as being the cure for the condition, such as an antidote for a poison or amputation for gangrene. He saw the human body as being capable of curing itself, and the duty of the physician to remove any impediments to the healthy function of each person. He promoted healthy lifestyle, nutrition, abstinence from alcohol and drugs, and used manipulative techniques to improve physiological function.
Still named his new school of medicine "osteopathy," reasoning that "the bone, osteon, was the starting point from which [he] was to ascertain the cause of pathological conditions." The object of osteopathy was to "improve upon the present systems of surgery, midwifery, and the treatment of general diseases."[citation needed] Its scientific foundation was the discipline of anatomy. Its philosophy was based on the understanding of the integration between body, mind and spirit[citation needed], the interrelatedness of structure and function, and the ability of the body to heal itself when mechanically sound. Osteopathic treatment must be a rational application of these principles in comprehensive patient care with a focus on the neuromusculoskeletal system as an integral part of health and disease processes. Over time he and his students and faculty developed a complete medical school curriculum which included a series of specialized physical treatments, now called Osteopathic Manipulative Treatment (OMT). Still founded the American School of Osteopathy (now the Andrew Taylor Still University, Kirksville College of Osteopathic Medicine) in Kirksville, Missouri, for the teaching of osteopathic medicine on May 10, 1892. While the state of Missouri, recognizing the equivalency of the curriculum, was willing to grant him a charter for awarding the M.D. degree, he remained dissatisfied with the limitations of allopathic medicine and instead chose to retain the distinction of the D.O. degree.
In the late 1800s Still taught that "dis-ease" was caused when bones were out of place and disrupted the flow of blood or the flow of nervous impulses; he therefore concluded that one could cure diseases by manipulating bones to restore the interrupted flow. Still stimulated his students to investigate these postulates. Research began in the 1890s at Kirksville and has continued there and at other osteopathic institutions ever since. The A.T. Still Research Institute was founded in 1913 and Louisa Burns, D.O. and others developed a rigorous series of scientific investigations of the relationships between musculoskeletal dysfunctions and health and disease. Still's critics point out that he never personally ran any controlled experiments to test his hypothesis; his supporters point out that many of Still's writings are philosophical rather than scientific in nature. He questioned the drug practices of his day and regarded surgery as a last resort. As medical science developed, osteopathic medicine gradually incorporated all its proven theories and practices.
By the 1960s, osteopathic medicine had become integrated into the American mainstream, and the reliance on manipulative therapies had fallen into less common usage. The osteopathic profession has evolved independently outside the US, where it has remained essentially a drug-free system based on manipulative techniques - a scope of practice similar to chiropractors. Chiropractic is a distinct manipulative profession that originated around 1895 in the US. The ancient Greek "father of medicine," Hippocrates, is said to have spoken highly of manual and manipulative therapies for a range of conditions.
# Osteopathic principles
These are the eight major principles of osteopathy and are widely accepted throughout the osteopathic community.
[3]
- The body is a unit.
- Structure and function are reciprocally inter-related.
- The body possesses self-regulatory mechanisms.
- The body has the inherent capacity to defend and repair itself.
- When the normal adaptability is disrupted, or when environmental changes overcome the body’s capacity for self maintenance, disease may ensue.
- The movement of body fluids is essential to the maintenance of health.
- The nerves play a crucial part in controlling the fluids of the body.
- There are somatic components to disease that are not only manifestations of disease, but also are factors that contribute to maintenance of the disease state.
These principles are not held by osteopathic physicians to be empirical laws, nor contradictions to medical principles; they are thought to be the underpinnings of the osteopathic philosophy on health and disease.
# Techniques of Osteopathic Manual Medicine
In the United States, physical or manual treatment carried out by D.O.s is referred to as Osteopathic Manual Medicine or Osteopathic Manipulative Medicine (both abbreviated OMM). In other countries, manual treatment by osteopathic physicians is simply referred to as osteopathic treatment.
The goal of OMM is the resolution of somatic dysfunction to reestablish the self-regulatory mechanisms of the body. There are various techniques applied to the musculoskeletal system as OMM. These are normally employed together with dietary, postural, and occupational advice, as well as counseling to help patients recover from illness and injury, and to minimize pain and disease. Most osteopathic physicians view manual therapies as a complement to physiotherapy, and use more invasive therapies (pharmaceuticals and surgery) where necessary.
## Scope of manual therapies
There is now a well-established body of scientific literature that makes a strong case for the use of manual therapies in the treatment of many neuromusculoskeletal pain syndromes, such as low back pain and tension headache, alongside exercise and other rehabilitative techniques.[citation needed] In recent years, mainstream medicine has begun to accept the use of manual therapies to treat spinal pain of mechanical origin.
More controversial is the use of manual therapies in the treatment of seemingly organic conditions, such as asthma, middle ear infections in children,[4] menstrual pain, and pulmonary infection. While research is beginning to shed some light in this area,[citation needed] exploration of the relationship between the NMS system and organic disease and the scope of manual therapies are in their infancy. Nevertheless, the sum of research and clinical experience to date suggests that osteopathic treatment can be a safe and cost-effective means of managing (or co-managing) certain diseases.
## Cranial osteopathy
Template:Splitsection
Cranial osteopathy, although well-established,[5]
is a contested issue within the profession; it is not known what proportion of osteopathic physicians are practitioners.
Cranial osteopathic physicians are trained to feel a very subtle, rhythmic shape change that is present throughout the head and body. This is known as the involuntary mechanism or the cranial rhythm. The movement is said to be very subtle, and it takes practitioners with a very finely developed sense of touch (palpation) to feel it. This rhythm was first described in the early 1900s by Dr. William G. Sutherland.[6]
The theory underlying cranial osteopathy is rejected by many physicians because it was previously understood that cranial bones fuse by the end of adolescence. However, histological studies have demonstrated the presence of Sharpey's fibres between the adjacent bones forming the sutural margins, and it is known that these specialized fibers form only at areas where tissue movement is allowed. It is, of course, accepted by most modern osteopathic physicians working within the cranial field, that the spheno-basilar symphysis (a large joint in the skull base) does indeed ossify (turn to bone) and the original principles of cranial osteopathy have thus evolved alongside increasing knowledge. Cranial osteopathic teaching refers to movement remaining within the thin bone of the sutures, and that flexibility within living bone occurs, in contrast to dried specimen bones. The brain does pulsate, but some research suggests this is related to the cardiovascular system.[7]
The same study looked at inter-operator reliability of palpating the 'cranial rhythm' and found there to be little agreement, although modern understandings in the cranial field describe a number of simultaneous rhythms with differing rates, relating to different aspects of function.[citation needed]
How this mechanism is related to health/disease has not been scientifically established. Some osteopathic physicians believe that healing dysfunctional cranial rhythmic impulses enhances cerebral spinal fluid flow to peripheral nerves, thereby enhancing metabolic outflow and nutrition inflow. Many without direct experience of the benefits of treatment dismiss cranial osteopathy as merely theoretical. However, patients of cranial osteopathic physicians have reported emotional releases, lightness and buoyancy, and visualizations. This technique is increasingly being recognised as especially suitable for newborn babies and young children, with particularly good results in the treatment of colic and crying.[citation needed] It is claimed that as their bones have not fully fused and hardened, they are more susceptible to the treatment.[citation needed] All in all, this practice appears to be popular with patients with an increasing demand for experienced practitioners.
Craniosacral therapy is based on the same principles but the practitioners have not attended medical school and are therefore not osteopathic medical physicians. Chiropractor & osteopathic physician, M.B. Dejarnette further developed craniopathic techniques inside of a complete Chiropractic system known as Sacro-Occipital Technique or simply "S.O.T."[8][9]
## Visceral osteopathy
Proponents of visceral osteopathy state that the visceral systems (the internal organs: digestive tract, respiratory system, etc.) rely on the interconnected synchronicity between the motion of all the organs and structures of the body, that at optimal health this harmonious relationship remains stable despite the body's endless varieties of motion. The theory is that both somato-visceral and viscero-somatic connections exist, and manipulation of the somatic system can affect the visceral system (and vice-versa).
Visceral osteopathy is said to relieve imbalances and restrictions in the interconnections between the motion of all the organs and structures of the body--namely, nerves, blood vessels, and fascial compartments. During the 1940s, osteopaths like H.V. Hoover and M.D. Young built on the pioneering work of Andrew Taylor Still to create this method of detailed assessment and highly specific manipulation. The efficacy and basis of this treatment remains controversial even within the osteopathic profession. Visceral manipulation was further promoted within osteopathic treatment by Jean-Pierre Barral in his recent series of books on the subject.[citation needed]
While neither cranial osteopathy nor visceral manipulation are the mainstay of most osteopathic medical practices, there is increasing interest in both of these areas from patients and practitioners alike. Training in cranial osteopathy in the UK has now reached validated MSc level, which aims to improve standards and contribute to the body of evidence with research-based studies carried out from within the profession.
# Osteopathy around the world
There are two main schools of thought within the osteopathic world. They are so different in practice as to be separate professions, but there have been attempts in the last few years to enhance exchange and dialogue between them.[10]
Osteopathic physicians in the United States are licensed medical practitioners. In other countries, osteopaths continue to rely on non-surgical, non-pharmaceutical approaches, and see themselves as a complete school of manual medicine or NMS specialists, complementary to most mainstream medical practices. Commonwealth osteopathic students may spend up to ten times as many hours training in osteopathic diagnosis and technique as their American counterparts. Because of this specialization, they have traditionally remained as an alternative to mainstream healthcare alongside naturopaths and chiropractors. In Commonwealth countries, osteopaths have also had to compete with physiotherapists, many of whom have integrated manipulative therapy into their practice. Nevertheless, osteopathic medicine is growing in size and mainstream acceptance in many countries of the Commonwealth and Europe. Osteopathic and allopathic physicians now work side by side in academic, hospital, and clinical settings, and osteopathic medical departments are now well-established in many public universities.
## Osteopathy in the United States
In the United States, osteopathy is only practiced by medical doctors. Graduates of osteopathic medical schools are awarded the Doctor of Osteopathic Medicine degree, and can become licensed to practice medicine as a physician or surgeon.
## Osteopathy in the United Kingdom
In the United Kingdom osteopathy developed as a distinct profession. The first osteopathic college was established in the UK in 1917 by Littlejohn, a Scot who had studied under Dr Andrew Taylor Still. Littlejohn altered the osteopathic curriculum to include the study of physiology. The UK school he founded, the British School of Osteopathy, was the first osteopathic education institution outside the USA, and it still exists today. British osteopaths use manipulative techniques based on the philosophy of Dr Andrew Taylor Still, but are not medical doctors. Some medical doctors do undertake osteopathic training as a postgraduate interest. The profession is subject to statutory regulation following the passing of the Osteopathy Act in 1993. The General Osteopathic Council (GOsC) was established by the act to regulate the profession. There are currently seven approved training institutions in the UK. There are approximately 5000 registered osteopaths in the UK, a small but growing profession. For the sake of comparison there are approximately 36,000 physiotherapists. Most medical services in the UK are delivered through the state funded National Health Service, osteopathy is largely excluded from this with most osteopaths working in private practice. Several large studies in the UK have produced evidence of the cost-effectiveness and clinical effectiveness of manipulation in the management of low back pain, the latest being the UK Back pain Exercise And Manipulation (UK BEAM) trial.[11]
[12]
There is an increasing interest in osteopathic medicine amongst patients, but barriers remain to osteopathic provision within the state system, among them opposition from the allopathic medical profession and physiotherapists.[citation needed] Many UK osteopaths are also naturopaths, with one osteopathic college offering a dual training in osteopathy & naturopathy (the British College of Osteopathic Medicine) and another offering a post-graduate programme (the College of Osteopaths).
In 2005 the General Medical Council of Great Britain announced that U.S.-trained D.O.s would be accepted for full medical practice rights in the United Kingdom. This decision was an important departure from the United Kingdom's long-standing tradition of exclusively manual, or "traditional" osteopathy.
## Osteopathy in Australia & New Zealand
In Australia the profession has developed along the same lines, and Osteopathy celebrates 100 years in Australia in 2007. The peak body representing Osteopaths in Australia is the Australian Osteopathic Association (#REDIRECT AOA), and in New Zealand the Osteopathic Society of New Zealand (OSNZ). Since the 1970's Australia has formally trained practitioners although many were trained less formally prior to that time. Both Australia and New Zealand require registration, and thus disallow osteopathic practice except by government registered practitioners. Workers' compensation, the various motor accident authorities, Medicare and private health insurancers all recognise and reimburse osteopathic treatment. Four publicly-funded Universities now offer osteopathic medical courses in Australia - RMIT, VU, SCU and UWS. It is offered at UNITEC in New Zealand. Australian courses consist of a bachelor's degree in clinical science (Osteopathy) followed by a Master's degree. Integration into the university system has given Australian osteopaths the opportunity to access public research funding, has raised the credibility of the profession, and focused attention on refining the scope of practice through clinical trials and basic research.
Australia now recognises the USA D.O. degree for full medical practice rights within Australia. Australia and the UK now recognise the USA medical educational model as the equivalent to its own.
## Osteopathy in Canada
In Canada osteopathic physicians are trained along similar lines to those in Britain and other Commonwealth countries. However, when US-trained osteopathic physicians visit or relocate to Canada or Great Britain, their parity with allopathic physicians is recognized and they have an unlimited scope of medical practice.
Note: with the exception of the Provice of Quebec, D.O.M.P. is no longer recognized by the Insurance industry as a covered practitioner, only a fully-fledged D.O.
In some countries, osteopathic medicine straddles the boundary between Allopathic medicine and alternative medicine, with a variety of approaches and philosophies being brought to the practice. Osteopathic physicians are trained in standard medical differential diagnosis and have diagnostic competences similar to primary care physicians, but with a scope of practice focused mainly on musculoskeletal conditions and treatment of some other conditions by manual means. Osteopathic physicians in these countries, except Canada, do not have prescribing rights, although the British Government has included osteopathic medicine in the list of Allied health professions that may be granted prescribing rights in the future.[13].
## Osteopathy in the European Union
Within the EU there is no standardized training or regulatory framework for osteopaths but attempts are being made to coordinate the profession within the union. There is a conflict between the principle of free movement of labour - a cornerstone of the EU - and the right to practice osteopathic medicine in different member states as there is cross-border equivalence in training and regulation of the profession. The UK's General Osteopathic Council, a regulatory body set up under the country's 1993 Osteopaths Act has issued a position paper on European regulation of osteopathy.[14] The teaching of osteopathy in the UK, France and (European Economic Area member) Switzerland is well established - but not all European nations have yet embraced this form of medicine.
In the UK, since the Osteopaths Act, osteopathy has been a recognised profession. Doctors within the country's National Health Service recognise osteopathy as a therapy and refer patients to its practitioners when other forms of treatment are not successful or are considered inappropriate[4] - but the NHS will not usually pay for any treatment.[15] Final year students following the B. Ost. degree course offered by the
British School of Osteopathy gain hands-on experience under the supervision of tutors, who are practicing osteopaths, in the school's Borough, south London, building in Europe's largest osteopathic clinic. The fees that patients, who do not need a doctor's referral, at the school's clinics are greatly subsidised - and people who qualify for pensions or some benefits get a 50 percent discount on them. Some people qualify for free treatment. The school, founded in 1917, also offers postgraduate qualifications, an M.Sc. postgraduate degree in pediatric osteopathy and a professional diploma in cranial osteopathy.[16]
# Criticism
Osteopathic medicine is subject to criticisms from those outside of the field, similar to those levelled at other types of alternative medicine, namely that evidence for the efficacy of the treatment is testimonial-based and not experiment based. Placebo-controlled trials show that osteopathy is no better than sham treatment for lower back pain[17] or for pain after knee/hip surgery[18].
The practice of osteopathy in the cranial field is considered even by some within the field as lacking scientific evidence.
As with all medical treatments, manipulative and manual therapies carry inherent risks of injury. Direct, forceful techniques are more likely than indirect techniques to cause injury, but - in general - the risk is small when performed by skilled practitioners. The skill of the practitioner also determines the relative safety of the technique. 'Neck cracking', i.e. cervical high-velocity low-amplitude thrusting, has received particular attention in the popular media because of a risk of arterial occlusion and consequently of stroke. However, the causal relationship between stroke and neck manipulation has never been established sufficiently to resolve the debate, with osteopaths and other manipulative therapists contending that the risk of injury is very small in any case. | https://www.wikidoc.org/index.php/Osteopathy | |
9307447015cc40ef163779465ea0d69327375924 | wikidoc | Otic polyp | Otic polyp
# Overview
An otic polyp (also called aural polyp) is a benign proliferation of chronic inflammatory cells associated with granulation tissue, in response to a longstanding inflammatory process of the middle ear.
# Signs and symptoms
Patients usually present with otorrhea, conductive hearing loss, and otalgia, while bleeding and a sensation of a mass are much less common.
# Imaging findings
Although imaging is not required to yield a diagnosis, it may be obtained to exclude other disorders, such as a concurrent cholesteatoma.
# Pathology findings
By gross description, there is usually a solitary, polypoid, reddish mass behind an intact ear drum (typmanic membrane). The tissue is often friable, measuring <2 cm in most cases. All tissue should be processed in order to exclude a concurrent cholesteatoma.
By microscopic exam, the polypoid appearance is maintained, showing a granulation-type tissue reaction with edematous stroma and a rich investment by capillaries. The surface of the polyp is covered by stratified squamous epitehlium with a prominent granular cell layer. The tissue is filled with lymphocytes, plasma cells, mast cells, histiocytes, and eosinophils. It is not uncommon to see plasma cells with Russell bodies and Mott cell formation. Depending on length of symptoms, multinucleated giant cells and calcifications may be seen. Other disorders may be concurrently present, especially since this is a post infectious/inflammatory disorder, and these include a cholesterol granuloma, "tunnel clusters" (glandular epithelial inclusions below the surface epithelium), and cholesteatoma.
## Immunohistochemistry
Immunohistochemistry is unnecessary for the diagnosis, but will highlight a mixed B- and T-cell population within the lymphoid component, without light chain (kappa or lambda) restriction. Any muscle markers would be negative.
# Differential diagnoses
The lesion presents in young patients, so the differential for a "polyp", especially when the lymphoid component is crushed or dominant, would include a rhabdomyosarcoma, extramedullary plasmacytoma, and a neuroendocrine adenoma of the middle ear.
# Management
Since this lesion is usually a complication of long standing otitis media, it is important to use an appropriate antibiotic therapy regimen. If the patient fails first line antibiotics, then second-line therapies should be employed, especially after appropriate culture and sensitivity testing. Surgery may be required if there is extension into the mastoid bone, or if a concurrent cholesteatoma is identified during surgery or biopsy. In general, patients have an excellent outcome after appropriate therapy.
# Epidemiology
This is an uncommon lesion, usually affecting young patients (mean age, 30 years), with a male to female ratio of 2:1. The middle ear is involved, although it may extend to the external auditory canal if there is tympanic membrane perforation. | Otic polyp
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An otic polyp (also called aural polyp) is a benign proliferation of chronic inflammatory cells associated with granulation tissue, in response to a longstanding inflammatory process of the middle ear.[1][2]
# Signs and symptoms
Patients usually present with otorrhea, conductive hearing loss, and otalgia, while bleeding and a sensation of a mass are much less common.[2]
# Imaging findings
Although imaging is not required to yield a diagnosis, it may be obtained to exclude other disorders, such as a concurrent cholesteatoma.
# Pathology findings
By gross description, there is usually a solitary, polypoid, reddish mass behind an intact ear drum (typmanic membrane). The tissue is often friable, measuring <2 cm in most cases. All tissue should be processed in order to exclude a concurrent cholesteatoma.[3]
By microscopic exam, the polypoid appearance is maintained, showing a granulation-type tissue reaction with edematous stroma and a rich investment by capillaries. The surface of the polyp is covered by stratified squamous epitehlium with a prominent granular cell layer. The tissue is filled with lymphocytes, plasma cells, mast cells, histiocytes, and eosinophils. It is not uncommon to see plasma cells with Russell bodies and Mott cell formation. Depending on length of symptoms, multinucleated giant cells and calcifications may be seen. Other disorders may be concurrently present, especially since this is a post infectious/inflammatory disorder, and these include a cholesterol granuloma, "tunnel clusters" (glandular epithelial inclusions below the surface epithelium), and cholesteatoma.[3][4][5]
## Immunohistochemistry
Immunohistochemistry is unnecessary for the diagnosis, but will highlight a mixed B- and T-cell population within the lymphoid component, without light chain (kappa or lambda) restriction. Any muscle markers would be negative.
# Differential diagnoses
The lesion presents in young patients, so the differential for a "polyp", especially when the lymphoid component is crushed or dominant, would include a rhabdomyosarcoma, extramedullary plasmacytoma, and a neuroendocrine adenoma of the middle ear.
# Management
Since this lesion is usually a complication of long standing otitis media, it is important to use an appropriate antibiotic therapy regimen. If the patient fails first line antibiotics, then second-line therapies should be employed, especially after appropriate culture and sensitivity testing. Surgery may be required if there is extension into the mastoid bone, or if a concurrent cholesteatoma is identified during surgery or biopsy. In general, patients have an excellent outcome after appropriate therapy.[1][2][3]
# Epidemiology
This is an uncommon lesion, usually affecting young patients (mean age, 30 years), with a male to female ratio of 2:1. The middle ear is involved, although it may extend to the external auditory canal if there is tympanic membrane perforation.[1][2][3] | https://www.wikidoc.org/index.php/Otic_polyp | |
f280f871c020d9446f259d8d36e83ae8c2bd501f | wikidoc | Otto Loewi | Otto Loewi
Otto Loewi (June 3, 1873 – December 25, 1961) was an Austrian-German-American pharmacologist. His discovery of acetylcholine helped enhance medical therapy and personally earned for him the 1936 Nobel Prize in Physiology or Medicine which he shared with Sir Henry Dale. He has been referred to as the "Father of Neuroscience."
# Biography
Loewi was born in Frankfurt, Germany. He received his medical doctoral degree from University of Strasbourg (then part of Germany) in 1896 where he also was a member of the fraternity Burschenschaft Germania Strassburg. He was never particularly interested in clinical work, so after seeing a number of deaths due to incurable diseases such as tuberculosis and pneumonia, he decided to direct his energies to pharmacology research.
Beginning in 1898, he spent many years in Austria, where his first lines of research were in the area of metabolism. Loewi investigated how vital organs respond to chemical and electrical stimulation. He also established their relative dependence on epinephrine for proper function. Consequently, he learnt how nerve impulses are transmitted by chemical messengers. The first chemical neurotransmitter that he identified was acetylcholine.
In 1903, he accepted an appointment at the University of Graz in Austria, where he would remain until being forced out of the country in 1938. In 1905 he received Austrian citizenship.
He married Guida Goldschmiedt in 1908. They had three sons and a daughter. He was the last Jew hired by the University between 1903 and the end of the war.
After being arrested, along with two of his sons, on the night of the German invasion of Austria, March 11, 1938, Loewi was released on condition that he "voluntarily" relinquish all his possessions to the Nazis. Loewi moved to the United States in 1940, where he became a research professor at the New York University College of Medicine. In 1946, he became a naturalized citizen of the United States. In 1954, he became a Foreign Member of the Royal Society. He died in New York City on December 25, 1961.
Shortly after Loewi's death in late 1961, his youngest son bestowed the gold Nobel medal on the Royal Society for the Advancement of Science in London. He gave the Nobel diploma to the University of Graz in Austria in 1983, where it currently resides, along with a bronze copy of a bust of Loewi. The original of the bust is at the Marine Biological Institute in Woods Hole, Massachusetts, Loewi's summer home from his arrival in the US until his death.
# Research
Before Loewi's experiments, it was unclear whether signalling across the synapse was bioelectrical or chemical. Loewi's famous experiment, published in 1921, largely answered this question. According to Loewi, the idea for his key experiment came to him in his sleep. He dissected out of frogs two beating hearts: one with the vagus nerve which controls heart rate attached, the other heart on its own. Both hearts were bathed in a saline solution (i.e. Ringer's solution). By electrically stimulating the vagus nerve, Loewi made the first heart beat slower. Then, Loewi took some of the liquid bathing the first heart and applied it to the second heart. The application of the liquid made the second heart also beat slower, proving that some soluble chemical released by the vagus nerve was controlling the heart rate. He called the unknown chemical Vagusstoff. It was later found that this chemical corresponded to acetylcholine (Kandel, et al 2000).
Loewi's investigations “On an augmentation of adrenaline release by cocaine” and “On the connection between digitalis and the action of calcium” were profound concepts and were studied relentlessly by others decades later.
He also clarified two mechanisms of eminent therapeutic importance: the blockade and the augmentation of nerve action by certain drugs.
He is almost as famous for the means by which the idea for his experiment came to him as he is for the experiment itself. On Easter Saturday 1920, he dreamed of an experiment that would prove once and for all that transmission of nerve impulses was chemical, not electrical. He woke up, scribbled the experiment onto a scrap of paper on his night-stand, and went back to sleep.
The next morning he arose very excited because he knew this dream had been very important. But he found, to his horror, that he couldn't read his midnight scribbles. That day, he said, was the longest day of his life, as he could not remember his dream. That night, however, he had the same dream. This time, he immediately went to his lab to perform the experiment.
Fourteen years later, Loewi was awarded the Nobel Prize in Physiology or Medicine, which he shared with Sir Henry Hallett Dale.
[[Image:LoewiNobel20040420CopyrightKaihsuTai.jpg|thumb|right|200px|The Nobel Prize diploma of Otto Loewi, housed at the University of Graz. | Otto Loewi
Template:Infobox Scientist
Otto Loewi (June 3, 1873 – December 25, 1961) was an Austrian-German-American pharmacologist. His discovery of acetylcholine helped enhance medical therapy and personally earned for him the 1936 Nobel Prize in Physiology or Medicine which he shared with Sir Henry Dale. He has been referred to as the "Father of Neuroscience."
# Biography
Loewi was born in Frankfurt, Germany. He received his medical doctoral degree from University of Strasbourg (then part of Germany) in 1896 where he also was a member of the fraternity Burschenschaft Germania Strassburg. He was never particularly interested in clinical work, so after seeing a number of deaths due to incurable diseases such as tuberculosis and pneumonia, he decided to direct his energies to pharmacology research.
Beginning in 1898, he spent many years in Austria, where his first lines of research were in the area of metabolism. Loewi investigated how vital organs respond to chemical and electrical stimulation. He also established their relative dependence on epinephrine for proper function. Consequently, he learnt how nerve impulses are transmitted by chemical messengers. The first chemical neurotransmitter that he identified was acetylcholine.
In 1903, he accepted an appointment at the University of Graz in Austria, where he would remain until being forced out of the country in 1938. In 1905 he received Austrian citizenship.
He married Guida Goldschmiedt in 1908. They had three sons and a daughter. He was the last Jew hired by the University between 1903 and the end of the war.
After being arrested, along with two of his sons, on the night of the German invasion of Austria, March 11, 1938, Loewi was released on condition that he "voluntarily" relinquish all his possessions to the Nazis. Loewi moved to the United States in 1940, where he became a research professor at the New York University College of Medicine. In 1946, he became a naturalized citizen of the United States. In 1954, he became a Foreign Member of the Royal Society. He died in New York City on December 25, 1961.
Shortly after Loewi's death in late 1961, his youngest son bestowed the gold Nobel medal on the Royal Society for the Advancement of Science in London. He gave the Nobel diploma to the University of Graz in Austria in 1983, where it currently resides, along with a bronze copy of a bust of Loewi. The original of the bust is at the Marine Biological Institute in Woods Hole, Massachusetts, Loewi's summer home from his arrival in the US until his death.
# Research
Before Loewi's experiments, it was unclear whether signalling across the synapse was bioelectrical or chemical. Loewi's famous experiment, published in 1921, largely answered this question. According to Loewi, the idea for his key experiment came to him in his sleep. He dissected out of frogs two beating hearts: one with the vagus nerve which controls heart rate attached, the other heart on its own. Both hearts were bathed in a saline solution (i.e. Ringer's solution). By electrically stimulating the vagus nerve, Loewi made the first heart beat slower. Then, Loewi took some of the liquid bathing the first heart and applied it to the second heart. The application of the liquid made the second heart also beat slower, proving that some soluble chemical released by the vagus nerve was controlling the heart rate. He called the unknown chemical Vagusstoff. It was later found that this chemical corresponded to acetylcholine (Kandel, et al 2000).
Loewi's investigations “On an augmentation of adrenaline release by cocaine” and “On the connection between digitalis and the action of calcium” were profound concepts and were studied relentlessly by others decades later.
He also clarified two mechanisms of eminent therapeutic importance: the blockade and the augmentation of nerve action by certain drugs.
He is almost as famous for the means by which the idea for his experiment came to him as he is for the experiment itself. On Easter Saturday 1920, he dreamed of an experiment that would prove once and for all that transmission of nerve impulses was chemical, not electrical. He woke up, scribbled the experiment onto a scrap of paper on his night-stand, and went back to sleep.
The next morning he arose very excited because he knew this dream had been very important. But he found, to his horror, that he couldn't read his midnight scribbles. That day, he said, was the longest day of his life, as he could not remember his dream. That night, however, he had the same dream. This time, he immediately went to his lab to perform the experiment.
Fourteen years later, Loewi was awarded the Nobel Prize in Physiology or Medicine, which he shared with Sir Henry Hallett Dale.
[[Image:LoewiNobel20040420CopyrightKaihsuTai.jpg|thumb|right|200px|The Nobel Prize diploma of Otto Loewi, housed at the University of Graz. | https://www.wikidoc.org/index.php/Otto_Loewi | |
ca953aeb557fb9b55e88d4fd5a6285310ac14c1b | wikidoc | Synephrine | Synephrine
# Overview
Synephrine, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine. p-synephrine (or formerly Sympatol and oxedrine ) and m-synephrine are known for their longer acting adrenergic effects compared to norepinephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange (Citrus species) products, both of the "sweet" and "bitter" variety. The preparations used in Traditional Chinese Medicine (TCM), also known as Zhi Shi, are the immature and dried whole oranges from Citrus aurantium (Fructus Aurantii Immaturus). Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with caffeine, as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved OTC drug. As a pharmaceutical, m-synephrine is still used as a sympathomimetic (i.e. for its hypertensive and vasoconstrictor properties), mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.
It is important to distinguish between studies concerning synephrine as a single chemical entity (and even here it should be borne in mind that synephrine can exist in the form of either of two stereoisomers, d- and l-synephrine, which are chemically and pharmacologically distinct), and synephrine which is mixed with other drugs and/or botanical extracts in a "Supplement", as well as synephrine which is present as only one chemical component in a naturally-occurring mixture of phytochemicals such as the rind or fruit of a bitter orange. Mixtures containing synephrine as only one of their chemical components (regardless of whether these are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as synephrine alone.
In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. Its molecular structure is based on a phenethylamine skeleton, and is related to those of many other drugs, and to the major neurotransmitters epinephrine and norepinephrine.
# Natural occurrences
Synephrine, although already known as a synthetic organic compound, was first isolated as a natural product from the leaves of various Citrus trees, and its presence noted in different Citrus juices, by Stewart and co-workers in the early 1960s. A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart. It has subsequently been detected in Evodia and Zanthoxylum species, all plants of the family Rutaceae.
Trace levels (0.003%) of synephrine have also been detected in the dried leaves of Pogostemon cablin (patchouli, Lamiaceae). It is also found in certain cactus species of the genera Coryphantha and Dolichothele.
However, this compound is found predominantly in a number of Citrus species, including "bitter" and "sweet" orange varieties.
## In Citrus
Extracts of unripe fruit from Asian cultivars of Citrus aurantium (commonly known as "bitter" orange), collected in China, were reported to contain synephrine levels of about 0.1 - 0.3%, or ~ 1 – 3 mg/g; Analysis of dried fruit of C. aurantium grown in Italy showed a concentration of synephrine of ~ 1 mg/g, with peel containing over three times more than the pulp.
Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~ 13-34 μg/g (corresponding to 13–34 mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp); from these results, it was calculated that eating one "average" Tarocco orange would result in the consumption of ~ 6 mg of synephrine.
An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed synephrine levels ranging from 0.05 mg/g - 0.0009 mg/g in those jams made from bitter oranges, and levels of 0.05 mg/g - 0.006 mg/g of synephrine in jams made from sweet oranges.
Synephrine has been found in marmalade made from Citrus unshiu (Satsuma mandarin) obtained in Japan, at a concentration of ~ 0.12 mg/g (or about 2.4 mg/20g serving). Most of the orange marmalades made in the US are produced using "sweet" oranges (C. sinensis), whereas "bitter" or Seville oranges (C. aurantium) are used for making the more traditional, bitterer marmalades in the United Kingdom.
A sample of commercial Japanese C. unshiu juice was found to contain ~ 0.36 mg/g synephrine (or roughly 360 mg/L), while in juice products obtained from a Satsuma mandarin variety grown in California, levels of synephrine ranged from 55 to 160 mg/L .
Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~ 10–22 mg/L synephrine; commercial orange soft drinks obtained on the Brazilian market had an average synephrine content of ~ 1 mg/L. Commercial Italian orange juices contained ~ 13–32 mg/L of synephrine
In a survey of over 50 citrus fruit juices, either commercially-prepared or hand-squeezed from fresh fruit, obtained on the US market, Avula and co-workers found synephrine levels ranging from ~ 4 – 60 mg/L; no synephrine was detected in juices from grapefruit, lime, or lemon.
An analysis of the synephrine levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results:
Marrs sweet orange (C. sinensis Tan.): ~ 85 mg/L; Nova tangerine (C. reticulata Tan.): ~ 78 mg/L; clementine (C. clementina Tan.): ~ 115 mg/L; Meyer lemon (C. limon Tan.) ~ 3 mg/kg; Ugli tangelo (C. reticulata × C. paradisi) ~ 47 mg/kg. No synephrine was detected in: Rio Red grapefruit (C. paradisi Macf.); Red-fleshed pummelo (C. grandis Tan.); or Wekiwa tangelo (C. reticulata × C. paradisi).
Numerous additional comparable analyses of the synephrine content of Citrus fruits and products derived from them may be found in the research literature.
## In Humans and other animals
Low levels of synephrine have been found in normal human urine, as well as in other mammalian tissue. To reduce the likelihood that the synephrine detected in urine had a dietary origin, the subjects tested by Ibrahim and co-workers abstained from the consumption of any citrus products for 48 hours prior to providing urine samples.
A recent study of synephrine in human blood platelets by D'Andrea and co-workers showed increased levels in platelets from patients suffering from aura-associated migraine (0.72 ng/108 platelets, compared to 0.33 ng/108 platelets in control subjects). Earlier, the same research group had reported a normal human blood plasma level of synephrine of 0.90-13.69 ng/mL.
## Stereoisomers
Since synephrine exists as either of two enantiomers (see Chemistry section below for further discussion), which do not produce identical biological effects (see Pharmacology section below) some researchers have examined the stereoisomeric composition of synephrine extracted from natural sources. Although it seems clear that synephrine is found in those Citrus species which have been studied predominantly as the l-isomer, low levels of d-synephrine have been detected in juice and marmalade made from C. unshiu, and low levels (0.002%) have been reported in fresh fruit from C. aurantium. There are indications that some d-synephrine may be formed by the racemization of l-synephrine as a result of the processing of fresh fruit, although this matter has not been completely clarified. However, regardless of the situation in Citrus species, Ranieri and McLaughlin reported the isolation of racemic (i.e. a mixture of equal amounts of d- and l- stereoisomers) synephrine from a cactus of the Dolichothele genus, under conditions that would be unlikely to cause a significant amount of racemization.
## Biosynthesis
The biosynthesis of synephrine in Citrus species is believed to follow the pathway: tyrosine → tyramine → N-methyltyramine → synephrine, involving the enzymes tyrosine decarboxylase in the first step, tyramine N-methyltransferase in the second, and N-methyl-tyramine-β-hydroxylase in the third. This pathway differs from that thought to occur in animals, involving octopamine: tyramine → octopamine → synephrine, where the conversion of tyramine to octopamine is mediated by dopamine-β-hydroxylase, and the conversion of octopamine to synephrine by phenylethanolamine N-methyltransferase.
# Presence in Nutritional/Dietary Supplements
Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents. Usually, the synephrine is present as a natural component of Citrus aurantium ("bitter orange"), bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical (i.e. extracted from a plant source and purified to chemical homogeneity). The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5 – 14 mg/g.
# Pharmaceutical Use
As a synthetic drug, synephrine first appeared in Europe in the late 1920s, under the name of Sympatol. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala. By 1930, Sympatol was referred to as a Boehringer product, while one of the first US Patents describing its preparation and use was assigned to Frederick Stearns & Co. in 1933. Despite the date of this patent, clinical and pharmacological research on synephrine obtained from Frederick Stearns & Co was being carried out in the US by 1930. Writing in 1931, Hartung reported that in 1930 the Council on Pharmacy and Chemistry of the American Medical Association had accepted synephrine for inclusion in its list of “New and Non-Official Remedies” as an agent for the treatment, by either oral or parenteral administration, "of attacks of hay fever, asthma, coughing, spasms of asthma and pertussis (whooping cough)." However, synephrine was dropped from the Council's list in 1934, and its apparent re-advertising as a new drug by the Stearns company ten years later elicited a scathing comment from the Editors of the Journal of the American Medical Association. The third edition (1965) of Drill's Pharmacology in Medicine stated, with reservations, that synephrine was "advertised as an antihistaminic to be used in the treatment of the common cold...", under the trade name of "Synephrin Tartrate", and indicated that the dose was 100 mg, given intramuscularly, or subcutaneously. Published in 1966, the Textbook of Organic Medicinal and Pharmaceutical Chemistry described synephrine (in the form of its racemic tartrate) as a sympathomimetic agent that was "less effective than epinephrine", and which had been used for the treatment of chronic hypertension, collapse due to shock, and other conditions leading to hypotension. In a later (1972) textbook, synephrine was described as a drug, sold in Europe, that was administered in situations involving shock, such as surgical or bacteremic shock, and spinal anesthesia-related shock. The recommended dose was given here as 25–50 mg, by intravenous, intramuscular or subcutaneous administration.
There is no mention of synephrine in editions of Drill's Pharmacology in Medicine later than the 3rd, nor is there any reference to synephrine in the 2012 Physicians' Desk Reference, nor in the current FDA "Orange Book".
One current reference source describes synephrine as a vasoconstrictor that has been given to hypotensive patients, orally or by injection, in doses of 20 – 100 mg.
One Website from a healthcare media company, accessed in February, 2013, refers to oxedrine as being indicated for hypotensive states, in oral doses of 100–150 mg tid, and as a "conjunctival decongestant" to be topically applied as a 0.5% solution. However, no supporting references are provided.
# Names
There has been some confusion about the biological effects of synephrine because of the similarity of this un-prefixed name to the names m-synephrine, Meta-synephrine and Neosynephrine, all of which refer to a related drug and naturally-occurring amine more commonly known as phenylephrine. Although there are chemical and pharmacological similarities between synephrine and phenylephrine, they are nevertheless different substances. The confusion is compounded by the fact that synephrine has been marketed as a drug under numerous different names, including Sympatol, Sympathol, Synthenate, and oxedrine, while phenylephrine has also been called m-Sympatol. The synephrine with which this article deals is sometimes referred to as p-synephrine in order to distinguish it from its positional isomers, m-synephrine and o-synephrine. A comprehensive listing of alternative names for synephrine may be found in the ChemSpider entry (see Chembox, at right). Confusion over the distinctions between p- and m-synephrine has even contaminated the primary research literature.
Even the name "p-synephrine" is not unambiguous, since it does not specify stereochemistry. The only completely unambiguous names for synephrine are: R-(-)-4-phenol (for the l-enantiomer); S-(+)-4-phenol (for the d-enantiomer); and R,S-4-phenol (for the racemate, or d,l-synephrine) (see Chemistry section]]).
# Chemistry
## Properties
In terms of molecular structure, synephrine has a phenethylamine skeleton, with a phenolic hydroxy- group, an alcoholic hydroxy- group, and an N-methylated amino-group. Alternatively, synephrine might be described as a phenylethanolamine with an N-methyl and p-hydroxy substituent. The amino-group confers basic properties on the molecule, whereas the phenolic -OH group is weakly acidic: the apparent (see original article for discussion) pKas for protonated synephrine are 9.55 (phenolic H) and 9.79 (ammonium H).
Common salts of racemic synephrine are its hydrochloride, C9H13NO2.HCl, m.p. 150-152°, the oxalate (C9H13NO2)2.C2H2O4, m.p. 221-222 °C, and the tartrate (Sympatol), (C9H13NO2)2.C4H6O6, m.p. 188-190 °C.
The presence of the hydroxy-group on the benzylic C of the synephrine molecule creates a chiral center, so the compound exists in the form of two enantiomers, d- and l- synephrine, or as the racemic mixture, d,l- synephrine. The dextrorotatory d-isomer corresponds to the S-configuration, and the levorotatory l-isomer to the R-configuration.
Racemic synephrine has been resolved using ammonium 3-bromo-camphor-8-sulfonate. The enantiomers were not characterized as their free bases, but converted to the hydrochloride salts, with the following properties:
S-(+)-C9H13NO2.HCl: m.p. 178 °C; = +42.0°, c 0.1 (H2O); R-(-)-C9H13NO2.HCl: m.p. 176 °C; = -39.0°, c 0.2 (H2O)
(-)-Synephrine, as the free base isolated from a Citrus source, has m.p. 162-164 °C (with decomposition).
The X-ray structure for synephrine has been determined.
## Synthesis
Early and seemingly inefficient syntheses of synephrine were discussed by Priestley and Moness, writing in 1940. These chemists optimized a route beginning with the O-benzoylation of p-hydroxy-phenacyl chloride, followed by reaction of the resulting O-protected chloride with N-methyl-benzylamine to give an amino-ketone. This intermediate was then hydrolyzed with HCl/alcohol to the p-hydroxy-aminoketone, and the product then reduced catalytically to give (racemic) synephrine.
A later synthesis, due to Bergmann and Sulzbacher, began with the O-benzylation of p-hydroxy-benzaldehyde, followed by a Reformatskii reaction of the protected aldehyde with ethyl bromoacetate/Zn to give the expected β-hydroxy ester. This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO2, ultimately yielding the p-benzyloxy-phenyloxazolidone. This was N-methylated using dimethyl sulfate, then hydrolyzed and O-debenzylated by heating with HCl, to give racemic synphrine.
## Structural Relationships
Much reference has been made in the literature (both lay and professional) of the structural kinship of synephrine with ephedrine, or with phenylephrine, often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties. However, from a chemical perspective, synephrine is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate.
Thus, replacement of the N-methyl group in synephrine with a hydrogen atom gives octopamine; replacement of the β-hydroxy group in synephrine by a H atom gives N-methyltyramine; replacement of the synephrine phenolic 4-OH group by a -H gives halostachine.
If the synephrine phenolic 4-OH group is shifted to the meta-, or 3-position on the benzene ring, the compound known as phenylephrine (or m-synephrine, or "Neo-synephrine") results; if the same group is shifted to the ortho-, or 2-position on the ring, o-synephrine results.
Addition of another phenolic -OH group to the 3-position of the benzene ring produces the neurotransmitter epinephrine; addition of a methyl group to the α-position in the side-chain of synephrine gives oxilofrine (or "methylsynephrine") (although it should be noted that four stereoisomers and two racemic modifications are possible for this substance).
Extension of the synephrine N-methyl substituent by one methylene unit to an N-ethyl gives the hypotensive experimental drug "Sterling #573"/"Aethyl-Sympatol".
The above structural relationships all involve a change at one position in the synephrine molecule, and numerous other similar changes, many of which have been explored, are possible. However, the structure of ephedrine differs from that of synephrine at two different positions: ephedrine has no substituent on the phenyl ring where synephrine has a 4-OH group, and ephedrine has a methyl group on the position α- to the N in the side-chain, where syneprine has only a H atom. Furthermore, "synephrine" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers.
The main differences of the synephrine isomers compared for example to the ephedrines are the hydroxy-substitutions on the benzene ring. Synephrines are direct sympathomimetic drugs while the ephedrines are both direct and indirect sympathomimetics. One of the main reasons for these differential effects is the obviously increased polarity of the hydroxy-substituted phenyl ethyl amines which renders them less able to penetrate the blood-brain barrier as illustrated in the examples for tyramine and the amphetamine analogs.
# Pharmacology
## Synopsis
Classical pharmacological studies on animals and isolated animal tissues showed that the principal actions of parenterally-administered synephrine included raising blood-pressure, dilating the pupil, and constricting peripheral blood vessels.
There is now ample evidence that synephrine produces most of its biological effects by acting as an agonist at (i.e. stimulating) adrenergic receptors, with a distinct preference for the α1 over the α2 sub-type. However, the potency of synephrine at these receptors is relatively low (i.e. relatively large concentrations of the drug are required to activate them). The potency of synephrine at adrenergic receptors of the β-class (regardless of sub-type) is much lower than at α-receptors. There is some evidence that synephrine also has weak activity at 5-HT receptors, and that it interacts with TAAR1 (trace adrenergic amine receptors).
In common with virtually all other simple phenylethanolamines (β-hydroxy-phenethylamines), the R-(-)-, or l-, enantiomer of synephrine is more potent than the S-(+)-, or d-, enantiomer in most, but not all preparations studied. However, the majority of studies have been conducted with a racemic mixture of the two enantiomers.
Since the details regarding such variables as test species, receptor source, route of administration, drug concentration, and stereochemical composition are important but often incomplete in other Reviews and Abstracts of research publications, many are provided in the more technical review below, in order to support as fully as possible the broad statements made in this Synposis.
## Pharmacology Research
Pharmacological studies on synephrine date back to the late 1920s, when it was observed that injected synephrine raised blood pressure, constricted peripheral blood vessels, dilated pupils, stimulated the uterus, and relaxed the intestines in experimental animals. Representative of this early work is the paper by Tainter and Seidenfeld, who were the first researchers to systematically compare the different effects of the two synephrine enantiomers, d- and l- synephrine, as well as of the racemate, d,l-synephrine, in various animal assays.
In experiments on anesthetized cats, Tainter and Seidenfeld confirmed earlier reports of the increase in blood pressure produced by intravenous doses of synephrine, showing that the median pressor doses for the isomers were: l-synephrine: 0.5 mg/kg; d,l-synephrine: 1.0 mg/kg; and d-synephrine: 2–20 mg/kg. These effects lasted 2–3 minutes, peaking at ~30 seconds after administration. l-Synephrine was thus the more potent enantiomer, with about 1/60 x the potency of the standard pressor l-epinephrine in the same assay.
A later study, by Lands and Grant, showed that a dose of ~ 0.6 mg/kg of racemic synephrine, given intravenously to anesthetized dogs, produced a rise in blood pressure of 34 mm Hg lasting 5 – 10 minutes, and estimated that this pressor activity was about 1/300 x that of epinephrine.
Using cats and dogs, Tainter and Seidenfeld observed that neither d- nor l-synephrine caused any changes in the tone of normal bronchi, in situ, even at "maximum" doses. Furthermore, the marked brocho-constriction produced by injections of histamine was not reversed by either l-synephrine or d,l-synephrine.
In experiments with isolated sheep carotid artery, d-, l- and d,l-synephrine all showed some vasoconstrictor activity: l-synephrine was the most potent, producing strong contractions at a concentration of 1:10000. d-Synephrine was about 1/2 as potent as the l-isomer, but d,l-synephrine (which would have been expected to have a potency of 1/2 that of l-synephrine even if the d-isomer were completely inactive) did not produce significant and irregular contractions until a concentration of 1:2500had been reached, implying an inhibitory interaction between the two enantiomers.
Qualitatively similar results were obtained in a rabbit ear preparation: 25 mg l-synephrine produced significant (50%) vasoconstriction, while the same concentration of d-synephrine elicited essentially no response. In contrast, d,l-synephrine did not produce any constriction up to 25 mg, but 25 – 50 mg caused a relaxation of the blood vessels, which again suggested that the d-isomer might be inhibiting the action of the l-isomer.
Experiments on strips of rabbit duodenum showed that l-synephrine caused a modest reduction in contractions at a concentration of 1:17000, but that the effects of the d- and d,l- forms were much weaker.
Racemic synephrine, given intramuscularly, or by instillation, was found to significantly reduce the inflammation caused by instillation of mustard oil into the eyes of rabbits.
Subcutaneous injection of racemic synephrine into rabbits was reported to cause a large rise in blood sugar.
In experiments on anesthetized cats, Papp and Szekeres found that synephrine (stereochemistry unspecified) raised the thresholds for auricular and ventricular fibrillation, an indication of anti-arrhythmic properties.
Evidence that synephrine might have some central effects comes from the research of Song and co-workers, who studied the effects of synephrine in mouse models of anti-depressant activity. These researchers observed that oral doses of 0.3 – 10 mg/kg of racemic syephrine were effective in shortening the duration of immobility produced in the assays, but did not cause any changes in spontaneous motor activity in separate tests. This characteristic immobility could be counteracted by the pre-administration of prazosin.
Subsequent experiments using the individual enanatiomers of synephrine revealed that although the d-isomer significantly reduced the duration of immobility in the tail suspension test, at an oral dose of 3 mg/kg, the l-isomer had no effect at the same dose.
In mice pre-treated with reserpine, an oral dose of 0.3 mg/kg d-synephrine significantly reversed the hypothermia, while l-synephrine required a dose of 1 mg/kg to be effective.
Experiments with slices of cerebral cortex taken from rat brain showed that d-synephrine inhibited the uptake of -norepinephrine with an IC50 = 5.8 μM; l-synephrine was less potent (IC50 = 13.5 μM).
d-Synephrine also competitively inhibited the binding of nisoxetine to rat brain cortical slices, with a Ki = 4.5 μM; l-synephrine was less potent (Ki = 8.2 μM).
In experiments on the release of -norepinephrine from rat brain cortical slices, however, the l-isomer of synephrine was a more potent enhancer of the release (EC50 = 8.2 μM) than the d-isomer (EC50 = 12.3 μM). This enhanced release by l-synephrine was blocked by nisoxetine.
Burgen and Iversen, examining the effect of a broad range of phenethylamine-based drugs on -norepinephrine-uptake in the isolated rat heart, observed that racemic synephrine was a relatively weak inhibitor (IC50 = 0.12 μM) of the uptake.
Another receptor-oriented study by Wikberg revealed that synephrine (stereochemistry unspecified) was a more potent agonist at guinea pig aorta α1 receptors (pD2 = 4.81) than at ileum α2 receptors (pD2 = 4.48), with a relative affinity ratio of α2/α1 = 0.10. Although clearly indicating a selectivity of synephrine for α1 receptors, its potency at this receptor sub-class is still relatively low, in comparison with that of phenylephrine (pD2 at α1 = 6.32).
Brown and co-workers examined the effects of the individual enantiomers of synephrine on α1 receptors in rat aorta, and on α2 receptors in rabbit saphenous vein. In the aorta preparation, l-synephrine gave a pD2 = 5.38 (potency relative to norepinephrine = 1/1000), while d-synephrine had a pD2 = 3.50 (potency relative to norepinephrine = 1/50000); in comparison, l-phenylephrine had pD2 = 7.50 (potency relative to norepinephrine ≃ 1/6). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10−6 M. In the rabbit saphenous assay, the pD2 of l-synephrine was 4.36 (potency relative to norepinephrine ≃ 1/1700), and that of d-synephrine was < 3.00; in comparison, l-phenylephrine had pD2 = 5.45 (potency relative to norepinephrine ≃ 1/140). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10−5 M.
A study of the effects of synephrine (stereochemistry unspecified) on strips of guinea pig aorta and on the field-stimulated guinea pig ileum showed that synephrine had an agonist potency of -logKa = 3.75 in the aorta assay. In comparison, epinephrine had a potency of -logKa = 5.70. There was no significant effect on the ileum at synephrine concentrations up to about 2 x 10−4M, indicating selectivity for the α1 receptor, but relatively low potency.
In binding experiments with central adrenergic receptors, using a preparation from rat cerebral cortex, l-synephrine had pIC50 = 3.35, and d-synephrine had pIC50 = 2.42 in competition against -prazosin (standard α1 ligand); against -yohimbine (standard α2 ligand), l-synephrine showed a pIC50 = 5.01, and d-synephrine showed a pIC50 = 4.17.
Experiments conducted by Hibino and co-workers also showed that synephrine (stereochemistry unspecified) produced a dose-dependent constriction of isolated rat aorta strips, in the concentration range 10−5 - 3 x 10−6 M. This constriction was found to be competitively antagonized by prazosin (a standard α1 antagonist) and ketanserin, with prazosin being the more potent antagonist (pA2 = 9.38, vs pA2 = 8.23 for ketanserin). Synephrine constrictions were also antagonized by BRL-15,572{{Used here as a selective 5-HT1D antagonist.}}, but not by SB-216,641{{Used here as a selective 5-HT1B antagonist.}}, or by propranolol (a common β antagonist).
In studies on guinea pig atria and trachea, Jordan and co-workers also found that synephrine had negligible activity on β1 and β2 receptors, being about 40000 x less potent than norepinephrine.
Experiments with cultured white fat cells from several animal species, including human, by Carpéné and co-workers showed that racemic synephrine produced lipolytic effects, but only at high concentrations (0.1-1 mM). The potency, expressed in terms of pD2 of synephrine in these species was as follows: rat: 4.38; hamster: 5.32; guinea pig: 4.31; human: 4.94. In comparison, isoprenaline had a pD2 = 8.29 and norepinephrine had pD2 = 6.80 in human white fat cells. The lipolytic effect of 1 mM/L of synephrine on rat white fat cells was antagonized by various β-antagonists with the following inhibitory concentrations (IC50): bupranolol: 0.11 μM; CGP-20,712A (β1 antagonist): 6.09 μM; ICI-118,551 (β2 antagonist): 3.58 μM; SR-5923A (β3 antagonist): 17 μM.
The binding of racemic synephrine to cloned human adrenergic receptors has been examined: Ma and co-workers found that synephrine bound to α1A, α2A and α2C with low affinity (pKi = 4.11 for α1A; 4.44 for α2A; 4.61 for α2C). Synephrine behaved as a partial agonist at α1A receptors, but as an antagonist at α2A and α2C sub-types.
Racemic synephrine has been shown to be an agonist of the TAAR1, although its potency at the human TAAR1 is relatively low (EC50 = 23700 nM; Emax = 81.2%).
# Pharmacokinetics
The pharmacokinetics of synephrine were studied by Hengstmann and Aulepp, who reported a peak plasma concentration at 1–2 hours, with an elimination half-life (T1/2) of ~ 2 hours.
# Metabolism
Studies of the metabolism of synephrine by monoamine oxidases derived from rat brain mitochondria showed that synephrine was a substrate for deamination by both MAO-A and MAO-B, with Km = 250 μM and Vmax = 32.6 nM/mg protein/30 minutes; there was some evidence for preferential deamination by MAO-A.
# Effects in humans
A number of studies of the effects of synephrine in humans, most of them focusing on its cardio-vascular properties, have been performed since its introduction as a synthetic drug around 1930. The paper by Stockton and co-workers is representative, describing the effects of racemic synephrine in humans with particular attention to differences resulting from different routes of administration. Thus, it was shown by these investigators that intramuscular injections (average effective dose = 200 mg) of the drug produced an increase in systolic blood pressure and pulse rate, without affecting the diastolic pressure. The blood pressure increase reached a maximum (~ 25 mm Hg)in 5 minutes following the injection, then gradually returned to normal over the course of 1 hour. Doses of drug greater than 200 mg caused side-effects such as heart palpitations, headache, sweating, and feelings of apprehension. When given intravenously, doses of 25–50 mg sufficed to produce a mean maximum increase in the blood pressure of 29 mm Hg in 2 minutes, and a return to baseline within 30 minutes. Respiration was generally not affected during these experiments. Subcutaneous administration of synephrine in doses ≤ 200 mg had no effects on blood pressure or pulse rate. Oral doses of 500 – 1500 mg of the drug did not affect blood pressure or respiration, but pulse rate was increased by ~ 12%, and the highest doses caused nausea and vomiting.
The i.m. administration of 75 – 500 mg of synephrine did not relieve acute asthma attacks, contradicting an earlier claim. However, the topical application of 1 - 3% solutions of the drug to the nasal mucosa of patients with sinusitis did produce a beneficial constriction without local irritation.
A more recent study showed that the administration of synephrine by continuous intravenous infusion, at the rate of 4 mg/minute, significantly increased mean arterial and systolic pressure, but diastolic pressure and heart rate were unaltered.; further details of this investigation are summarized in a review by Fugh-Berman and Myers.
There are a number of studies, references to many of which may be found in the review by Stohs and co-workers. dealing with the effects produced by dietary supplements and herbal medications that contain synephrine as only one of many different chemical ingredients. These are outside the scope of the present article (see also the "Safety/Efficacy/Controversy" sub-section).
# Toxicology
The acute toxicities of racemic synephrine in different animals, reported in terms of "maximum tolerated dose" after s.c administration, were as follows: mouse: 300 mg/kg; rat: 400 mg/kg; guinea pig: 400 mg/kg. "Lethal doses", given s.c., were found to be: mouse: 400 mg/kg; rat: 500 mg/kg; guinea pig: 500 mg/kg. Another study of this compound, administered i.v. in mice, gave an LD50 = 270 mg/kg.
The "subchronic toxicity" of synephrine was judged to be low in mice, after administration of oral doses of 30 and 300 mg/kg over a period of 28 days, in a recent study employing modern methodology carried out by Arbo and co-workers. Generally, this treatment did not result in significant alterations in biochemical or hematological parameters, nor in relative organ weights, but some changes were noted in glutathione (GSH) concentration, and in the activity of glutathione peroxidase (GPx).
# Safety/Efficacy/Controversy
Information about the safety and efficacy of synephrine used as a single drug may be deduced from the foregoing review of the literature in this Article. This information is, by and large, not contended. However, there exists considerable controversy about the safety and/or efficacy of synephrine-containing preparations, which are often confused with synephrine alone, sometimes with m-synephrine, and much has been written about such preparations in the medical literature and on the Internet. Since this body of literature deals with mixtures containing synephrine as only one of several biologically-active components, even, in some cases, without explicit confirmation of the presence of synephrine, further discussion is outside the scope of this article.
# Invertebrates
In insects, synephrine has been found to be a very potent agonist at many invertebrate octopamine receptor preparations, and is even more potent than octopamine at a locust (Schistocerca americana gregaria) nerve-muscle preparation. Synephrine (racemic) is also more potent than octopamine (racemic) at inducing light-emission in the firefly (Photinus species) light organ. Synephrine exhibits similarly high potency in stimulating adenylate cyclase activity and in decreasing clotting time in lobster (Homarus americanus) hematocytes. Racemic synephrine was found to increase cAMP in the abdominal epidermis of the blood-sucking bug, Rhodnius prolixus. Rachinsky reported that synephrine was equipotent with octopamine in stimulating JH (juvenile hormone) release in the corpora allata of honey bee (Apis mellifera), but Woodring and Hoffmann found that synephrine had no effect on the synthesis of JH III, in in vitro preparations from the cricket, Gryllus bimaculatus. | Synephrine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Synephrine, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine.[1] p-synephrine (or formerly Sympatol and oxedrine [BAN]) and m-synephrine are known for their longer acting adrenergic effects compared to norepinephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange (Citrus species) products, both of the "sweet" and "bitter" variety. The preparations used in Traditional Chinese Medicine (TCM), also known as Zhi Shi, are the immature and dried whole oranges from Citrus aurantium (Fructus Aurantii Immaturus). Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with caffeine, as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved OTC drug. As a pharmaceutical, m-synephrine is still used as a sympathomimetic (i.e. for its hypertensive and vasoconstrictor properties), mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.[lower-alpha 1]
It is important to distinguish between studies concerning synephrine as a single chemical entity (and even here it should be borne in mind that synephrine can exist in the form of either of two stereoisomers, d- and l-synephrine, which are chemically and pharmacologically distinct), and synephrine which is mixed with other drugs and/or botanical extracts in a "Supplement", as well as synephrine which is present as only one chemical component in a naturally-occurring mixture of phytochemicals such as the rind or fruit of a bitter orange. Mixtures containing synephrine as only one of their chemical components (regardless of whether these are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as synephrine alone.[2]
In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. Its molecular structure is based on a phenethylamine skeleton, and is related to those of many other drugs, and to the major neurotransmitters epinephrine and norepinephrine.
# Natural occurrences
Synephrine, although already known as a synthetic organic compound, was first isolated as a natural product from the leaves of various Citrus trees, and its presence noted in different Citrus juices, by Stewart and co-workers in the early 1960s.[3][4] A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart.[5] It has subsequently been detected in Evodia[6] and Zanthoxylum species,[7] all plants of the family Rutaceae.
Trace levels (0.003%) of synephrine have also been detected in the dried leaves of Pogostemon cablin (patchouli, Lamiaceae).[8] It is also found in certain cactus species of the genera Coryphantha and Dolichothele.[9]
However, this compound is found predominantly in a number of Citrus species, including "bitter" and "sweet" orange varieties.
## In Citrus
Extracts of unripe fruit from Asian cultivars of Citrus aurantium (commonly known as "bitter" orange), collected in China, were reported to contain synephrine levels of about 0.1 - 0.3%, or ~ 1 – 3 mg/g;[10] Analysis of dried fruit of C. aurantium grown in Italy showed a concentration of synephrine of ~ 1 mg/g, with peel containing over three times more than the pulp.[11]
Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~ 13-34 μg/g (corresponding to 13–34 mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp); from these results, it was calculated that eating one "average" Tarocco orange would result in the consumption of ~ 6 mg of synephrine.[12]
An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed synephrine levels ranging from 0.05 mg/g - 0.0009 mg/g[lower-alpha 2] in those jams made from bitter oranges, and levels of 0.05 mg/g - 0.006 mg/g[lower-alpha 3] of synephrine in jams made from sweet oranges.[13]
Synephrine has been found in marmalade made from Citrus unshiu (Satsuma mandarin)[14] obtained in Japan, at a concentration of ~ 0.12 mg/g (or about 2.4 mg/20g serving).[15] Most of the orange marmalades made in the US are produced using "sweet" oranges (C. sinensis), whereas "bitter" or Seville oranges (C. aurantium) are used for making the more traditional, bitterer marmalades in the United Kingdom.[16]
A sample of commercial Japanese C. unshiu juice was found to contain ~ 0.36 mg/g synephrine (or roughly 360 mg/L),[15] while in juice products obtained from a Satsuma mandarin variety grown in California, levels of synephrine ranged from 55 to 160 mg/L .[17]
Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~ 10–22 mg/L synephrine; commercial orange soft drinks obtained on the Brazilian market had an average synephrine content of ~ 1 mg/L.[18] Commercial Italian orange juices contained ~ 13–32 mg/L of synephrine[12]
In a survey of over 50 citrus fruit juices, either commercially-prepared or hand-squeezed from fresh fruit, obtained on the US market, Avula and co-workers found synephrine levels ranging from ~ 4 – 60 mg/L;[lower-alpha 4] no synephrine was detected in juices from grapefruit, lime, or lemon.[13]
An analysis of the synephrine levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results:
Marrs sweet orange (C. sinensis Tan.): ~ 85 mg/L; Nova tangerine (C. reticulata Tan.): ~ 78 mg/L; clementine (C. clementina Tan.): ~ 115 mg/L; Meyer lemon (C. limon Tan.) ~ 3 mg/kg; Ugli tangelo (C. reticulata × C. paradisi) ~ 47 mg/kg. No synephrine was detected in: Rio Red grapefruit (C. paradisi Macf.); Red-fleshed pummelo (C. grandis Tan.); or Wekiwa tangelo (C. reticulata × C. paradisi).[14][19]
Numerous additional comparable analyses of the synephrine content of Citrus fruits and products derived from them may be found in the research literature.
## In Humans and other animals
Low levels of synephrine have been found in normal human urine,[20][21] as well as in other mammalian tissue.[22][23] To reduce the likelihood that the synephrine detected in urine had a dietary origin, the subjects tested by Ibrahim and co-workers abstained from the consumption of any citrus products for 48 hours prior to providing urine samples.[20]
A recent study of synephrine in human blood platelets by D'Andrea and co-workers showed increased levels in platelets from patients suffering from aura-associated migraine (0.72 ng/108 platelets, compared to 0.33 ng/108 platelets in control subjects).[24] Earlier, the same research group had reported a normal human blood plasma level of synephrine of 0.90-13.69 ng/mL.[25]
## Stereoisomers
Since synephrine exists as either of two enantiomers (see Chemistry section below for further discussion), which do not produce identical biological effects (see Pharmacology section below) some researchers have examined the stereoisomeric composition of synephrine extracted from natural sources. Although it seems clear that synephrine is found in those Citrus species which have been studied predominantly as the l-isomer,[15][26] low levels of d-synephrine have been detected in juice and marmalade made from C. unshiu,[15] and low levels (0.002%) have been reported in fresh fruit from C. aurantium.[26] There are indications that some d-synephrine may be formed by the racemization of l-synephrine as a result of the processing of fresh fruit, although this matter has not been completely clarified.[27][28] However, regardless of the situation in Citrus species, Ranieri and McLaughlin reported the isolation of racemic (i.e. a mixture of equal amounts of d- and l- stereoisomers) synephrine from a cactus of the Dolichothele genus, under conditions that would be unlikely to cause a significant amount of racemization.[29]
## Biosynthesis
The biosynthesis of synephrine in Citrus species is believed to follow the pathway: tyrosine → tyramine → N-methyltyramine → synephrine, involving the enzymes tyrosine decarboxylase in the first step, tyramine N-methyltransferase in the second, and N-methyl-tyramine-β-hydroxylase in the third.[30][31] This pathway differs from that thought to occur in animals, involving octopamine: tyramine → octopamine → synephrine, where the conversion of tyramine to octopamine is mediated by dopamine-β-hydroxylase, and the conversion of octopamine to synephrine by phenylethanolamine N-methyltransferase.[25][30]
# Presence in Nutritional/Dietary Supplements
Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents. Usually, the synephrine is present as a natural component of Citrus aurantium ("bitter orange"), bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical (i.e. extracted from a plant source and purified to chemical homogeneity).[16][35][36] The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5 – 14 mg/g.[35]
# Pharmaceutical Use
As a synthetic drug, synephrine first appeared in Europe in the late 1920s, under the name of Sympatol. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala.[37] By 1930, Sympatol was referred to as a Boehringer product,[38] while one of the first US Patents describing its preparation and use was assigned to Frederick Stearns & Co. in 1933.[39] Despite the date of this patent, clinical and pharmacological research on synephrine obtained from Frederick Stearns & Co was being carried out in the US by 1930.[40][41] Writing in 1931, Hartung reported that in 1930 the Council on Pharmacy and Chemistry of the American Medical Association had accepted synephrine for inclusion in its list of “New and Non-Official Remedies” as an agent for the treatment, by either oral or parenteral administration, "of attacks of hay fever, asthma, coughing, spasms of asthma and pertussis (whooping cough)."[42][43] However, synephrine was dropped from the Council's list in 1934, and its apparent re-advertising as a new drug by the Stearns company ten years later elicited a scathing comment from the Editors of the Journal of the American Medical Association.[44] The third edition (1965) of Drill's Pharmacology in Medicine stated, with reservations, that synephrine was "advertised as an antihistaminic to be used in the treatment of the common cold...", under the trade name of "Synephrin Tartrate", and indicated that the dose was 100 mg, given intramuscularly, or subcutaneously.[45] Published in 1966, the Textbook of Organic Medicinal and Pharmaceutical Chemistry described synephrine (in the form of its racemic tartrate) as a sympathomimetic agent that was "less effective than epinephrine", and which had been used for the treatment of chronic hypertension, collapse due to shock, and other conditions leading to hypotension.[46] In a later (1972) textbook, synephrine was described as a drug, sold in Europe, that was administered in situations involving shock, such as surgical or bacteremic shock, and spinal anesthesia-related shock. The recommended dose was given here as 25–50 mg, by intravenous, intramuscular or subcutaneous administration.[47]
There is no mention of synephrine in editions of Drill's Pharmacology in Medicine later than the 3rd, nor is there any reference to synephrine in the 2012 Physicians' Desk Reference, nor in the current FDA "Orange Book".
One current reference source describes synephrine as a vasoconstrictor that has been given to hypotensive patients, orally or by injection, in doses of 20 – 100 mg.[48]
One Website from a healthcare media company, accessed in February, 2013, refers to oxedrine as being indicated for hypotensive states, in oral doses of 100–150 mg tid, and as a "conjunctival decongestant" to be topically applied as a 0.5% solution.[49] However, no supporting references are provided.
# Names
There has been some confusion about the biological effects of synephrine because of the similarity of this un-prefixed name to the names m-synephrine, Meta-synephrine and Neosynephrine, all of which refer to a related drug and naturally-occurring amine more commonly known as phenylephrine. Although there are chemical and pharmacological similarities between synephrine and phenylephrine, they are nevertheless different substances. The confusion is compounded by the fact that synephrine has been marketed as a drug under numerous different names, including Sympatol, Sympathol, Synthenate, and oxedrine, while phenylephrine has also been called m-Sympatol. The synephrine with which this article deals is sometimes referred to as p-synephrine in order to distinguish it from its positional isomers, m-synephrine and o-synephrine. A comprehensive listing of alternative names for synephrine may be found in the ChemSpider entry (see Chembox, at right). Confusion over the distinctions between p- and m-synephrine has even contaminated the primary research literature.[lower-alpha 5]
Even the name "p-synephrine" is not unambiguous, since it does not specify stereochemistry. The only completely unambiguous names for synephrine are: R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the l-enantiomer); S-(+)-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the d-enantiomer); and R,S-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the racemate, or d,l-synephrine) (see Chemistry section]]).
# Chemistry
## Properties
In terms of molecular structure, synephrine has a phenethylamine skeleton, with a phenolic hydroxy- group, an alcoholic hydroxy- group, and an N-methylated amino-group. Alternatively, synephrine might be described as a phenylethanolamine with an N-methyl and p-hydroxy substituent. The amino-group confers basic properties on the molecule, whereas the phenolic -OH group is weakly acidic: the apparent (see original article for discussion) pKas for protonated synephrine are 9.55 (phenolic H) and 9.79 (ammonium H).[52]
Common salts of racemic synephrine are its hydrochloride, C9H13NO2.HCl, m.p. 150-152°,[53] the oxalate (C9H13NO2)2.C2H2O4, m.p. 221-222 °C,[3] and the tartrate (Sympatol), (C9H13NO2)2.C4H6O6, m.p. 188-190 °C.[46][54]
The presence of the hydroxy-group on the benzylic C of the synephrine molecule creates a chiral center, so the compound exists in the form of two enantiomers, d- and l- synephrine, or as the racemic mixture, d,l- synephrine. The dextrorotatory d-isomer corresponds to the S-configuration, and the levorotatory l-isomer to the R-configuration.[55]
Racemic synephrine has been resolved using ammonium 3-bromo-camphor-8-sulfonate.[11][55] The enantiomers were not characterized as their free bases, but converted to the hydrochloride salts, with the following properties:[55]
S-(+)-C9H13NO2.HCl: m.p. 178 °C; [α] = +42.0°, c 0.1 (H2O); R-(-)-C9H13NO2.HCl: m.p. 176 °C; [α] = -39.0°, c 0.2 (H2O)
(-)-Synephrine, as the free base isolated from a Citrus source, has m.p. 162-164 °C (with decomposition).[3][4]
The X-ray structure for synephrine has been determined.[55]
## Synthesis
Early and seemingly inefficient syntheses of synephrine were discussed by Priestley and Moness, writing in 1940.[56] These chemists optimized a route beginning with the O-benzoylation of p-hydroxy-phenacyl chloride, followed by reaction of the resulting O-protected chloride with N-methyl-benzylamine to give an amino-ketone. This intermediate was then hydrolyzed with HCl/alcohol to the p-hydroxy-aminoketone, and the product then reduced catalytically to give (racemic) synephrine.
A later synthesis, due to Bergmann and Sulzbacher, began with the O-benzylation of p-hydroxy-benzaldehyde, followed by a Reformatskii reaction of the protected aldehyde with ethyl bromoacetate/Zn to give the expected β-hydroxy ester. This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO2, ultimately yielding the p-benzyloxy-phenyloxazolidone. This was N-methylated using dimethyl sulfate, then hydrolyzed and O-debenzylated by heating with HCl, to give racemic synphrine.[57]
## Structural Relationships
Much reference has been made in the literature (both lay and professional) of the structural kinship of synephrine with ephedrine, or with phenylephrine, often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties. However, from a chemical perspective, synephrine is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate.
Thus, replacement of the N-methyl group in synephrine with a hydrogen atom gives octopamine; replacement of the β-hydroxy group in synephrine by a H atom gives N-methyltyramine; replacement of the synephrine phenolic 4-OH group by a -H gives halostachine.
If the synephrine phenolic 4-OH group is shifted to the meta-, or 3-position on the benzene ring, the compound known as phenylephrine (or m-synephrine, or "Neo-synephrine") results; if the same group is shifted to the ortho-, or 2-position on the ring, o-synephrine results.
Addition of another phenolic -OH group to the 3-position of the benzene ring produces the neurotransmitter epinephrine; addition of a methyl group to the α-position in the side-chain of synephrine gives oxilofrine (or "methylsynephrine") (although it should be noted that four stereoisomers and two racemic modifications are possible for this substance).
Extension of the synephrine N-methyl substituent by one methylene unit to an N-ethyl gives the hypotensive experimental drug "Sterling #573"/"Aethyl-Sympatol".[58][59]
The above structural relationships all involve a change at one position in the synephrine molecule, and numerous other similar changes, many of which have been explored, are possible. However, the structure of ephedrine differs from that of synephrine at two different positions: ephedrine has no substituent on the phenyl ring where synephrine has a 4-OH group, and ephedrine has a methyl group on the position α- to the N in the side-chain, where syneprine has only a H atom. Furthermore, "synephrine" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers.
The main differences of the synephrine isomers compared for example to the ephedrines are the hydroxy-substitutions on the benzene ring. Synephrines are direct sympathomimetic drugs while the ephedrines are both direct and indirect sympathomimetics. One of the main reasons for these differential effects is the obviously increased polarity of the hydroxy-substituted phenyl ethyl amines which renders them less able to penetrate the blood-brain barrier as illustrated in the examples for tyramine and the amphetamine analogs.[60]
# Pharmacology
## Synopsis
Classical pharmacological studies on animals and isolated animal tissues showed that the principal actions of parenterally-administered synephrine included raising blood-pressure, dilating the pupil, and constricting peripheral blood vessels.
There is now ample evidence that synephrine produces most of its biological effects by acting as an agonist at (i.e. stimulating) adrenergic receptors, with a distinct preference for the α1 over the α2 sub-type. However, the potency of synephrine at these receptors is relatively low (i.e. relatively large concentrations of the drug are required to activate them). The potency of synephrine at adrenergic receptors of the β-class (regardless of sub-type) is much lower than at α-receptors. There is some evidence that synephrine also has weak activity at 5-HT receptors, and that it interacts with TAAR1 (trace adrenergic amine receptors).
In common with virtually all other simple phenylethanolamines (β-hydroxy-phenethylamines), the R-(-)-, or l-, enantiomer of synephrine is more potent than the S-(+)-, or d-, enantiomer in most, but not all preparations studied. However, the majority of studies have been conducted with a racemic mixture of the two enantiomers.
Since the details regarding such variables as test species, receptor source, route of administration, drug concentration, and stereochemical composition are important but often incomplete in other Reviews and Abstracts of research publications, many are provided in the more technical review below, in order to support as fully as possible the broad statements made in this Synposis.
## Pharmacology Research
Pharmacological studies on synephrine date back to the late 1920s, when it was observed that injected synephrine raised blood pressure, constricted peripheral blood vessels, dilated pupils, stimulated the uterus, and relaxed the intestines in experimental animals.[37][37][61][62] Representative of this early work is the paper by Tainter and Seidenfeld, who were the first researchers to systematically compare the different effects of the two synephrine enantiomers, d- and l- synephrine, as well as of the racemate, d,l-synephrine, in various animal assays.[41]
In experiments on anesthetized cats, Tainter and Seidenfeld confirmed earlier reports of the increase in blood pressure produced by intravenous doses of synephrine, showing that the median pressor doses for the isomers were: l-synephrine: 0.5 mg/kg; d,l-synephrine: 1.0 mg/kg; and d-synephrine: 2–20 mg/kg. These effects lasted 2–3 minutes, peaking at ~30 seconds after administration. l-Synephrine was thus the more potent enantiomer, with about 1/60 x the potency of the standard pressor l-epinephrine in the same assay.
A later study, by Lands and Grant, showed that a dose of ~ 0.6 mg/kg of racemic synephrine, given intravenously to anesthetized dogs, produced a rise in blood pressure of 34 mm Hg lasting 5 – 10 minutes, and estimated that this pressor activity was about 1/300 x that of epinephrine.[63]
Using cats and dogs, Tainter and Seidenfeld observed that neither d- nor l-synephrine caused any changes in the tone of normal bronchi, in situ, even at "maximum" doses. Furthermore, the marked brocho-constriction produced by injections of histamine was not reversed by either l-synephrine or d,l-synephrine.[41]
In experiments with isolated sheep carotid artery, d-, l- and d,l-synephrine all showed some vasoconstrictor activity: l-synephrine was the most potent, producing strong contractions at a concentration of 1:10000.[lower-alpha 6] d-Synephrine was about 1/2 as potent as the l-isomer, but d,l-synephrine (which would have been expected to have a potency of 1/2 that of l-synephrine even if the d-isomer were completely inactive) did not produce significant and irregular contractions until a concentration of 1:2500[lower-alpha 7]had been reached, implying an inhibitory interaction between the two enantiomers.[41]
Qualitatively similar results were obtained in a rabbit ear preparation: 25 mg l-synephrine produced significant (50%) vasoconstriction, while the same concentration of d-synephrine elicited essentially no response. In contrast, d,l-synephrine did not produce any constriction up to 25 mg, but 25 – 50 mg caused a relaxation of the blood vessels, which again suggested that the d-isomer might be inhibiting the action of the l-isomer.[41]
Experiments on strips of rabbit duodenum showed that l-synephrine caused a modest reduction in contractions at a concentration of 1:17000,[lower-alpha 8] but that the effects of the d- and d,l- forms were much weaker.[41]
Racemic synephrine, given intramuscularly, or by instillation, was found to significantly reduce the inflammation caused by instillation of mustard oil into the eyes of rabbits.[41]
Subcutaneous injection of racemic synephrine into rabbits was reported to cause a large rise in blood sugar.[43]
In experiments on anesthetized cats, Papp and Szekeres found that synephrine (stereochemistry unspecified) raised the thresholds for auricular and ventricular fibrillation, an indication of anti-arrhythmic properties.[64]
Evidence that synephrine might have some central effects comes from the research of Song and co-workers, who studied the effects of synephrine in mouse models[lower-alpha 9] of anti-depressant activity.[65] These researchers observed that oral doses of 0.3 – 10 mg/kg of racemic syephrine were effective in shortening the duration of immobility[lower-alpha 10] produced in the assays, but did not cause any changes in spontaneous motor activity in separate tests. This characteristic immobility could be counteracted by the pre-administration of prazosin.[lower-alpha 11]
Subsequent experiments using the individual enanatiomers of synephrine revealed that although the d-isomer significantly reduced the duration of immobility in the tail suspension test, at an oral dose of 3 mg/kg, the l-isomer had no effect at the same dose.
In mice pre-treated with reserpine,[lower-alpha 12] an oral dose of 0.3 mg/kg d-synephrine significantly reversed the hypothermia, while l-synephrine required a dose of 1 mg/kg to be effective.
Experiments with slices of cerebral cortex taken from rat brain showed that d-synephrine inhibited the uptake of [3H]-norepinephrine with an IC50 = 5.8 μM; l-synephrine was less potent (IC50 = 13.5 μM).
d-Synephrine also competitively inhibited the binding of nisoxetine[lower-alpha 13] to rat brain cortical slices, with a Ki = 4.5 μM; l-synephrine was less potent (Ki = 8.2 μM).
In experiments on the release of [3H]-norepinephrine from rat brain cortical slices, however, the l-isomer of synephrine was a more potent enhancer of the release (EC50 = 8.2 μM) than the d-isomer (EC50 = 12.3 μM). This enhanced release by l-synephrine was blocked by nisoxetine.[66]
Burgen and Iversen, examining the effect of a broad range of phenethylamine-based drugs on [14C]-norepinephrine-uptake in the isolated rat heart, observed that racemic synephrine[lower-alpha 14] was a relatively weak inhibitor (IC50 = 0.12 μM) of the uptake.[67]
Another receptor-oriented study by Wikberg revealed that synephrine (stereochemistry unspecified) was a more potent agonist at guinea pig aorta α1 receptors (pD2 = 4.81) than at ileum α2 receptors (pD2 = 4.48), with a relative affinity ratio of α2/α1 = 0.10. Although clearly indicating a selectivity of synephrine for α1 receptors, its potency at this receptor sub-class is still relatively low, in comparison with that of phenylephrine (pD2 at α1 = 6.32).[68]
Brown and co-workers examined the effects of the individual enantiomers of synephrine on α1 receptors in rat aorta, and on α2 receptors in rabbit saphenous vein. In the aorta preparation, l-synephrine gave a pD2 = 5.38 (potency relative to norepinephrine = 1/1000), while d-synephrine had a pD2 = 3.50 (potency relative to norepinephrine = 1/50000); in comparison, l-phenylephrine had pD2 = 7.50 (potency relative to norepinephrine ≃ 1/6). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10−6 M. In the rabbit saphenous assay, the pD2 of l-synephrine was 4.36 (potency relative to norepinephrine ≃ 1/1700), and that of d-synephrine was < 3.00; in comparison, l-phenylephrine had pD2 = 5.45 (potency relative to norepinephrine ≃ 1/140). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10−5 M.[69]
A study of the effects of synephrine (stereochemistry unspecified) on strips of guinea pig aorta and on the field-stimulated guinea pig ileum showed that synephrine had an agonist potency of -logKa = 3.75 in the aorta assay. In comparison, epinephrine had a potency of -logKa = 5.70. There was no significant effect on the ileum at synephrine concentrations up to about 2 x 10−4M, indicating selectivity for the α1 receptor, but relatively low potency.[70]
In binding experiments with central adrenergic receptors, using a preparation from rat cerebral cortex, l-synephrine had pIC50 = 3.35, and d-synephrine had pIC50 = 2.42 in competition against [3H]-prazosin (standard α1 ligand); against [3H]-yohimbine (standard α2 ligand), l-synephrine showed a pIC50 = 5.01, and d-synephrine showed a pIC50 = 4.17.[69]
Experiments conducted by Hibino and co-workers also showed that synephrine (stereochemistry unspecified) produced a dose-dependent constriction of isolated rat aorta strips, in the concentration range 10−5 - 3 x 10−6 M. This constriction was found to be competitively antagonized by prazosin (a standard α1 antagonist) and ketanserin,[lower-alpha 15] with prazosin being the more potent antagonist (pA2 = 9.38, vs pA2 = 8.23 for ketanserin). Synephrine constrictions were also antagonized by BRL-15,572{{Used here as a selective 5-HT1D antagonist.}}, but not by SB-216,641{{Used here as a selective 5-HT1B antagonist.}}, or by propranolol (a common β antagonist).[71]
In studies on guinea pig atria and trachea, Jordan and co-workers also found that synephrine had negligible activity on β1 and β2 receptors, being about 40000 x less potent than norepinephrine.[72]
Experiments with cultured white fat cells from several animal species, including human, by Carpéné and co-workers showed that racemic synephrine produced lipolytic effects, but only at high concentrations (0.1-1 mM). The potency, expressed in terms of pD2 of synephrine in these species was as follows: rat: 4.38; hamster: 5.32; guinea pig: 4.31; human: 4.94. In comparison, isoprenaline had a pD2 = 8.29 and norepinephrine had pD2 = 6.80 in human white fat cells. The lipolytic effect of 1 mM/L of synephrine on rat white fat cells was antagonized by various β-antagonists with the following inhibitory concentrations (IC50): bupranolol:[lower-alpha 16] 0.11 μM; CGP-20,712A (β1 antagonist): 6.09 μM; ICI-118,551 (β2 antagonist): 3.58 μM; SR-5923A (β3 antagonist): 17 μM.[73]
The binding of racemic synephrine to cloned human adrenergic receptors has been examined: Ma and co-workers found that synephrine bound to α1A, α2A and α2C with low affinity (pKi = 4.11 for α1A; 4.44 for α2A; 4.61 for α2C). Synephrine behaved as a partial agonist at α1A receptors, but as an antagonist at α2A and α2C sub-types.[74]
Racemic synephrine has been shown to be an agonist of the TAAR1,[75] although its potency at the human TAAR1 is relatively low (EC50 = 23700 nM; Emax = 81.2%).[76]
# Pharmacokinetics
The pharmacokinetics of synephrine were studied by Hengstmann and Aulepp, who reported a peak plasma concentration at 1–2 hours, with an elimination half-life (T1/2) of ~ 2 hours.[77]
# Metabolism
Studies of the metabolism of synephrine by monoamine oxidases derived from rat brain mitochondria showed that synephrine was a substrate for deamination by both MAO-A and MAO-B, with Km = 250 μM and Vmax = 32.6 nM/mg protein/30 minutes; there was some evidence for preferential deamination by MAO-A.[78]
# Effects in humans
A number of studies of the effects of synephrine in humans, most of them focusing on its cardio-vascular properties, have been performed since its introduction as a synthetic drug around 1930.[40][79][80][81][82][83] The paper by Stockton and co-workers is representative, describing the effects of racemic synephrine in humans with particular attention to differences resulting from different routes of administration. Thus, it was shown by these investigators that intramuscular injections (average effective dose = 200 mg) of the drug produced an increase in systolic blood pressure and pulse rate, without affecting the diastolic pressure. The blood pressure increase reached a maximum (~ 25 mm Hg)in 5 minutes following the injection, then gradually returned to normal over the course of 1 hour. Doses of drug greater than 200 mg caused side-effects such as heart palpitations, headache, sweating, and feelings of apprehension. When given intravenously, doses of 25–50 mg sufficed to produce a mean maximum increase in the blood pressure of 29 mm Hg in 2 minutes, and a return to baseline within 30 minutes. Respiration was generally not affected during these experiments. Subcutaneous administration of synephrine in doses ≤ 200 mg had no effects on blood pressure or pulse rate. Oral doses of 500 – 1500 mg of the drug did not affect blood pressure or respiration, but pulse rate was increased by ~ 12%, and the highest doses caused nausea and vomiting.[40]
The i.m. administration of 75 – 500 mg of synephrine did not relieve acute asthma attacks, contradicting an earlier claim.[84] However, the topical application of 1 - 3% solutions of the drug to the nasal mucosa of patients with sinusitis did produce a beneficial constriction without local irritation.[40]
A more recent study showed that the administration of synephrine by continuous intravenous infusion, at the rate of 4 mg/minute, significantly increased mean arterial and systolic pressure, but diastolic pressure and heart rate were unaltered.;[83] further details of this investigation are summarized in a review by Fugh-Berman and Myers.[85]
There are a number of studies, references to many of which may be found in the review by Stohs and co-workers.[86] dealing with the effects produced by dietary supplements and herbal medications that contain synephrine as only one of many different chemical ingredients. These are outside the scope of the present article (see also the "Safety/Efficacy/Controversy" sub-section).
# Toxicology
The acute toxicities of racemic synephrine in different animals, reported in terms of "maximum tolerated dose" after s.c administration, were as follows: mouse: 300 mg/kg; rat: 400 mg/kg; guinea pig: 400 mg/kg. "Lethal doses", given s.c., were found to be: mouse: 400 mg/kg; rat: 500 mg/kg; guinea pig: 500 mg/kg.[37] Another study of this compound,[lower-alpha 17] administered i.v. in mice, gave an LD50 = 270 mg/kg.[63]
The "subchronic toxicity" of synephrine was judged to be low in mice, after administration of oral doses of 30 and 300 mg/kg over a period of 28 days, in a recent study employing modern methodology carried out by Arbo and co-workers. Generally, this treatment did not result in significant alterations in biochemical or hematological parameters, nor in relative organ weights, but some changes were noted in glutathione (GSH) concentration, and in the activity of glutathione peroxidase (GPx).[87]
# Safety/Efficacy/Controversy
Information about the safety and efficacy of synephrine used as a single drug may be deduced from the foregoing review of the literature in this Article. This information is, by and large, not contended. However, there exists considerable controversy about the safety and/or efficacy of synephrine-containing preparations, which are often confused with synephrine alone, sometimes with m-synephrine, and much has been written about such preparations in the medical literature and on the Internet.[16][50][86][88][89][90][91][92][93][94][95][96] Since this body of literature deals with mixtures containing synephrine as only one of several biologically-active components, even, in some cases, without explicit confirmation of the presence of synephrine, further discussion is outside the scope of this article.
# Invertebrates
In insects, synephrine has been found to be a very potent agonist at many invertebrate octopamine receptor preparations, and is even more potent than octopamine at a locust (Schistocerca americana gregaria) nerve-muscle preparation.[97] Synephrine (racemic) is also more potent than octopamine (racemic) at inducing light-emission in the firefly (Photinus species) light organ.[98] Synephrine exhibits similarly high potency in stimulating adenylate cyclase activity and in decreasing clotting time in lobster (Homarus americanus) hematocytes.[99] Racemic synephrine was found to increase cAMP in the abdominal epidermis of the blood-sucking bug, Rhodnius prolixus.[100] Rachinsky reported that synephrine was equipotent with octopamine in stimulating JH (juvenile hormone) release in the corpora allata of honey bee (Apis mellifera),[101] but Woodring and Hoffmann found that synephrine had no effect on the synthesis of JH III, in in vitro preparations from the cricket, Gryllus bimaculatus.[102] | https://www.wikidoc.org/index.php/Oxedrine | |
f506c970f0695cf54123bc9a05c2e1050bd9f7ac | wikidoc | Oxilorphan | Oxilorphan
Oxilorphan is an opioid antagonist from the morphinan family of drugs.
Oxilorphan is a non-selective opioid which is a μ antagonist but a κ partial agonist. It has similar effects to naloxone, and around the same potency as an antagonist.
Oxilorphan has some weak partial agonist effects and can produce hallucinogenic effects at high doses, suggesting some kappa opioid agonist action. It was trialled for the treatment of opiate addiction, but was not developed commercially. | Oxilorphan
Oxilorphan is an opioid antagonist from the morphinan family of drugs.
Oxilorphan is a non-selective opioid which is a μ antagonist but a κ partial agonist. It has similar effects to naloxone, and around the same potency as an antagonist.[1]
Oxilorphan has some weak partial agonist effects[2] and can produce hallucinogenic effects at high doses, suggesting some kappa opioid agonist action.[3] It was trialled for the treatment of opiate addiction, but was not developed commercially.[4]
Template:Pharm-stub | https://www.wikidoc.org/index.php/Oxilorphan | |
2aa74cc7a80853a9de09a9593f9b906abdc81c57 | wikidoc | Oxiracetam | Oxiracetam
# Overview
Oxiracetam (ISF 2522) is a nootropic drug of the racetam family and very mild stimulant. Several studies suggest that the substance is safe even when high doses are consumed for a long period of time. However, the mechanism of action of the racetam drug family is still a matter of research. Oxiracetam is not approved by Food and Drug Administration for any medical use in the United States.
# Clinical findings
There has been effort put into investigating the possible use of oxiracetam as a medication to attenuate the symptoms of dementia. However, no convincing results were obtained from studies where patients suffering from Alzheimer's dementia or organic solvent abuse were given 800 mg of the drug orally twice daily.
The proven effects of the drug are limited to beneficial effects that lead to higher scores in tests for logical performance, attention, concentration, memory and spatial orientation. These tests were performed on patients with mild to moderate dementia and ADHD, and the doses were 800–2400 mg orally twice a day for one to six months. Improvement has also been seen in patients with exogenic post-concussion syndrome, organic brain syndromes and other dementias. According to V. Gallai et al, oxiracetam is more effective than piracetam for this purpose.
Research shows oxiracetam improves hippocampally-mediated learning performance by increasing membrane-bound protein kinase C (PKC). When compared to control mice, oxiracetam-treated DBA mice demonstrated a significant increase in spatial learning performance as determined by the Morris water navigation task. This increase in performance was correlated to an increase in membrane-bound PKC.
# Pharmacokinetics
Oxiracetam is well absorbed from the gastrointestinal tract with a bioavailability of 56-82%.
Peak serum levels are reached within one to three hours after a single 800 mg or 2000 mg oral dose, with the maximal serum concentration reaching between 19-31 µg/ml at these doses.
Oxiracetam is mainly cleared renally and thus 84% is excreted unchanged in the urine.
The half-life of oxiracetam in healthy individuals is about 8 hours, whereas it is 10–68 hours in patients with renal impairment.
There is some penetration of the blood–brain barrier with brain concentrations reaching 5.3% of that in the blood (measured one hour after a single 2000 mg intravenous dose).
Clearance rates range from 9 to 95 ml/min and steady-state concentrations when 800 mg is given twice daily range from 60 µM to 530 µM.
The highest concentrations of oxiracetam is found in the septum pellucidum, followed by the hippocampus, the cerebral cortex and with the lowest concentrations in the striatum after a 200 mg/kg oral dose given to rats. | Oxiracetam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Oxiracetam (ISF 2522) is a nootropic drug of the racetam family and very mild stimulant.[1][2] Several studies suggest that the substance is safe even when high doses are consumed for a long period of time.[3][4][5] However, the mechanism of action of the racetam drug family is still a matter of research. Oxiracetam is not approved by Food and Drug Administration for any medical use in the United States.
# Clinical findings
There has been effort put into investigating the possible use of oxiracetam as a medication to attenuate the symptoms of dementia.[6] However, no convincing results were obtained from studies where patients suffering from Alzheimer's dementia or organic solvent abuse were given 800 mg of the drug orally twice daily.[6]
The proven effects of the drug are limited to beneficial effects that lead to higher scores in tests for logical performance, attention, concentration, memory and spatial orientation. These tests were performed on patients with mild to moderate dementia and ADHD, and the doses were 800–2400 mg orally twice a day for one to six months. Improvement has also been seen in patients with exogenic post-concussion syndrome, organic brain syndromes and other dementias. According to V. Gallai et al, oxiracetam is more effective than piracetam for this purpose.[6]
Research shows oxiracetam improves hippocampally-mediated learning performance by increasing membrane-bound protein kinase C (PKC). When compared to control mice, oxiracetam-treated DBA mice demonstrated a significant increase in spatial learning performance as determined by the Morris water navigation task. This increase in performance was correlated to an increase in membrane-bound PKC.[7]
# Pharmacokinetics
Oxiracetam is well absorbed from the gastrointestinal tract with a bioavailability of 56-82%.[8]
Peak serum levels are reached within one to three hours after a single 800 mg or 2000 mg oral dose, with the maximal serum concentration reaching between 19-31 µg/ml at these doses.
Oxiracetam is mainly cleared renally and thus 84% is excreted unchanged in the urine.
The half-life of oxiracetam in healthy individuals is about 8 hours, whereas it is 10–68 hours in patients with renal impairment.
There is some penetration of the blood–brain barrier with brain concentrations reaching 5.3% of that in the blood (measured one hour after a single 2000 mg intravenous dose).[6]
Clearance rates range from 9 to 95 ml/min and steady-state concentrations when 800 mg is given twice daily range from 60 µM to 530 µM.
The highest concentrations of oxiracetam is found in the septum pellucidum, followed by the hippocampus, the cerebral cortex and with the lowest concentrations in the striatum after a 200 mg/kg oral dose given to rats.[6] | https://www.wikidoc.org/index.php/Oxiracetam | |
31f56fc0128e1c492ea3fe3d91c71370bcac0126 | wikidoc | Oxprenolol | Oxprenolol
# Overview
Oxprenolol (Trasacor, Trasicor, Coretal, Laracor, Slow-Pren, Captol, Corbeton, Slow-Trasicor, Tevacor, Trasitensin, Trasidex) is a non-selective beta blocker with some intrinsic sympathomimetic activity. It is used for the treatment of angina pectoris, abnormal heart rhythms and high blood pressure.
Oxprenolol is a lipophilic beta blocker which passes the blood–brain barrier more easily than water soluble beta blockers. As such, it is associated with a higher incidence of CNS-related side effects than hydrophilic ligands such as atenolol, sotalol and nadolol.
Oxprenolol is a potent beta blocker and should not be administered to asthmatics under any circumstances due to their low beta levels as a result of depletion due to other asthma medication, and because it can cause irreversible, often fatal, airway failure and inflammation.
# Stereochemistry
Oxprenolol is a chiral compound, the beta blocker is used as a racemate, e. g. a 1:1 mixture of (R)-(+)-oxprenolol and (S)-(–)-oxprenolol. Analytical methods (HPLC) for the separation and quantification of (R)-(+)-oxprenolol and (S)-(–)-oxprenolol in urine and in pharmaceutical formulations have been described in the literature. | Oxprenolol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Oxprenolol (Trasacor, Trasicor, Coretal, Laracor, Slow-Pren, Captol, Corbeton, Slow-Trasicor, Tevacor, Trasitensin, Trasidex) is a non-selective beta blocker with some intrinsic sympathomimetic activity. It is used for the treatment of angina pectoris, abnormal heart rhythms and high blood pressure.
Oxprenolol is a lipophilic beta blocker which passes the blood–brain barrier more easily than water soluble beta blockers. As such, it is associated with a higher incidence of CNS-related side effects than hydrophilic ligands such as atenolol, sotalol and nadolol.[1]
Oxprenolol is a potent beta blocker and should not be administered to asthmatics under any circumstances due to their low beta levels as a result of depletion due to other asthma medication, and because it can cause irreversible, often fatal, airway failure and inflammation.[2]
# Stereochemistry
Oxprenolol is a chiral compound, the beta blocker is used as a racemate, e. g. a 1:1 mixture of (R)-(+)-oxprenolol and (S)-(–)-oxprenolol. Analytical methods (HPLC) for the separation and quantification of (R)-(+)-oxprenolol and (S)-(–)-oxprenolol in urine and in pharmaceutical formulations have been described in the literature.[3] | https://www.wikidoc.org/index.php/Oxprenolol | |
e4dc39fa1b6924ada78921f56100d8aa1f3280d0 | wikidoc | Ozenoxacin | Ozenoxacin
# 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
Ozenoxacin is a quinolone antimicrobial that is FDA approved for the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older. Common adverse reactions include rosacea and seborrheic dermatitis which were reported in 1 adult patient treated with ozenoxacin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ozenoxacin is indicated for the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older.
- Apply a thin layer of ozenoxacin topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2</sup in pediatric patients less than 12 years of age.
- Wash hands after applying ozenoxacin cream.
- Ozenoxacin cream is for topical use only.
- Not for oral, ophthalmic, intranasal, or intravaginal use.
- The treated area may be covered with a sterile bandage or gauze dressing.
- Cream: 1%, pale yellow cream. Each gram of ozenoxacin contains 10 mg of ozenoxacin.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Ozenoxacin is indicated for the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older.
- Apply a thin layer of ozenoxacin topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age.
- Wash hands after applying ozenoxacin cream.
- Ozenoxacin cream is for topical use only.
- Not for oral, ophthalmic, intranasal, or intravaginal use.
- The treated area may be covered with a sterile bandage or gauze dressing.
- Cream: 1%, pale yellow cream. Each gram of ozenoxacin contains 10 mg of ozenoxacin.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- The prolonged use of ozenoxacin may result in overgrowth of nonsusceptible bacteria and fungi. If such infections occur during therapy, discontinue use and institute appropriate supportive measures.
# 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 profile of ozenoxacin was assessed in two clinical trials (Trial 1 and Trial 2) in 362 adult and pediatric patients two months of age and older with impetigo. The patients used at least one dose from a 5-day, twice a day regimen of ozenoxacin. Control groups included 361 patients who used placebo and 152 patients who used retapamulin ointment. The median age of the patients enrolled in the clinical trials was 10 years; 3 % of patients were 2 months to less than 2 years of age, 55 % of patients were 2 to less than 12 years of age, 11 % of patients were 12 to less than 18 years of age, and 31 % of patients were 18 years of age or older.
- Adverse reactions (rosacea and seborrheic dermatitis) were reported in 1 adult patient treated with ozenoxacin.
## Postmarketing Experience
There is limited information regarding Ozenoxacin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ozenoxacin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no available data on the use of ozenoxacin in pregnant women to inform a drug associated risk. Systemic absorption of ozenoxacin in humans is negligible following topical administration of ozenoxacin (up to twice the concentration of the marketed formulation). Due to the negligible systemic exposure, it is not expected that maternal use of ozenoxacin will result in fetal exposure to the drug.
- Animal reproduction studies were not conducted with ozenoxacin. However, toxicity studies conducted in pregnant rats and rabbits administered the oral form of ozenoxacin showed no significant adverse developmental effects (at >10,000 times the maximum human plasma concentration seen with dermal application of ozenoxacin).
- The estimated background risk of major birth defects and miscarriage for the indicated population are 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ozenoxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ozenoxacin during labor and delivery.
### Nursing Mothers
- No data are available regarding the presence of ozenoxacin in human milk, and the effects of ozenoxacin on the breastfed infant or on milk production. However, breastfeeding is not expected to result in exposure of the child to ozenoxacin due to the negligible systemic absorption of ozenoxacin in humans following topical administration of ozenoxacin. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ozenoxacin and any potential adverse effects on the breast-fed child from ozenoxacin or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of ozenoxacin in the treatment of impetigo have been established in pediatric patients 2 months to 17 years of age. Use of ozenoxacin in pediatric patients (2 months to 17 years of age) is supported by evidence from adequate and well-controlled studies of ozenoxacin in which 251 pediatric patients received at least one dose of ozenoxacin. The median age of the patients enrolled in the clinical trials was 10 years; 3 % of patients were 2 months to less than 2 years of age, 55 % of patients were 2 to less than 12 years of age, 11 % of patients were 12 to less than 18 years of age, and 31 % of patients were 18 years of age or older. In these studies, the maximum dose applied was approximately 0.5 g of ozenoxacin applied twice daily for up to 5 days (i.e., up to 10 applications total).
- The safety profile of ozenoxacin in pediatric patients 2 months and older was similar to that of adults.
- The safety and effectiveness of ozenoxacin in pediatric patients younger than 2 months of age have not been established.
### Geriatic Use
- Clinical studies of ozenoxacin did not include sufficient numbers of subjects aged 65 and older 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.
### Gender
There is no FDA guidance on the use of Ozenoxacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ozenoxacin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ozenoxacin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ozenoxacin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ozenoxacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ozenoxacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Apply a thin layer of ozenoxacin topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age.
- Wash hands after applying ozenoxacin cream.
- Ozenoxacin cream is for topical use only.
- Not for oral, ophthalmic, intranasal, or intravaginal use.
- The treated area may be covered with a sterile bandage or gauze dressing.
### Monitoring
- The absence or reduction in signs and symptoms of impetigo including, exudate or pus, crusting, tissue warmth, pain, erythema, and itching may indicate efficacy.
# IV Compatibility
There is limited information regarding the compatibility of Ozenoxacin and IV administrations.
# Overdosage
- Any sign or symptom of overdose, either topically or by accidental ingestion, should be treated symptomatically. No specific antidote is known.
# Pharmacology
## Mechanism of Action
- Ozenoxacin is an antimicrobial drug.
## Structure
## Pharmacodynamics
- The exposure response relationship for ozenoxacin following topical application has not been studied, however; a relationship is unlikely because systemic exposure following topical application is negligible.
## Pharmacokinetics
- Four pharmacokinetic studies were conducted in 110 patients utilizing varying strengths of ozenoxacin cream, up to 2% (twice the concentration of the marketed formulation). Three of these studies assessed systemic absorption in healthy subjects and in subjects with impetigo. These studies were conducted with either single or repeated application of up to 1 g ozenoxacin cream to intact or abraded skin (up to 200 cm2 surface area). No systemic absorption was observed in 84 of 86 subjects, and negligible systemic absorption was observed at the level of detection (0.489 ng/mL) in 2 subjects.
- Plasma protein binding of -ozenoxacin was moderate (~80 to 85%) and did not appear to be dependent on concentration. Since negligible systemic absorption was observed in clinical studies, tissue distribution has not been investigated in humans.
Metabolism
- Ozenoxacin was not metabolized in the presence of fresh human skin discs and was minimally metabolized in human hepatocytes.
Excretion
- Studies have not been investigated in humans due to the negligible systemic absorption observed in clinical studies.
- Ozenoxacin is a quinolone antimicrobial drug. The mechanism of action involves the inhibition of bacterial DNA replication enzymes, DNA gyrase A and topoisomerase IV. Ozenoxacin has been shown to be bactericidal against S. aureus and S. pyogenes organisms.
- The mechanism of quinolone resistance can arise through mutations of one or more of the genes that encode DNA gyrase or topoisomerase IV. Resistant organisms will typically carry a combination of mutations within gyrA and parC subunits.
- Overall the frequency of resistant mutants selected by ozenoxacin is ≤10-10.
- Ozenoxacin has been tested in combination with 17 other commonly used antimicrobial agents against S. aureus and S.pyogenes. Antagonism interactions with ozenoxacin were observed with ciprofloxacin against S. aureus.
- Ozenoxacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.
- Gram-positive bacteria
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus pyogenes
## Nonclinical Toxicology
- Long-term studies in animals to evaluate carcinogenic potential have not been conducted with ozenoxacin.
- Ozenoxacin demonstrated no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the Ames test, mouse lymphoma cell assay, or when evaluated in vivo in a rat micronucleus test with demonstrated systemic exposure.
- Oral doses of ozenoxacin did not affect mating and fertility in male and female rats treated up to 500 mg/kg/day (about 8500 and 16,000 times respectively, the maximum human plasma concentration seen with dermal application of ozenoxacin 1% cream).
# Clinical Studies
- The safety and efficacy of ozenoxacin for the treatment of impetigo was evaluated in two multi-center, randomized, double-blind placebo controlled clinical trials (Trial 1 (NCT01397461) and Trial 2, (NCT02090764)). Sevenhundred twenty-three (723) subjects two months of age and older with an affected body surface area of up to 100 cm2, and not exceeding 2% for subjects aged 2 months to 11 years were randomized to ozenoxacin or placebo. Subjects applied ozenoxacin or placebo twice daily for 5 days. Subjects with underlying skin disease (e.g., preexisting eczematous dermatitis), skin trauma, clinical evidence of secondary infection, or systemic signs and symptoms of infection (such as fever), were excluded from these studies.
- Overall clinical success was defined as no need for additional antimicrobial therapy of the baseline affected area(s) and absence/reduction in clinical signs and symptoms assessed at the end of therapy (Day 6-7), as follows: absence of exudates/pus, crusting, tissue warmth, and pain; and erythema/inflammation, tissue edema, and itching assessed as less than mild in Trial 1; and absence of blistering, exudates/pus, crusting, and itching/pain, and mild or improved erythema/inflammation in Trial 2. Table 2 below presents the results for clinical response at the end of therapy.
- The most commonly identified bacteria were S. aureus and S. pyogenes. Table 3 below presents the results for clinical success at end of therapy in subjects with S.aureus or S.pyogenes at baseline.
# How Supplied
- Ozenoxacin cream, 1% is a pale yellow cream supplied in 10-, 30-, and 45-gram tubes. Each gram of cream contains 10 mg of ozenoxacin.
- NDC 43538-320-10 (10-gram tube)
- NDC 43538-320-30 (30-gram tube)
- NDC 43538-320-45 (45-gram tube)
## Storage
- Store at 20ºC - 25ºC (68ºF - 77ºF); excursions permitted to 15ºC to 30ºC (59ºF - 86ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients (and/or their caregivers or guardians) using ozenoxacin of the following information and instructions:
- Use ozenoxacin as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.
- Ozenoxacin is for external use only.Do not swallow ozenoxacin or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area.
- The treated area may be covered by a sterile bandage or gauze dressing.
- Use the medication for the entire time recommended by the healthcare practitioner, even though symptoms may have improved.
- Notify the healthcare practitioner if there is no improvement in symptoms within 3 days after starting use of ozenoxacin.
# Precautions with Alcohol
Alcohol-Ozenoxacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Xepi
# Look-Alike Drug Names
There is limited information regarding Ozenoxacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Ozenoxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
# Disclaimer
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# Overview
Ozenoxacin is a quinolone antimicrobial that is FDA approved for the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older. Common adverse reactions include rosacea and seborrheic dermatitis which were reported in 1 adult patient treated with ozenoxacin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ozenoxacin is indicated for the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older.
- Apply a thin layer of ozenoxacin topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2</sup in pediatric patients less than 12 years of age.
- Wash hands after applying ozenoxacin cream.
- Ozenoxacin cream is for topical use only.
- Not for oral, ophthalmic, intranasal, or intravaginal use.
- The treated area may be covered with a sterile bandage or gauze dressing.
- Cream: 1%, pale yellow cream. Each gram of ozenoxacin contains 10 mg of ozenoxacin.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Ozenoxacin is indicated for the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older.
- Apply a thin layer of ozenoxacin topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age.
- Wash hands after applying ozenoxacin cream.
- Ozenoxacin cream is for topical use only.
- Not for oral, ophthalmic, intranasal, or intravaginal use.
- The treated area may be covered with a sterile bandage or gauze dressing.
- Cream: 1%, pale yellow cream. Each gram of ozenoxacin contains 10 mg of ozenoxacin.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ozenoxacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- The prolonged use of ozenoxacin may result in overgrowth of nonsusceptible bacteria and fungi. If such infections occur during therapy, discontinue use and institute appropriate supportive measures.
# 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 profile of ozenoxacin was assessed in two clinical trials (Trial 1 and Trial 2) in 362 adult and pediatric patients two months of age and older with impetigo. The patients used at least one dose from a 5-day, twice a day regimen of ozenoxacin. Control groups included 361 patients who used placebo and 152 patients who used retapamulin ointment. The median age of the patients enrolled in the clinical trials was 10 years; 3 % of patients were 2 months to less than 2 years of age, 55 % of patients were 2 to less than 12 years of age, 11 % of patients were 12 to less than 18 years of age, and 31 % of patients were 18 years of age or older.
- Adverse reactions (rosacea and seborrheic dermatitis) were reported in 1 adult patient treated with ozenoxacin.
## Postmarketing Experience
There is limited information regarding Ozenoxacin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ozenoxacin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no available data on the use of ozenoxacin in pregnant women to inform a drug associated risk. Systemic absorption of ozenoxacin in humans is negligible following topical administration of ozenoxacin (up to twice the concentration of the marketed formulation). Due to the negligible systemic exposure, it is not expected that maternal use of ozenoxacin will result in fetal exposure to the drug.
- Animal reproduction studies were not conducted with ozenoxacin. However, toxicity studies conducted in pregnant rats and rabbits administered the oral form of ozenoxacin showed no significant adverse developmental effects (at >10,000 times the maximum human plasma concentration seen with dermal application of ozenoxacin).
- The estimated background risk of major birth defects and miscarriage for the indicated population are 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ozenoxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ozenoxacin during labor and delivery.
### Nursing Mothers
- No data are available regarding the presence of ozenoxacin in human milk, and the effects of ozenoxacin on the breastfed infant or on milk production. However, breastfeeding is not expected to result in exposure of the child to ozenoxacin due to the negligible systemic absorption of ozenoxacin in humans following topical administration of ozenoxacin. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ozenoxacin and any potential adverse effects on the breast-fed child from ozenoxacin or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of ozenoxacin in the treatment of impetigo have been established in pediatric patients 2 months to 17 years of age. Use of ozenoxacin in pediatric patients (2 months to 17 years of age) is supported by evidence from adequate and well-controlled studies of ozenoxacin in which 251 pediatric patients received at least one dose of ozenoxacin. The median age of the patients enrolled in the clinical trials was 10 years; 3 % of patients were 2 months to less than 2 years of age, 55 % of patients were 2 to less than 12 years of age, 11 % of patients were 12 to less than 18 years of age, and 31 % of patients were 18 years of age or older. In these studies, the maximum dose applied was approximately 0.5 g of ozenoxacin applied twice daily for up to 5 days (i.e., up to 10 applications total).
- The safety profile of ozenoxacin in pediatric patients 2 months and older was similar to that of adults.
- The safety and effectiveness of ozenoxacin in pediatric patients younger than 2 months of age have not been established.
### Geriatic Use
- Clinical studies of ozenoxacin did not include sufficient numbers of subjects aged 65 and older 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.
### Gender
There is no FDA guidance on the use of Ozenoxacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ozenoxacin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ozenoxacin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ozenoxacin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ozenoxacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ozenoxacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Apply a thin layer of ozenoxacin topically to the affected area twice daily for five days. Affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age.
- Wash hands after applying ozenoxacin cream.
- Ozenoxacin cream is for topical use only.
- Not for oral, ophthalmic, intranasal, or intravaginal use.
- The treated area may be covered with a sterile bandage or gauze dressing.
### Monitoring
- The absence or reduction in signs and symptoms of impetigo including, exudate or pus, crusting, tissue warmth, pain, erythema, and itching may indicate efficacy.
# IV Compatibility
There is limited information regarding the compatibility of Ozenoxacin and IV administrations.
# Overdosage
- Any sign or symptom of overdose, either topically or by accidental ingestion, should be treated symptomatically. No specific antidote is known.
# Pharmacology
## Mechanism of Action
- Ozenoxacin is an antimicrobial drug.
## Structure
## Pharmacodynamics
- The exposure response relationship for ozenoxacin following topical application has not been studied, however; a relationship is unlikely because systemic exposure following topical application is negligible.
## Pharmacokinetics
- Four pharmacokinetic studies were conducted in 110 patients utilizing varying strengths of ozenoxacin cream, up to 2% (twice the concentration of the marketed formulation). Three of these studies assessed systemic absorption in healthy subjects and in subjects with impetigo. These studies were conducted with either single or repeated application of up to 1 g ozenoxacin cream to intact or abraded skin (up to 200 cm2 surface area). No systemic absorption was observed in 84 of 86 subjects, and negligible systemic absorption was observed at the level of detection (0.489 ng/mL) in 2 subjects.
- Plasma protein binding of [14C]-ozenoxacin was moderate (~80 to 85%) and did not appear to be dependent on concentration. Since negligible systemic absorption was observed in clinical studies, tissue distribution has not been investigated in humans.
Metabolism
- Ozenoxacin was not metabolized in the presence of fresh human skin discs and was minimally metabolized in human hepatocytes.
Excretion
- Studies have not been investigated in humans due to the negligible systemic absorption observed in clinical studies.
- Ozenoxacin is a quinolone antimicrobial drug. The mechanism of action involves the inhibition of bacterial DNA replication enzymes, DNA gyrase A and topoisomerase IV. Ozenoxacin has been shown to be bactericidal against S. aureus and S. pyogenes organisms.
- The mechanism of quinolone resistance can arise through mutations of one or more of the genes that encode DNA gyrase or topoisomerase IV. Resistant organisms will typically carry a combination of mutations within gyrA and parC subunits.
- Overall the frequency of resistant mutants selected by ozenoxacin is ≤10-10.
- Ozenoxacin has been tested in combination with 17 other commonly used antimicrobial agents against S. aureus and S.pyogenes. Antagonism interactions with ozenoxacin were observed with ciprofloxacin against S. aureus.
- Ozenoxacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.
- Gram-positive bacteria
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus pyogenes
## Nonclinical Toxicology
- Long-term studies in animals to evaluate carcinogenic potential have not been conducted with ozenoxacin.
- Ozenoxacin demonstrated no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the Ames test, mouse lymphoma cell assay, or when evaluated in vivo in a rat micronucleus test with demonstrated systemic exposure.
- Oral doses of ozenoxacin did not affect mating and fertility in male and female rats treated up to 500 mg/kg/day (about 8500 and 16,000 times respectively, the maximum human plasma concentration seen with dermal application of ozenoxacin 1% cream).
# Clinical Studies
- The safety and efficacy of ozenoxacin for the treatment of impetigo was evaluated in two multi-center, randomized, double-blind placebo controlled clinical trials (Trial 1 (NCT01397461) and Trial 2, (NCT02090764)). Sevenhundred twenty-three (723) subjects two months of age and older with an affected body surface area of up to 100 cm2, and not exceeding 2% for subjects aged 2 months to 11 years were randomized to ozenoxacin or placebo. Subjects applied ozenoxacin or placebo twice daily for 5 days. Subjects with underlying skin disease (e.g., preexisting eczematous dermatitis), skin trauma, clinical evidence of secondary infection, or systemic signs and symptoms of infection (such as fever), were excluded from these studies.
- Overall clinical success was defined as no need for additional antimicrobial therapy of the baseline affected area(s) and absence/reduction in clinical signs and symptoms assessed at the end of therapy (Day 6-7), as follows: absence of exudates/pus, crusting, tissue warmth, and pain; and erythema/inflammation, tissue edema, and itching assessed as less than mild in Trial 1; and absence of blistering, exudates/pus, crusting, and itching/pain, and mild or improved erythema/inflammation in Trial 2. Table 2 below presents the results for clinical response at the end of therapy.
- The most commonly identified bacteria were S. aureus and S. pyogenes. Table 3 below presents the results for clinical success at end of therapy in subjects with S.aureus or S.pyogenes at baseline.
# How Supplied
- Ozenoxacin cream, 1% is a pale yellow cream supplied in 10-, 30-, and 45-gram tubes. Each gram of cream contains 10 mg of ozenoxacin.
- NDC 43538-320-10 (10-gram tube)
- NDC 43538-320-30 (30-gram tube)
- NDC 43538-320-45 (45-gram tube)
## Storage
- Store at 20ºC - 25ºC (68ºF - 77ºF); excursions permitted to 15ºC to 30ºC (59ºF - 86ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients (and/or their caregivers or guardians) using ozenoxacin of the following information and instructions:
- Use ozenoxacin as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.
- Ozenoxacin is for external use only.Do not swallow ozenoxacin or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area.
- The treated area may be covered by a sterile bandage or gauze dressing.
- Use the medication for the entire time recommended by the healthcare practitioner, even though symptoms may have improved.
- Notify the healthcare practitioner if there is no improvement in symptoms within 3 days after starting use of ozenoxacin.
# Precautions with Alcohol
Alcohol-Ozenoxacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Xepi
# Look-Alike Drug Names
There is limited information regarding Ozenoxacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Ozenoxacin | |
f121bc3232dbf2e22b10090a55b19748d66d231a | wikidoc | P-selectin | P-selectin
P-selectin is a protein that in humans is encoded by the SELP gene.
P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets. In unactivated endothelial cells, it is stored in granules called Weibel-Palade bodies. In unactivated platelets P-selectin is stored in α-granules.
Other names for P-selectin include CD62P, Granule Membrane Protein 140 (GMP-140), and Platelet Activation-Dependent Granule to External Membrane Protein (PADGEM). It was first identified in endothelial cells in 1989.
# Gene and regulation
P-selectin is located on chromosome 1q21-q24, spans > 50 kb and contains 17 exons in humans. P-selectin is constitutively expressed in megakaryocytes (the precursor of platelets) and endothelial cells. P-selectin expression is induced by two distinct mechanisms. First, P-selectin is synthesized by megakaryocytes and endothelial cells, where it is sorted into the membranes of secretory granules. When megakaryocytes and endothelial cells are activated by agonists such as thrombin, P-selectin is rapidly translocated to the plasma membrane from granules. Secondly, increased levels of P-selectin mRNA and protein are induced by inflammatory mediators such as tumor necrosis factor-a (TNF-a), LPS, and interleukin-4 (IL-4). Although TNF-a and LPS increase levels of both mRNA and protein in murine models, they do not appear to affect mRNA in human endothelial cells, while IL-4 increases P-selectin transcription in both species. The elevated synthesis of P-selectin may play an important role in the delivery of protein to the cell surface. In ischemic stroke patients, plasma P-selectin concentration was reported to be highly correlated to plasminogen activator inhibitor-1 activity and tissue plasminogen activator activity.
# Structure
P-selectin is found in endothelial cells and platelets where it is stored in Weibel-Palade bodies and α-granules, respectively. In response to inflammatory cytokines such as IL-4 and IL-13, P-selectin is translocated to the plasma membrane in endothelial cells. The extracellular region of P-selectin is composed of three different domains like other selectin types; a C-type lectin-like domain in the N-terminus, an EGF-like domain and a complement-binding protein-like domains (same as complement regulatory proteins: CRP) having short consensus repeats (~60 amino acids). The number of CRP repeats is the major feature differentiating the type of selectin in extracellular region. In human, P-selectin has nine repeats while E-selectin contains six and L-selectin has only two. P-selectin is anchored in transmembrane region that is followed by a short cytoplasmic tail region.
# Ligand
The primary ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) which is expressed on almost all leukocytes, although P-selectin also binds to heparan sulfate and fucoidan. PSGL-1 is situated on various hematopoietic cells such as neutrophils, eosinophils, lymphocytes, and monocytes, in which it mediates tethering and adhesion of these cells. However, PSGL-1 is not specific for P-selectin, as it can also function as a ligand for both E- and L-selectin.
# Function
P-selectin plays an essential role in the initial recruitment of leukocytes (white blood cells) to the site of injury during inflammation. When endothelial cells are activated by molecules such as histamine or thrombin during inflammation, P-selectin moves from an internal cell location to the endothelial cell surface.
Thrombin is one trigger which can stimulate endothelial-cell release of P-selectin and recent studies suggest an additional Ca2+-independent pathway involved in the release of P-selectin.
Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different than those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses.
P-selectin is also very important in the recruitment and aggregation of platelets at areas of vascular injury. In a quiescent platelet, P-selectin is located on the inner wall of α-granules. Platelet activation (through agonists such as thrombin, Type II collagen and ADP) results in "membrane flipping" where the platelet releases α- and dense granules and the inner walls of the granules are exposed on the outside of the cell. The P-selectin then promotes platelet aggregation through platelet-fibrin and platelet-platelet binding.
P-selectin attaches to the actin cytoskeleton through anchor proteins that are still poorly characterized.
# Role in cancer
P-selectin has a functional role in tumour metastasis similar to E-selectin. P-selectin is expressed on the surface of both stimulated endothelial cells and activated platelets, and helps cancer cells invade into the bloodstream for metastasis and provides local multiple growth factors, respectively. Moreover, platelets facilitate tumor metastasis by forming complexes with tumour cells and leukocytes in the vasculature, thus preventing recognition by macrophages. This is thought to contribute to the seeding of tumour microemboli in distant organs. In vivo mice experiments have shown that a reduction in circulating platelets could reduce cancer metastasis.
The oligosaccharide sialylated Lewis x (sLe(x)) is expressed on the surface of tumor cells and can be recognized by E-selectin and P-selectin, playing on a key role in metastasis of the tumor. However, in the 4T1 breast cancer cell line, E-selectin reactivity is sLe(x) dependent while P-selectin reactivity is sLe(x)-independent, suggesting P-selectin binding is Ca2+-independent and sulfation-dependent. One of the sulfated ligands is chondroitin sulfate, a type of glycosaminoglycan (GAG). Its activity in tumor metastasis has been probed by the addition of heparin that functions to blocks tumor metastasis. In addition to GAGs, mucin is of interest in P-selectin mediated tumor metastasis. Selective removal of mucin results in reduced interaction between P-selectin and platelets in vivo and in vitro.
Heparin has long been known to represent antiheparanase activity that is to keep an endoglycosidase from degrading heparin sulfate, one of the glycosaminoglycans, and to effectively inhibit P-selectin. Despite a striking effect of heparin on tumor progression shown in a number of clinical trials, the use of heparin as anti-cancer agent is limited because of its risk, which might induce adverse bleeding complications. Given those reasons, development of new compounds that target P-selectin is now emerging for cancer therapy. Among them, the inhibitory activity of semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) to P-selectin was shown by the attenuation of tumor metastasis in vivo animal model, indicating the inhibition of interaction between tumor cell and endothelial cell is significant for blocking tumor dissemination.
# As a drug target
Crizanlizumab is a monoclonal antibody against P-selectin. It is undergoing clinical trials. | P-selectin
P-selectin is a protein that in humans is encoded by the SELP gene.[1]
P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets. In unactivated endothelial cells, it is stored in granules called Weibel-Palade bodies. In unactivated platelets P-selectin is stored in α-granules.
Other names for P-selectin include CD62P, Granule Membrane Protein 140 (GMP-140), and Platelet Activation-Dependent Granule to External Membrane Protein (PADGEM). It was first identified in endothelial cells in 1989.[2]
# Gene and regulation
P-selectin is located on chromosome 1q21-q24, spans > 50 kb and contains 17 exons in humans.[3] P-selectin is constitutively expressed in megakaryocytes (the precursor of platelets) and endothelial cells.[4] P-selectin expression is induced by two distinct mechanisms. First, P-selectin is synthesized by megakaryocytes and endothelial cells, where it is sorted into the membranes of secretory granules.[5] When megakaryocytes and endothelial cells are activated by agonists such as thrombin, P-selectin is rapidly translocated to the plasma membrane from granules.[6] Secondly, increased levels of P-selectin mRNA and protein are induced by inflammatory mediators such as tumor necrosis factor-a (TNF-a), LPS, and interleukin-4 (IL-4). Although TNF-a and LPS increase levels of both mRNA and protein in murine models, they do not appear to affect mRNA in human endothelial cells, while IL-4 increases P-selectin transcription in both species.[7][8][9] The elevated synthesis of P-selectin may play an important role in the delivery of protein to the cell surface. In ischemic stroke patients, plasma P-selectin concentration was reported to be highly correlated to plasminogen activator inhibitor-1 activity and tissue plasminogen activator activity.[10]
# Structure
P-selectin is found in endothelial cells and platelets where it is stored in Weibel-Palade bodies and α-granules, respectively. In response to inflammatory cytokines such as IL-4 and IL-13, P-selectin is translocated to the plasma membrane in endothelial cells.[11] The extracellular region of P-selectin is composed of three different domains like other selectin types; a C-type lectin-like domain in the N-terminus, an EGF-like domain and a complement-binding protein-like domains (same as complement regulatory proteins: CRP) having short consensus repeats (~60 amino acids). The number of CRP repeats is the major feature differentiating the type of selectin in extracellular region. In human, P-selectin has nine repeats while E-selectin contains six and L-selectin has only two. P-selectin is anchored in transmembrane region that is followed by a short cytoplasmic tail region.[12]
# Ligand
The primary ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) which is expressed on almost all leukocytes, although P-selectin also binds to heparan sulfate and fucoidan. PSGL-1 is situated on various hematopoietic cells such as neutrophils, eosinophils, lymphocytes, and monocytes, in which it mediates tethering and adhesion of these cells. However, PSGL-1 is not specific for P-selectin, as it can also function as a ligand for both E- and L-selectin.[13]
# Function
P-selectin plays an essential role in the initial recruitment of leukocytes (white blood cells) to the site of injury during inflammation. When endothelial cells are activated by molecules such as histamine or thrombin during inflammation, P-selectin moves from an internal cell location to the endothelial cell surface.
Thrombin is one trigger which can stimulate endothelial-cell release of P-selectin and recent studies suggest an additional Ca2+-independent pathway involved in the release of P-selectin.[14]
Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different than those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses.[15]
P-selectin is also very important in the recruitment and aggregation of platelets at areas of vascular injury. In a quiescent platelet, P-selectin is located on the inner wall of α-granules. Platelet activation (through agonists such as thrombin, Type II collagen and ADP) results in "membrane flipping" where the platelet releases α- and dense granules and the inner walls of the granules are exposed on the outside of the cell. The P-selectin then promotes platelet aggregation through platelet-fibrin and platelet-platelet binding.
P-selectin attaches to the actin cytoskeleton through anchor proteins that are still poorly characterized.
# Role in cancer
P-selectin has a functional role in tumour metastasis similar to E-selectin.[16] P-selectin is expressed on the surface of both stimulated endothelial cells and activated platelets, and helps cancer cells invade into the bloodstream for metastasis and provides local multiple growth factors, respectively.[17] Moreover, platelets facilitate tumor metastasis by forming complexes with tumour cells and leukocytes in the vasculature, thus preventing recognition by macrophages. This is thought to contribute to the seeding of tumour microemboli in distant organs.[18] In vivo mice experiments have shown that a reduction in circulating platelets could reduce cancer metastasis.[19]
The oligosaccharide sialylated Lewis x (sLe(x)) is expressed on the surface of tumor cells and can be recognized by E-selectin and P-selectin, playing on a key role in metastasis of the tumor. However, in the 4T1 breast cancer cell line, E-selectin reactivity is sLe(x) dependent while P-selectin reactivity is sLe(x)-independent, suggesting P-selectin binding is Ca2+-independent and sulfation-dependent.[20] One of the sulfated ligands is chondroitin sulfate, a type of glycosaminoglycan (GAG). Its activity in tumor metastasis has been probed by the addition of heparin that functions to blocks tumor metastasis. In addition to GAGs, mucin is of interest in P-selectin mediated tumor metastasis.[21] Selective removal of mucin results in reduced interaction between P-selectin and platelets in vivo and in vitro.[18]
Heparin has long been known to represent antiheparanase activity that is to keep an endoglycosidase from degrading heparin sulfate, one of the glycosaminoglycans, and to effectively inhibit P-selectin.[22] Despite a striking effect of heparin on tumor progression shown in a number of clinical trials,[23] the use of heparin as anti-cancer agent is limited because of its risk, which might induce adverse bleeding complications. Given those reasons, development of new compounds that target P-selectin is now emerging for cancer therapy. Among them, the inhibitory activity of semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) to P-selectin was shown by the attenuation of tumor metastasis in vivo animal model, indicating the inhibition of interaction between tumor cell and endothelial cell is significant for blocking tumor dissemination.[24]
# As a drug target
Crizanlizumab is a monoclonal antibody against P-selectin.[25] It is undergoing clinical trials. | https://www.wikidoc.org/index.php/P-selectin | |
04f693662f8cb744b66f730c7bc05d5513e346f0 | wikidoc | P16 (gene) | P16 (gene)
# Overview
Cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4), also known as CDKN2A, is a human gene.
This gene generates several transcript variants which differ in their first exons. At least three alternatively-spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, MDM2, a protein responsible for the degradation of p53 . In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.
p16 is a tumour suppressor gene. Mutations in p16 increase the risk of developing a variety of cancers, notably melanoma. p16 is an important gene in regulating the cell cycle.
Recent research on the p16 gene, published in Nature in September 2006, indicates that its increased expression as organisms age reduces the proliferation of stem cells. This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.
The p16 gene has an alternative reading frame (ARF) that encodes the p14 ARF protein. this is involved in stabilising P53 and is positively regulated by E2F.
p16INK4a is a major product of the CDKN2A locus. Its alternate reading frame product is p14ARF. p16INK4a regulates the cell cycle by binding and deactivating various cyclin-CDKcomplexes. A study published in 2007 in the New England Journal of medicine established that there is a strong association between polymorphisms on chromosome 9p21.3 (SNP, rs1333049) and coronary artery disease. This region codes for the INK4 proteins p16INK4a and p15INK4b. The corresponding genes are CDKN2A and CDKN2B. The proteins may inhibit cell growth induced by Transforming Growth Factor-beta. | P16 (gene)
# Overview
Cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4), also known as CDKN2A, is a human gene.
This gene generates several transcript variants which differ in their first exons. At least three alternatively-spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, MDM2, a protein responsible for the degradation of p53 [1]. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.[2]
p16 is a tumour suppressor gene. Mutations in p16 increase the risk of developing a variety of cancers, notably melanoma. p16 is an important gene in regulating the cell cycle.
Recent research on the p16 gene, published in Nature in September 2006, indicates that its increased expression as organisms age reduces the proliferation of stem cells. This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.
The p16 gene has an alternative reading frame (ARF) that encodes the p14 ARF protein. this is involved in stabilising P53 and is positively regulated by E2F.
p16INK4a is a major product of the CDKN2A locus. Its alternate reading frame product is p14ARF. p16INK4a regulates the cell cycle by binding and deactivating various cyclin-CDKcomplexes. A study published in 2007 in the New England Journal of medicine established that there is a strong association between polymorphisms on chromosome 9p21.3 (SNP, rs1333049) and coronary artery disease. This region codes for the INK4 proteins p16INK4a and p15INK4b. The corresponding genes are CDKN2A and CDKN2B. The proteins may inhibit cell growth induced by Transforming Growth Factor-beta. | https://www.wikidoc.org/index.php/P16_(gene) | |
19184fd799ce43301c40563ba8cccc496ad08412 | wikidoc | Sildenafil | Sildenafil
# 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
Sildenafil is a Phosphodiesterase 5 Inhibitor that is FDA approved for the treatment of pulmonary arterial hypertension. Common adverse reactions include erythema，flushing, indigestion, headache, insomnia, visual disturbance, epistaxis, nasal congestion and rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Pulmonary arterial hypertension (WHO Group I)
- Indication
- Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy.
- Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%).
- Limitation of Use
- Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity.
- Dosing information
- Recommended dosage: 20 mg PO tid. Administer sildenafil tablet doses 4 to 6 hours apart.
- In the clinical trial no greater efficacy was achieved with the use of higher doses.
- Treatment with doses higher than 20 mg TID is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label –Guideline-Supported Use of Sildenafil in adult patients.
### Non–Guideline-Supported Use
### Achalasia
- Dosing information
- 50 mg/day
### Sexual dysfunction
- Dosing information
- 50 mg/day
### Drug-induced impotence
- Dosing information
- 25 mg/day or 50 mg/day
### Drug withdrawal, Nitric oxide
- Dosing information
- 50 mg/day
### Female sexual arousal disorder
- Dosing information
- 25-100 mg/day
- ‘’‘ 10-100 mg/day
### In vitro fertilization
- Dosing information
- 25 mg vaginal suppository intravaginally 4 times a day
### Premature Ejaction
- Dosing information
- 50 mg/day, ,
- 50- 100 mg/day
### Secondary Raynaud's phenomenon
- Dosing information
- sildenafil 50 mg twice a day to 200 mg once a day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- FDA Package Insert for Sildenafil contains no information regarding FDA-labeled indications and dosage information for children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Sildenafil in pediatric patients.
### Non–Guideline-Supported Use
### Drug withdrawal, Nitric oxide
- Dosing information
- Not applicable
# Contraindications
Sildenafil tablets are contraindicated in patients with:
- Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension.
- Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil.
# Warnings
### Mortality with Pediatric Use
- In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil citrate dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil citrate, particularly chronic use, is not recommended in children.
### Hypotension
- Sildenafil citrate has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil citrate, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension , fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate.
### Worsening Pulmonary Vascular Occlusive Disease
- Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil citrate to patients with veno-occlusive disease, administration of sildenafil citrate to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil citrate is administered, consider the possibility of associated PVOD.
### Epistaxis
- The incidence of epistaxis was 13% in patients taking sildenafil citrate with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil citrate 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil citrate-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).
- The safety of sildenafil citrate is unknown in patients with bleeding disorders or active peptic ulceration.
### Visual Loss
- When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing 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. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational study evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. It is not possible to determine whether these events are related directly to the use of PDE-5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
- Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil citrate. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors.
- There are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil citrate with caution in these patients.
### Hearing Loss
- Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil citrate. In some of the cases, medical conditions and other factors were reported that may have played a role. 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 sildenafil citrate, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.
- Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil citrate.
### Combination with other PDE-5 inhibitors
- Sildenafil is also marketed as Sildenafil citrate®. The safety and efficacy of combinations of sildenafil citrate with Sildenafil citrate or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil citrate not to take Sildenafil citrate or other PDE5 inhibitors.
### Priapism
- Use sildenafil citrate with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.
### Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia
- In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil citrate than by those randomized to placebo. The effectiveness and safety of sildenafil citrate in the treatment of PAH secondary to sickle cell anemia has not been established.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Safety data of sildenafil citrate in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil citrate-treated patients with PAH, WHO Group I Diagnostic Classification.
- The overall frequency of discontinuation in sildenafil citrate-treated patients 20 mg TID was 3% and was the same for the placebo group.
- In Study 1, the adverse reactions that were reported by at least 3% of sildenafil citrate-treated patients (20 mg TID) and were more frequent in sildenafil citrate-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature.
- At doses higher than the recommended 20 mg TID, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.
- The incidence of retinal hemorrhage with sildenafil citrate 20 mg TID was 1.4% versus 0% placebo and for all sildenafil citrate doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg TID and at all doses studied was 1.4% for sildenafil citrate versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy.
- In a placebo-controlled fixed dose titration study (Study 2) of sildenafil citrate (starting with recommended dose of 20 mg TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil citrate + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 .
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of - Sildenafil (marketed for both PAH and erectile dysfunction). 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.
### Cardiovascular Events
- In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors.
### Nervous system
- Seizure, seizure recurrence
# Drug Interactions
### Nitrates
- Concomitant use of sildenafil citrate with nitrates in any form is contraindicated.
### Ritonavir and other Potent CYP3A Inhibitors
- Concomitant use of sildenafil citrate with ritonavir and other potent CYP3A inhibitors is not recommended.
### Other drugs that reduce blood pressure
- Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope.
- Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
- Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sildenafil in women who are pregnant.
### Labor and Delivery
- The safety and efficacy of sildenafil citrate during labor and delivery has not been studied.
### Nursing Mothers
- It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when sildenafil citrate is administered to a nursing woman.
### Pediatric Use
- In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil citrate, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered TID.
- The primary objective of the study was to assess the effect of sildenafil citrate on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil citrate did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study.
- After completing the 16-week controlled study, a patient originally randomized to sildenafil citrate remained on his/her dose of sildenafil citrate or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil citrate. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6:
- During the study, there were 42 reported deaths with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil citrate doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil citrate, particularly chronic use, is not recommended in children.
### Geriatic Use
- Clinical studies of sildenafil citrate 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, 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 Sildenafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sildenafil with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required (including severe impairment CLcr < 30 mL/min).
### Hepatic Impairment
- No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sildenafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sildenafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Sildenafil contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.
- In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
# Pharmacology
## Mechanism of Action
- Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
- Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.
- In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.
## Structure
- Sildenafil citrate, USP, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as Sildenafil citrate® for erectile dysfunction.
- Sildenafil citrate, USP is designated chemically as 1- pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
## Pharmacodynamics
### Effects of Sildenafil citrate on Hemodynamic Measures
- Patients on all Sildenafil citrate doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators . Data on other hemodynamic measures for the Sildenafil citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6minute walk distance is unknown.
- mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate *The number of patients per treatment group varied slightly for each parameter due to missing assessments.
- In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg, there were no significant differences in the effects on hemodynamic variables between doses.
### Effects of Sildenafil Citrateon Blood Pressure
- Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates.
- Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg TID to patients with PAH, no clinically relevant effects on ECG were reported.
- After chronic dosing of 80 mg TID sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.
- After chronic dosing of 80 mg TID sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.
- After chronic dosing of 80 mg TID sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).
### Effects of Sildenafil Citrateon Vision
- At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.
## Pharmacokinetics
### Absorption and Distribution
- Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25% to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
- Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).
### Metabolism and Excretion
- Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.
- After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
### Population Pharmacokinetics
- Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.
- In patients with PAH, the average steady-state concentrations were 20% to 50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.
Geriatric Patients
- Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.
Renal Impairment
- In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 200% and 79%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.
Hepatic Impairment
- In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax(47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
### Drug Interaction Studies
- Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.
- Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.
- The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively.
## Nonclinical Toxicology
CYP3A Inhibitors and Beta Blockers
- Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).
CYP3A4 inducers including bosentan
- Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.
- Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.
Epoprostenol
- The mean reduction of sildenafil (80 mg three times a day) bioavailability when administered with epoprostenol was 28%, resulting in about 22% lower mean average steady-state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.
- No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Alcohol
- Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
# Clinical Studies
## Studies of Adults with Pulmonary Arterial Hypertension
### Study 1 Sildenafil Citrate monotherapy (20 mg, 40 mg, and 80 mg three times a day)
- A randomized, double-blind, placebo-controlled study of sildenafil citrate (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
- Patients were randomized to receive placebo (n=70) or sildenafil citrate 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) TID for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).
- The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil citrate. These increases were significantly different from placebo, but the sildenafil citrate dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg TID. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.
- Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters.
- Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
- Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil citrate. Without a control group, these data must be interpreted cautiously.
### Study 2 (Sildenafil Citrate co-administered with epoprostenol)
- A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil citrate (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.
- At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.
- There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil citrate group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil citrate group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).
- Patients on sildenafil citrate achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil citrate (95% CI: -5.7, -2.1) (p = 0.00003).
- Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil citrate-treated patients and that sildenafil citrate-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.
- Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil citrate compared to placebo. More than twice as many sildenafil citrate-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.
### Study 3 (Sildenafil Citrate monotherapy (1 mg, 5 mg, and 20 mg three times a day)
- A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart
- catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of sildenafil citrate: 1 mg, 5 mg, and 20 mg, three times a day.
- At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.
- The primary efficacy endpoint was the change from baseline at Week 12 (at
least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38 to 41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12).
### Study 4 (Sildenafil Citrate added to bosentan therapy – lack of effect on exercise capacity)
- A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.
# How Supplied
- Sildenafil tablets, 20 mg, are supplied as white to off-white, round shaped film-coated tablets with debossing ‘AN 351’ on one side and plain on the other side, containing sildenafil citrate, USP equivalent to the nominally indicated amount of sildenafil.
- They are available as follows:
- Bottles of 90: NDC 68001-176-05
## Storage
- Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Read this Patient Information before you start taking sildenafil citrate and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil citrate, ask your doctor or pharmacist.
### What is the most important information I should know about sildenafil citrate?
- Never take sildenafil citrate with any nitrate medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include:
- Medicines that treat chest pain (angina)
- Nitroglycerin in any form including tablets, patches, sprays, and ointments
- Isosorbide mononitrate or dinitrate
- Street drugs called “poppers” (amyl nitrate or nitrite)
- Ask your doctor or pharmacist if you are not sure if you are taking a nitrate medicine.
### What is sildenafil citrate?
- Sildenafil citrate is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs.
- Sildenafil citrate improves the ability to exercise and can slow down worsening changes in your physical condition.
- Sildenafil citrate is not for use in children
- Adding sildenafil citrate to another medication used to treat PAH, bosentan (Tracleer®), does not result in improvement in your ability to exercise.
- Sildenafil citrate contains the same medicine as Sildenafil citrate® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil citrate with Sildenafil citrate or other PDE-5 inhibitors.
### Who should not take sildenafil citrate?
- Do not take sildenafil citrate if you:
- Take nitrate medicines. See “What is the most important information I should know about sildenafil citrate?”
- Are allergic to sildenafil or any other ingredient in sildenafil tablets. See “What are the ingredients in sildenafil tablets?” at the end of this leaflet.
### What should I tell my doctor before taking sildenafil citrate?
- Tell your doctor about all of your medical conditions, including if you
- Have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack
- Have a disease called pulmonary veno-occlusive disease (PVOD)
- Have high or low blood pressure or blood circulation problems
- Have an eye problem called retinitis pigmentosa
- Have or had loss of sight in one or both eyes
- Have any problem with the shape of your penis or Peyronie’s disease
- Have any blood cell problems such sickle cell anemia
- Have a stomach ulcer or any bleeding problems
- Are pregnant or planning to become pregnant. It is not known if sildenafil citrate could harm your unborn baby.
- Are breastfeeding. It is not known if sildenafil citrate passes into your breast milk or if it could harm your baby.
- Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal products.
- Sildenafil citrate and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil citrate.
- Especially tell your doctor if you take
- Nitrate medicines. See “What is the most important information I should know about sildenafil citrate?”
- Ritonavir (Norvir®) or other medicines used to treat HIV infection
- Ketoconazole (Nizoral®)
- Itraconazole (Sporanox)
- High blood pressure medicine
- Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.
### How should I take sildenafil citrate?
- Take sildenafil citrate exactly as your doctor tells you.
- Sildenafil citrate may be prescribed to you as
- Sildenafil tablets
- Take sildenafil tablets 3 times a day about 4 to 6 hours apart.
- Take sildenafil tablets at the same times every day.
- If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time.
- Do not take more than one dose of sildenafil citrate at a time.
- Do not change your dose or stop taking sildenafil citrate on your own. Talk to your doctor first.
- If you take too much sildenafil citrate, call your doctor or go to the nearest hospital emergency room.
### What are the possible side effects of sildenafil citrate?
- Low blood pressure. Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy.
- More shortness of breath than usual. Tell your doctor if you get more short of breath after you start sildenafil citrate. More shortness of breath than usual may be due to your underlying medical condition.
- Decreased eyesight or loss of sight in one or both eyes (NAION). If you notice a sudden decrease or loss of eyesight, talk to your doctor right away.
- Sudden decrease or loss of hearing. If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil citrate, or to other diseases or medicines, to other factors, or to a combination of factors.
- Heart attack, stroke, irregular heartbeats, and death. Most of these happened in men who already had heart problems.
- Erections that last several hours. Tell your doctor right away if you have an erection that lasts more than 4 hours.
### The most common side effects with sildenafil citrate include:
- Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children.
Tell your doctor if you have any side effect that bothers you or doesn’t go away.
These are not all the possible side effects of sildenafil citrate. 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 I store sildenafil tablets?
- Store sildenafil tablets at controlled room temperature, between 68°F to 77°F (20°C to 25°C).
- Keep sildenafil citrate and all medicines away from children.
### General information about sildenafil citrate
- Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil citrate for a condition for which it was not prescribed. Do not give sildenafil citrate to other people, even if they have the same symptoms you have. It could harm them.
- This patient leaflet summarizes the most important information about sildenafil citrate. If you would like more information about sildenafil citrate, talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil citrate that is written for health professionals. For more information go to www.amneal.com or call 1-877-835-5472.
### What are the ingredients in sildenafil tablets?
- Sildenafil tablets
Active ingredients: sildenafil citrate
Inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
- This product’s label may have been updated. For current full prescribing information, please visit
- www.amneal.com
- This Patient Information has been approved by the U.S. Food and Drug Administration
- Manufactured by:
Amneal Pharmaceuticals Co. (I) Pvt. Ltd.
Ahmedabad, INDIA 382220
For BluePoint Laboratories
Rev. 03/2014
# Precautions with Alcohol
- Alcohol-Sildenafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Viagra
- Revatio
# Look-Alike Drug Names
Viagra - Allegra
# Drug Shortage Status
# Price | Sildenafil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Sildenafil is a Phosphodiesterase 5 Inhibitor that is FDA approved for the treatment of pulmonary arterial hypertension. Common adverse reactions include erythema，flushing, indigestion, headache, insomnia, visual disturbance, epistaxis, nasal congestion and rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Pulmonary arterial hypertension (WHO Group I)
- Indication
- Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy.
- Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%).
- Limitation of Use
- Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity.
- Dosing information
- Recommended dosage: 20 mg PO tid. Administer sildenafil tablet doses 4 to 6 hours apart.
- In the clinical trial no greater efficacy was achieved with the use of higher doses.
- Treatment with doses higher than 20 mg TID is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label –Guideline-Supported Use of Sildenafil in adult patients.
### Non–Guideline-Supported Use
### Achalasia
- Dosing information
- 50 mg/day[1]
### Sexual dysfunction
- Dosing information
- 50 mg/day [2]
### Drug-induced impotence
- Dosing information
- 25 mg/day or 50 mg/day [3]
### Drug withdrawal, Nitric oxide
- Dosing information
- 50 mg/day [4]
### Female sexual arousal disorder
- Dosing information
- 25-100 mg/day[5]
- ‘’‘ 10-100 mg/day [6]
### In vitro fertilization
- Dosing information
- 25 mg vaginal suppository intravaginally 4 times a day [7]
### Premature Ejaction
- Dosing information
- 50 mg/day[8], [9], [10]
- 50- 100 mg/day [11]
### Secondary Raynaud's phenomenon
- Dosing information
- sildenafil 50 mg twice a day to 200 mg once a day[12]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- FDA Package Insert for Sildenafil contains no information regarding FDA-labeled indications and dosage information for children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Sildenafil in pediatric patients.
### Non–Guideline-Supported Use
### Drug withdrawal, Nitric oxide
- Dosing information
- Not applicable [13]
# Contraindications
Sildenafil tablets are contraindicated in patients with:
- Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension.
- Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil.
# Warnings
### Mortality with Pediatric Use
- In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil citrate dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil citrate, particularly chronic use, is not recommended in children.
### Hypotension
- Sildenafil citrate has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil citrate, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate.
### Worsening Pulmonary Vascular Occlusive Disease
- Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil citrate to patients with veno-occlusive disease, administration of sildenafil citrate to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil citrate is administered, consider the possibility of associated PVOD.
### Epistaxis
- The incidence of epistaxis was 13% in patients taking sildenafil citrate with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil citrate 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil citrate-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).
- The safety of sildenafil citrate is unknown in patients with bleeding disorders or active peptic ulceration.
### Visual Loss
- When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing 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. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational study evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. It is not possible to determine whether these events are related directly to the use of PDE-5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
- Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil citrate. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors.
- There are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil citrate with caution in these patients.
### Hearing Loss
- Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil citrate. In some of the cases, medical conditions and other factors were reported that may have played a role. 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 sildenafil citrate, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.
- Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil citrate.
### Combination with other PDE-5 inhibitors
- Sildenafil is also marketed as Sildenafil citrate®. The safety and efficacy of combinations of sildenafil citrate with Sildenafil citrate or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil citrate not to take Sildenafil citrate or other PDE5 inhibitors.
### Priapism
- Use sildenafil citrate with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.
### Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia
- In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil citrate than by those randomized to placebo. The effectiveness and safety of sildenafil citrate in the treatment of PAH secondary to sickle cell anemia has not been established.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Safety data of sildenafil citrate in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil citrate-treated patients with PAH, WHO Group I Diagnostic Classification.
- The overall frequency of discontinuation in sildenafil citrate-treated patients 20 mg TID was 3% and was the same for the placebo group.
- In Study 1, the adverse reactions that were reported by at least 3% of sildenafil citrate-treated patients (20 mg TID) and were more frequent in sildenafil citrate-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature.
- At doses higher than the recommended 20 mg TID, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.
- The incidence of retinal hemorrhage with sildenafil citrate 20 mg TID was 1.4% versus 0% placebo and for all sildenafil citrate doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg TID and at all doses studied was 1.4% for sildenafil citrate versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy.
- In a placebo-controlled fixed dose titration study (Study 2) of sildenafil citrate (starting with recommended dose of 20 mg TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil citrate + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 .
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of * Sildenafil (marketed for both PAH and erectile dysfunction). 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.
### Cardiovascular Events
- In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors.
### Nervous system
- Seizure, seizure recurrence
# Drug Interactions
### Nitrates
- Concomitant use of sildenafil citrate with nitrates in any form is contraindicated.
### Ritonavir and other Potent CYP3A Inhibitors
- Concomitant use of sildenafil citrate with ritonavir and other potent CYP3A inhibitors is not recommended.
### Other drugs that reduce blood pressure
- Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope.
- Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
- Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sildenafil in women who are pregnant.
### Labor and Delivery
- The safety and efficacy of sildenafil citrate during labor and delivery has not been studied.
### Nursing Mothers
- It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when sildenafil citrate is administered to a nursing woman.
### Pediatric Use
- In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil citrate, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered TID.
- The primary objective of the study was to assess the effect of sildenafil citrate on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil citrate did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study.
- After completing the 16-week controlled study, a patient originally randomized to sildenafil citrate remained on his/her dose of sildenafil citrate or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil citrate. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6:
- During the study, there were 42 reported deaths with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil citrate doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil citrate, particularly chronic use, is not recommended in children.
### Geriatic Use
- Clinical studies of sildenafil citrate 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, 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 Sildenafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sildenafil with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required (including severe impairment CLcr < 30 mL/min).
### Hepatic Impairment
- No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sildenafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sildenafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Sildenafil contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.
- In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
# Pharmacology
## Mechanism of Action
- Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
- Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.
- In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.
## Structure
- Sildenafil citrate, USP, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as Sildenafil citrate® for erectile dysfunction.
- Sildenafil citrate, USP is designated chemically as 1-[ [3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
## Pharmacodynamics
### Effects of Sildenafil citrate on Hemodynamic Measures
- Patients on all Sildenafil citrate doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)]. Data on other hemodynamic measures for the Sildenafil citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6minute walk distance is unknown.
- mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate *The number of patients per treatment group varied slightly for each parameter due to missing assessments.
- In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg, there were no significant differences in the effects on hemodynamic variables between doses.
### Effects of Sildenafil Citrateon Blood Pressure
- Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates.
- Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg TID to patients with PAH, no clinically relevant effects on ECG were reported.
- After chronic dosing of 80 mg TID sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.
- After chronic dosing of 80 mg TID sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.
- After chronic dosing of 80 mg TID sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).
### Effects of Sildenafil Citrateon Vision
- At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.
## Pharmacokinetics
### Absorption and Distribution
- Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25% to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
- Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).
### Metabolism and Excretion
- Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.
- After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
### Population Pharmacokinetics
- Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.
- In patients with PAH, the average steady-state concentrations were 20% to 50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.
Geriatric Patients
- Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.
Renal Impairment
- In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 200% and 79%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.
Hepatic Impairment
- In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax(47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
### Drug Interaction Studies
- Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.
- Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.
- The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively.
## Nonclinical Toxicology
CYP3A Inhibitors and Beta Blockers
- Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).
CYP3A4 inducers including bosentan
- Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.
- Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.
Epoprostenol
- The mean reduction of sildenafil (80 mg three times a day) bioavailability when administered with epoprostenol was 28%, resulting in about 22% lower mean average steady-state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.
- No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Alcohol
- Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
# Clinical Studies
## Studies of Adults with Pulmonary Arterial Hypertension
### Study 1 Sildenafil Citrate monotherapy (20 mg, 40 mg, and 80 mg three times a day)
- A randomized, double-blind, placebo-controlled study of sildenafil citrate (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
- Patients were randomized to receive placebo (n=70) or sildenafil citrate 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) TID for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).
- The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil citrate. These increases were significantly different from placebo, but the sildenafil citrate dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg TID. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.
- Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters.
- Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
- Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil citrate. Without a control group, these data must be interpreted cautiously.
### Study 2 (Sildenafil Citrate co-administered with epoprostenol)
- A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil citrate (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.
- At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.
- There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil citrate group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil citrate group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).
- Patients on sildenafil citrate achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil citrate (95% CI: -5.7, -2.1) (p = 0.00003).
- Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil citrate-treated patients and that sildenafil citrate-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.
- Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil citrate compared to placebo. More than twice as many sildenafil citrate-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.
### Study 3 (Sildenafil Citrate monotherapy (1 mg, 5 mg, and 20 mg three times a day)
- A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart
- catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of sildenafil citrate: 1 mg, 5 mg, and 20 mg, three times a day.
- At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.
- The primary efficacy endpoint was the change from baseline at Week 12 (at
least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38 to 41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12).
### Study 4 (Sildenafil Citrate added to bosentan therapy – lack of effect on exercise capacity)
- A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.
# How Supplied
- Sildenafil tablets, 20 mg, are supplied as white to off-white, round shaped film-coated tablets with debossing ‘AN 351’ on one side and plain on the other side, containing sildenafil citrate, USP equivalent to the nominally indicated amount of sildenafil.
- They are available as follows:
- Bottles of 90: NDC 68001-176-05
## Storage
- Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Read this Patient Information before you start taking sildenafil citrate and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil citrate, ask your doctor or pharmacist.
### What is the most important information I should know about sildenafil citrate?
- Never take sildenafil citrate with any nitrate medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include:
- Medicines that treat chest pain (angina)
- Nitroglycerin in any form including tablets, patches, sprays, and ointments
- Isosorbide mononitrate or dinitrate
- Street drugs called “poppers” (amyl nitrate or nitrite)
- Ask your doctor or pharmacist if you are not sure if you are taking a nitrate medicine.
### What is sildenafil citrate?
- Sildenafil citrate is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs.
- Sildenafil citrate improves the ability to exercise and can slow down worsening changes in your physical condition.
- Sildenafil citrate is not for use in children
- Adding sildenafil citrate to another medication used to treat PAH, bosentan (Tracleer®), does not result in improvement in your ability to exercise.
- Sildenafil citrate contains the same medicine as Sildenafil citrate® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil citrate with Sildenafil citrate or other PDE-5 inhibitors.
### Who should not take sildenafil citrate?
- Do not take sildenafil citrate if you:
- Take nitrate medicines. See “What is the most important information I should know about sildenafil citrate?”
- Are allergic to sildenafil or any other ingredient in sildenafil tablets. See “What are the ingredients in sildenafil tablets?” at the end of this leaflet.
### What should I tell my doctor before taking sildenafil citrate?
- Tell your doctor about all of your medical conditions, including if you
- Have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack
- Have a disease called pulmonary veno-occlusive disease (PVOD)
- Have high or low blood pressure or blood circulation problems
- Have an eye problem called retinitis pigmentosa
- Have or had loss of sight in one or both eyes
- Have any problem with the shape of your penis or Peyronie’s disease
- Have any blood cell problems such sickle cell anemia
- Have a stomach ulcer or any bleeding problems
- Are pregnant or planning to become pregnant. It is not known if sildenafil citrate could harm your unborn baby.
- Are breastfeeding. It is not known if sildenafil citrate passes into your breast milk or if it could harm your baby.
- Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal products.
- Sildenafil citrate and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil citrate.
- Especially tell your doctor if you take
- Nitrate medicines. See “What is the most important information I should know about sildenafil citrate?”
- Ritonavir (Norvir®) or other medicines used to treat HIV infection
- Ketoconazole (Nizoral®)
- Itraconazole (Sporanox)
- High blood pressure medicine
- Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.
### How should I take sildenafil citrate?
- Take sildenafil citrate exactly as your doctor tells you.
- Sildenafil citrate may be prescribed to you as
- Sildenafil tablets
- Take sildenafil tablets 3 times a day about 4 to 6 hours apart.
- Take sildenafil tablets at the same times every day.
- If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time.
- Do not take more than one dose of sildenafil citrate at a time.
- Do not change your dose or stop taking sildenafil citrate on your own. Talk to your doctor first.
- If you take too much sildenafil citrate, call your doctor or go to the nearest hospital emergency room.
### What are the possible side effects of sildenafil citrate?
- Low blood pressure. Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy.
- More shortness of breath than usual. Tell your doctor if you get more short of breath after you start sildenafil citrate. More shortness of breath than usual may be due to your underlying medical condition.
- Decreased eyesight or loss of sight in one or both eyes (NAION). If you notice a sudden decrease or loss of eyesight, talk to your doctor right away.
- Sudden decrease or loss of hearing. If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil citrate, or to other diseases or medicines, to other factors, or to a combination of factors.
- Heart attack, stroke, irregular heartbeats, and death. Most of these happened in men who already had heart problems.
- Erections that last several hours. Tell your doctor right away if you have an erection that lasts more than 4 hours.
### The most common side effects with sildenafil citrate include:
- Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children.
Tell your doctor if you have any side effect that bothers you or doesn’t go away.
These are not all the possible side effects of sildenafil citrate. 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 I store sildenafil tablets?
- Store sildenafil tablets at controlled room temperature, between 68°F to 77°F (20°C to 25°C).
- Keep sildenafil citrate and all medicines away from children.
### General information about sildenafil citrate
- Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil citrate for a condition for which it was not prescribed. Do not give sildenafil citrate to other people, even if they have the same symptoms you have. It could harm them.
- This patient leaflet summarizes the most important information about sildenafil citrate. If you would like more information about sildenafil citrate, talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil citrate that is written for health professionals. For more information go to www.amneal.com or call 1-877-835-5472.
### What are the ingredients in sildenafil tablets?
- Sildenafil tablets
Active ingredients: sildenafil citrate
Inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
- This product’s label may have been updated. For current full prescribing information, please visit
- www.amneal.com
- This Patient Information has been approved by the U.S. Food and Drug Administration
- Manufactured by:
Amneal Pharmaceuticals Co. (I) Pvt. Ltd.
Ahmedabad, INDIA 382220
For BluePoint Laboratories
Rev. 03/2014
# Precautions with Alcohol
- Alcohol-Sildenafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Viagra
- Revatio
# Look-Alike Drug Names
Viagra - Allegra
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/PDE-5_inhibitors | |
133aa53c7646858bccca8f8a158ecfd67a340261 | wikidoc | PDZ domain | PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, and animals. PDZ is an acronym combining the first letters of three proteins — post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (zo-1) — which were first discovered to share the domain. PDZ domains are also referred to as DHR (Dlg homologous region) or GLGF (glycine-leucine-glycine-phenylalanine) domains. These domains help anchor transmembrane proteins to the cytoskeleton and hold together signaling complexes.
There are roughly 260 human PDZ domains, though since several PDZ domain containing proteins hold several domains, the actual number of PDZ proteins is closer to 180. Listed below are some of the better studied members of this family.
- Erbin
- Htra1
- Htra2
- Htra3
- PSD-95
- SAP97
- PTP-BL
# Human proteins containing this domain
AAG12; AHNAK; AHNAK2; AIP1; APBA1; APBA2; APBA3; ARHGAP21;
ARHGAP23; ARHGEF11; ARHGEF12; C14orf112; C16orf65; CASK; CNKSR2; CNKSR3;
DFNB31; DLG1; DLG2; DLG3; DLG4; DLG5; DVL1; DVL1L1;
DVL2; DVL3; ERBB2IP; FRMPD1; FRMPD2; FRMPD2L1; FRMPD3; FRMPD4;
GIPC1; GIPC2; GIPC3; GOPC; GRASP; GRIP1; GRIP2; HTRA1;
HTRA2; HTRA3; HTRA4; IL16; INADL; KIAA1849; LDB3; LIMK1;
LIMK2; LIN7A; LIN7B; LIN7C; LMO7; LNX1; LNX2; LOC392742;
LOC392862; LRRC7; MAGI-3; MAGI1; MAGI2; MAGI3; MAGIX; MAST1;
MAST2; MAST3; MAST4; MLLT4; MPDZ; MPP1; MPP2; MPP3;
MPP4; MPP5; MPP6; MPP7; MYO18A; NOS1; PARD3; PARD3B;
PARD6A; PARD6B; PARD6G; PDLIM1; PDLIM2; PDLIM3; PDLIM4; PDLIM5;
PDLIM7; PDZD11; PDZD2; PDZD3; PDZD4; PDZD5A; PDZD7; PDZD8;
PDZK1; PDZRN3; PDZRN4; PICK1; PPP1R9A; PPP1R9B; PREX1; PRX;
PSCDBP; PTPN13; PTPN3; PTPN4; RAPGEF2; RAPGEF6; RGS12; RGS3;
RHPN1; RIMS1; RIMS2; SCRIB; SDCBP; SDCBP2; SHANK1; SHANK2;
SHANK3; SHROOM2; SHROOM3; SHROOM4; SIPA1; SIPA1L1; SIPA1L2; SIPA1L3;
SLC9A3R1; SLC9A3R2; SNTA1; SNTB1; SNTB2; SNTG1; SNTG2; SNX27;
SPAL2; STXBP4; SYNJ2BP; SYNPO2; SYNPO2L; TAX1BP3; TIAM1; TIAM2;
TJP1; TJP2; TJP3; USH1C; WHRN; | PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, and animals[1]. PDZ is an acronym combining the first letters of three proteins — post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (DlgA), and zonula occludens-1 protein (zo-1) — which were first discovered to share the domain. PDZ domains are also referred to as DHR (Dlg homologous region) or GLGF (glycine-leucine-glycine-phenylalanine) domains. These domains help anchor transmembrane proteins to the cytoskeleton and hold together signaling complexes[2].
There are roughly 260 human PDZ domains, though since several PDZ domain containing proteins hold several domains, the actual number of PDZ proteins is closer to 180. Listed below are some of the better studied members of this family.
- Erbin
- Htra1
- Htra2
- Htra3
- PSD-95
- SAP97
- PTP-BL [3]
# Human proteins containing this domain
AAG12; AHNAK; AHNAK2; AIP1; APBA1; APBA2; APBA3; ARHGAP21;
ARHGAP23; ARHGEF11; ARHGEF12; C14orf112; C16orf65; CASK; CNKSR2; CNKSR3;
DFNB31; DLG1; DLG2; DLG3; DLG4; DLG5; DVL1; DVL1L1;
DVL2; DVL3; ERBB2IP; FRMPD1; FRMPD2; FRMPD2L1; FRMPD3; FRMPD4;
GIPC1; GIPC2; GIPC3; GOPC; GRASP; GRIP1; GRIP2; HTRA1;
HTRA2; HTRA3; HTRA4; IL16; INADL; KIAA1849; LDB3; LIMK1;
LIMK2; LIN7A; LIN7B; LIN7C; LMO7; LNX1; LNX2; LOC392742;
LOC392862; LRRC7; MAGI-3; MAGI1; MAGI2; MAGI3; MAGIX; MAST1;
MAST2; MAST3; MAST4; MLLT4; MPDZ; MPP1; MPP2; MPP3;
MPP4; MPP5; MPP6; MPP7; MYO18A; NOS1; PARD3; PARD3B;
PARD6A; PARD6B; PARD6G; PDLIM1; PDLIM2; PDLIM3; PDLIM4; PDLIM5;
PDLIM7; PDZD11; PDZD2; PDZD3; PDZD4; PDZD5A; PDZD7; PDZD8;
PDZK1; PDZRN3; PDZRN4; PICK1; PPP1R9A; PPP1R9B; PREX1; PRX;
PSCDBP; PTPN13; PTPN3; PTPN4; RAPGEF2; RAPGEF6; RGS12; RGS3;
RHPN1; RIMS1; RIMS2; SCRIB; SDCBP; SDCBP2; SHANK1; SHANK2;
SHANK3; SHROOM2; SHROOM3; SHROOM4; SIPA1; SIPA1L1; SIPA1L2; SIPA1L3;
SLC9A3R1; SLC9A3R2; SNTA1; SNTB1; SNTB2; SNTG1; SNTG2; SNX27;
SPAL2; STXBP4; SYNJ2BP; SYNPO2; SYNPO2L; TAX1BP3; TIAM1; TIAM2;
TJP1; TJP2; TJP3; USH1C; WHRN; | https://www.wikidoc.org/index.php/PDZ_(biology) | |
4e839fa3842f06dd3c2321c981c8760032cd5d3f | wikidoc | PEGylation | PEGylation
# Overview
PEGylation is the process of covalent attachment of poly(ethylene glycol) polymer chains to another molecule, normally a drug or therapeutic protein. PEGylation is routinely achieved by incubation of a reactive derivative of PEG with the target macromolecule. The covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system (reduced immunogenicity and antigenicity), increase the hydrodynamic size (size in solution) of the agent which prolongs its circulatory time by reducing renal clearance. PEGylation can also provide water solubility to hydrophobic drugs and proteins.
# History
In 1970s, pioneering research by Davis, Abuchowski and colleagues foresaw the potential of the conjugation of Polyethylene glycol (PEG) to Proteins. This technique is now well established and is known as PEGylation.
PEGylation, is a process of attaching the strands of the polymer PEG to molecules most typically peptides, proteins, and antibody fragments, that can help to meet the challenges of improving the safety and efficiency of many therapeutics. It produces alterations in the physiochemical properties including changes in conformation, electrostatic binding, hydrophobicity etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns.
PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as:
- Improved drug solubility
- Reduced dosage frequency, without diminished efficacy with potentially reduced toxicity
- Extended circulating life
- Increased drug stability
- Enhanced protection from proteolytic degradation
The PEGylated drugs are having the following commercial advantages also:
- Opportunities for new delivery formats and dosing regimens
- Extended patent life of previously approved drugs
# PEGylated Pharmaceuticals on the Market
The clinical value of PEGylation is now well established. ADAGEN (PEG- bovine adenosine deaminase) manufactured by Enzon Pharmaceuticals, Inc., US was the first PEGylated protein approved by FDA in March 1990, to enter the market. It is used to treat X-linked severe combined immunogenicity syndrome, as an alternative to bone marrow transplantation and enzyme replacement by gene therapy. Since the introduction of ADAGEN, a large number of PEGylated protein and peptide pharmaceuticals have followed and many others are under clinical trial or under development stages. Some of the successful examples are:
- PEGASYS: PEGylated alpha-interferons for use in the treatment of hepatis C (Hoffman-La Roche)
- PEG-Intron: PEGylated alpha -interferons for chronic hepatis C (Schering-Plough / Enzon)
- Oncaspar: PEGylated L-asparaginase for the treatment of acute lymphoblastic leukemia in patients who are hypersensitive to the native unmodified form of L-asparaginase (Enzon)
- Neulasta: PEGylated recombinant methionyl human granulocyte colony stimulating factor for severe cancer chemotherapy induced neutropenia (Amgen)
- Doxil: PEGylated liposome containing doxorubicin for the treatment of Cancer (Sequus)
# PEG Moiety Properties
PEG is a particularly attractive polymer for conjugation. The specific characteristics of PEG moieties relevant to pharmaceutical applications are:
- Water solubility
- High mobility in solution
- Lack of toxicity and immunogenicity
- Ready clearance from the body
- Altered distribution in the body
# PEGylation Process
The first step of the PEGylation is the suitable functionalization of the PEG polymer at one or both terminals. PEGs that are activated at each terminus with the same reactive moiety is known as “homobifunctional”, where as if the functional groups present are different, then the PEG derivative is referred as “heterobifunctional” or “heterofunctional.” The chemically active or activated derivatives of the PEG polymer are prepared to attach the PEG to the desired molecule.
The choice of the suitable functional group for the PEG derivative is based on the type of available reactive group on the molecule that will be coupled to the PEG. For proteins, typical reactive amino acids include lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, tyrosine. The N-terminal amino group and the C-terminal carboxylic acid can also be used.
The techniques used to form first generation PEG derivatives are generally reacting the PEG polymer with a group that is reactive with hydroxyl groups, typically anhydrides, acid chlorides, chloroformates and carbonates. In the second generation PEGylation chemistry more efficient functional groups such as aldehyde, esters, amides etc made available for conjugation.
As applications of PEGylation have become more and more advanced and sophisticated, there has been an increase in need for heterobifunctional PEGs for conjugation. These heterobifunctional PEGs are very much useful in linking two entities, where a hydrophilic, flexible and biocompatible spacer is needed. Preferred end groups for heterobifunctional PEGs are maleimide, vinyl sulphones, pyridyl disulphide, amine, carboxylic acids and NHS esters.
# Allergic Responses
In general the immune reaction to PEGylated products is no different than that of the underlying molecule that the agent is conjugated to. The risk of complement activation is correlated with the antigenicity of the moiety that is being PEGylated. Rarely patients who are repeatedly exposed to PEGylated proteins will develop anti-PEG antibodies (eg. PEG-Uricase or Krystexxa). The Hershfield laboratory at Duke University has experience in measuring anti-PEG antibody responses in humans. It is believed that the Epitope for anti-PEG IgG is the repeating unit of polyethylene glycol. The incidence of anti-PEG IgG in the population is unknown. The PEGylated Echo contrast agent Definity (echo contrast dye) is
associated with a risk of allergic reactions in 0.006% to 0.008% of patients. | PEGylation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
PEGylation is the process of covalent attachment of poly(ethylene glycol) polymer chains to another molecule, normally a drug or therapeutic protein. PEGylation is routinely achieved by incubation of a reactive derivative of PEG with the target macromolecule. The covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system (reduced immunogenicity and antigenicity), increase the hydrodynamic size (size in solution) of the agent which prolongs its circulatory time by reducing renal clearance. PEGylation can also provide water solubility to hydrophobic drugs and proteins.
# History
In 1970s, pioneering research by Davis, Abuchowski and colleagues foresaw the potential of the conjugation of Polyethylene glycol (PEG) to Proteins. This technique is now well established and is known as PEGylation.
PEGylation, is a process of attaching the strands of the polymer PEG to molecules most typically peptides, proteins, and antibody fragments, that can help to meet the challenges of improving the safety and efficiency of many therapeutics. It produces alterations in the physiochemical properties including changes in conformation, electrostatic binding, hydrophobicity etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns.
PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as:
• Improved drug solubility
• Reduced dosage frequency, without diminished efficacy with potentially reduced toxicity
• Extended circulating life
• Increased drug stability
• Enhanced protection from proteolytic degradation
The PEGylated drugs are having the following commercial advantages also:
• Opportunities for new delivery formats and dosing regimens
• Extended patent life of previously approved drugs
# PEGylated Pharmaceuticals on the Market
The clinical value of PEGylation is now well established. ADAGEN (PEG- bovine adenosine deaminase) manufactured by Enzon Pharmaceuticals, Inc., US was the first PEGylated protein approved by FDA in March 1990, to enter the market. It is used to treat X-linked severe combined immunogenicity syndrome, as an alternative to bone marrow transplantation and enzyme replacement by gene therapy. Since the introduction of ADAGEN, a large number of PEGylated protein and peptide pharmaceuticals have followed and many others are under clinical trial or under development stages. Some of the successful examples are:
• PEGASYS: PEGylated alpha-interferons for use in the treatment of hepatis C (Hoffman-La Roche)
• PEG-Intron: PEGylated alpha -interferons for chronic hepatis C (Schering-Plough / Enzon)
• Oncaspar: PEGylated L-asparaginase for the treatment of acute lymphoblastic leukemia in patients who are hypersensitive to the native unmodified form of L-asparaginase (Enzon)
• Neulasta: PEGylated recombinant methionyl human granulocyte colony stimulating factor for severe cancer chemotherapy induced neutropenia (Amgen)
• Doxil: PEGylated liposome containing doxorubicin for the treatment of Cancer (Sequus)
# PEG Moiety Properties
PEG is a particularly attractive polymer for conjugation. The specific characteristics of PEG moieties relevant to pharmaceutical applications are:
• Water solubility
• High mobility in solution
• Lack of toxicity and immunogenicity
• Ready clearance from the body
• Altered distribution in the body
# PEGylation Process
The first step of the PEGylation is the suitable functionalization of the PEG polymer at one or both terminals. PEGs that are activated at each terminus with the same reactive moiety is known as “homobifunctional”, where as if the functional groups present are different, then the PEG derivative is referred as “heterobifunctional” or “heterofunctional.” The chemically active or activated derivatives of the PEG polymer are prepared to attach the PEG to the desired molecule.
The choice of the suitable functional group for the PEG derivative is based on the type of available reactive group on the molecule that will be coupled to the PEG. For proteins, typical reactive amino acids include lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, tyrosine. The N-terminal amino group and the C-terminal carboxylic acid can also be used.
The techniques used to form first generation PEG derivatives are generally reacting the PEG polymer with a group that is reactive with hydroxyl groups, typically anhydrides, acid chlorides, chloroformates and carbonates. In the second generation PEGylation chemistry more efficient functional groups such as aldehyde, esters, amides etc made available for conjugation.
As applications of PEGylation have become more and more advanced and sophisticated, there has been an increase in need for heterobifunctional PEGs for conjugation. These heterobifunctional PEGs are very much useful in linking two entities, where a hydrophilic, flexible and biocompatible spacer is needed. Preferred end groups for heterobifunctional PEGs are maleimide, vinyl sulphones, pyridyl disulphide, amine, carboxylic acids and NHS esters.
# Allergic Responses
In general the immune reaction to PEGylated products is no different than that of the underlying molecule that the agent is conjugated to. The risk of complement activation is correlated with the antigenicity of the moiety that is being PEGylated. Rarely patients who are repeatedly exposed to PEGylated proteins will develop anti-PEG antibodies (eg. PEG-Uricase or Krystexxa). The Hershfield laboratory at Duke University has experience in measuring anti-PEG antibody responses in humans. It is believed that the Epitope for anti-PEG IgG is the repeating unit of polyethylene glycol. The incidence of anti-PEG IgG in the population is unknown. The PEGylated Echo contrast agent Definity (echo contrast dye) is
associated with a risk of allergic reactions in 0.006% to 0.008% of patients. | https://www.wikidoc.org/index.php/PEGylation | |
90e505de31ecaed3d60c3df4256f3ce15ef14493 | wikidoc | Peptide YY | Peptide YY
Peptide YY (PYY) also known as peptide tyrosine tyrosine is a peptide that in humans is encoded by the PYY gene. Peptide YY is a short (36-amino acid) peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; similarly, when injected directly into the central nervous system, PYY is also anorexigenic, i.e., it reduces appetite.
Dietary fibers from fruits, vegetables, and whole grains, consumed, increase the speed of transit of intestinal chyme into the ileum, to raise PYY3-36, and induce satiety. Peptide YY can be produced as the result of enzymatic breakdown of crude fish proteins and ingested as a food product.
# Structure
Peptide YY is related to the pancreatic peptide family by having 18 of its 36 amino acids located in the same positions as pancreatic peptide. The two major forms of peptide YY are PYY1-36 and PYY3-36, which have PP fold structural motifs. However, the most common form of circulating PYY immunoreactivity is PYY3-36, which binds to the Y2 receptor (Y2R) of the Y family of receptors. Peptide YY3-36 (PYY) is a linear polypeptide consisting of 34 amino acids with structural homology to NPY and pancreatic polypeptide.
# Release
PYY is found in L cells in the mucosa of gastrointestinal tract, especially in ileum and colon. Also, a small amount of PYY, about 1-10%, is found in the esophagus, stomach, duodenum and jejunum. PYY concentration in the circulation increases postprandially (after food ingestion) and decreases by fasting. In addition, PYY is produced by a discrete population of neurons in the brainstem, specifically localized to the gigantocellular reticular nucleus of the medulla oblongata. C. R. Gustavsen et al. had found PYY-producing cells located in the islets of Langerhans in rats. They were observed either alone or co-localized with glucagon or PP.
# Function
PYY exerts its action through NPY receptors; it inhibits gastric motility and increases water and electrolyte absorption in the colon. PYY may also suppress pancreatic secretion. It is secreted by the neuroendocrine cells in the ileum and colon in response to a meal, and has been shown to reduce appetite. PYY works by slowing the gastric emptying; hence, it increases efficiency of digestion and nutrient absorption after a meal. Research has also indicated PYY may be useful in removing aluminium accumulated in the brain.
# Animal studies
Several studies have shown acute peripheral administration of PYY3-36 inhibits feeding of rodents and primates. Other studies on Y2R-knockout mice have shown no anorectic effect on them. These findings indicate PYY3-36 has an anorectic (losing appetite) effect, which is suggested to be mediated by Y2R. PYY-knockout female mice increase in body weight and fat mass. PYY-knockout mice, on the other hand, are resistant to obesity, but have higher fat mass and lower glucose tolerance when fed a high-fat diet, compared to control mice. Thus, PYY also plays a very important role in energy homeostasis by balancing food intake. PYY oral spray was found to promote fullness. Viral gene therapy of the salivary glands resulted in long-term intake reduction.
# Relevance to obesity
Leptin also reduces appetite in response to feeding, but obese people develop a resistance to leptin. Obese people secrete less PYY than non-obese people, and attempts to use PYY directly as a weight-loss drug have met with some success. Researchers noted the caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30% in obese subjects (P<0.001) and 31% in lean subjects (P<0.001).
While some studies have shown obese persons have lower circulating level of PYY postprandially, other studies have reported they have normal sensitivity to the anorectic effect of PYY3-36. Thus, reduction in PYY sensitivity may not be one of the causes of obesity, in contrast to the reduction of leptin sensitivity. The anorectic effect of PYY could possibly be a future obesity drug.
The consumption of protein boosts PYY levels, so some benefit was observed in experimental subjects in reducing hunger and promoting weight loss. This could partially explain the weight-loss experienced with high-protein diets, but the high thermic effect of protein appears to be the leading cause.
Obese patients undergoing gastric bypass showed marked metabolic adaptations, resulting in frequent diabetes remission 1 year later. When the confounding of calorie restriction is factored out, β-cell function improves rapidly, very possibly under the influence of enhanced GLP-1 responsiveness. Insulin sensitivity improves in proportion to weight loss, with a possible involvement of PYY. | Peptide YY
Peptide YY (PYY) also known as peptide tyrosine tyrosine is a peptide that in humans is encoded by the PYY gene.[1] Peptide YY is a short (36-amino acid) peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; similarly, when injected directly into the central nervous system, PYY is also anorexigenic, i.e., it reduces appetite.[2]
Dietary fibers from fruits, vegetables, and whole grains, consumed, increase the speed of transit of intestinal chyme into the ileum, to raise PYY3-36, and induce satiety. Peptide YY can be produced as the result of enzymatic breakdown of crude fish proteins and ingested as a food product.[3]
# Structure
Peptide YY is related to the pancreatic peptide family by having 18 of its 36 amino acids located in the same positions as pancreatic peptide.[4] The two major forms of peptide YY are PYY1-36 and PYY3-36, which have PP fold structural motifs. However, the most common form of circulating PYY immunoreactivity is PYY3-36, which binds to the Y2 receptor (Y2R) of the Y family of receptors.[5] Peptide YY3-36 (PYY) is a linear polypeptide consisting of 34 amino acids with structural homology to NPY and pancreatic polypeptide.
# Release
PYY is found in L cells in the mucosa of gastrointestinal tract, especially in ileum and colon. Also, a small amount of PYY, about 1-10%, is found in the esophagus, stomach, duodenum and jejunum.[6] PYY concentration in the circulation increases postprandially (after food ingestion) and decreases by fasting.[5] In addition, PYY is produced by a discrete population of neurons in the brainstem, specifically localized to the gigantocellular reticular nucleus of the medulla oblongata.[7] C. R. Gustavsen et al. had found PYY-producing cells located in the islets of Langerhans in rats. They were observed either alone or co-localized with glucagon or PP.[8]
# Function
PYY exerts its action through NPY receptors; it inhibits gastric motility and increases water and electrolyte absorption in the colon.[9] PYY may also suppress pancreatic secretion. It is secreted by the neuroendocrine cells in the ileum and colon in response to a meal, and has been shown to reduce appetite. PYY works by slowing the gastric emptying; hence, it increases efficiency of digestion and nutrient absorption after a meal. Research has also indicated PYY may be useful in removing aluminium accumulated in the brain.[citation needed]
# Animal studies
Several studies have shown acute peripheral administration of PYY3-36 inhibits feeding of rodents and primates. Other studies on Y2R-knockout mice have shown no anorectic effect on them. These findings indicate PYY3-36 has an anorectic (losing appetite) effect, which is suggested to be mediated by Y2R. PYY-knockout female mice increase in body weight and fat mass. PYY-knockout mice, on the other hand, are resistant to obesity, but have higher fat mass and lower glucose tolerance when fed a high-fat diet, compared to control mice. Thus, PYY also plays a very important role in energy homeostasis by balancing food intake.[5] PYY oral spray was found to promote fullness.[10] Viral gene therapy of the salivary glands resulted in long-term intake reduction.[11]
# Relevance to obesity
Leptin also reduces appetite in response to feeding, but obese people develop a resistance to leptin. Obese people secrete less PYY than non-obese people,[12] and attempts to use PYY directly as a weight-loss drug have met with some success. Researchers noted the caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30% in obese subjects (P<0.001) and 31% in lean subjects (P<0.001).[13]
While some studies have shown obese persons have lower circulating level of PYY postprandially, other studies have reported they have normal sensitivity to the anorectic effect of PYY3-36. Thus, reduction in PYY sensitivity may not be one of the causes of obesity, in contrast to the reduction of leptin sensitivity. The anorectic effect of PYY could possibly be a future obesity drug.[5]
The consumption of protein boosts PYY levels, so some benefit was observed in experimental subjects in reducing hunger and promoting weight loss.[14] This could partially explain the weight-loss experienced with high-protein diets, but the high thermic effect of protein appears to be the leading cause.
Obese patients undergoing gastric bypass showed marked metabolic adaptations, resulting in frequent diabetes remission 1 year later. When the confounding of calorie restriction is factored out, β-cell function improves rapidly, very possibly under the influence of enhanced GLP-1 responsiveness. Insulin sensitivity improves in proportion to weight loss, with a possible involvement of PYY.[15] | https://www.wikidoc.org/index.php/PYY | |
295013772807e42a15c0dc824ee1d4f6fa8055bd | wikidoc | Pachygyria | Pachygyria
# Overview
Pachygyria (from the Greek "pachy" meaning "thick" or "fat" gyri) is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy.
# Pathogenesis
Pachygyria, lissencephaly (smooth brain), and polymicrogyria (multiple small gyri) are all the results of abnormal cell migration. The abnormal migration is typically associated with a disorganized cellular architecture, failure to form six layers of cortical neurons (a four-layer cortex is common), and functional problems. The abnormal formation of the brain may be associated with seizures, developmental delay, and mental dysfunctions.
Normally, the brain cells begin to develop in the periventricular region (germinal matrix) and then migrate from medial to lateral, to form the cerebral cortex.
# Clinical Presentation
The term 'pachygyria' does not directly relate to a specific malformation but rather is used to generally describe physical characteristics of the brain in association with several neuronal migration disorders; most commonly disorders relating to varied degrees of lissencephaly. Lissencephaly is present in 1 of 85,470 births and the life span of those affected is short as only a few survive past the age of 20.
Pachygyria is a condition identified by a type of cortical genetic malformation. Clinicians will subjectively determine the malformation based on the degree of malposition and the extent of thickened abnormal grey differentiation present.
# Diagnosis
Different imaging modalities are commonly used for diagnosis. Computed tomography (CT) is a lower-resolution imaging modality available, however, cerebral cortex malformations are more easily visualized in vivo and classified using high-resolution magnetic resonance imaging (MRI) equipment.
Diffuse pachygyria (a mild form of lissencephaly) can be seen on a MRI as thickened cerebral cortices with few and large gyri and incomplete development of the Sylvian fissures
# Signs/Symptoms
Malformations of the cerebral cortex can cause:
- Fetal lethality
- Major developmental disabilities
- Reproductive damage
- Severe epilepsy
- Reduced longevity
- Varying degrees of mental retardation
- Intractable epilepsy
- Spasticity
A patient’s cognitive ability ranges correlate to the thickness of any subcortical band present and the degree of pachygyria.
# Connections to Epilepsy, Lissencephaly, and Subcortical Band Heterotopia
Various degrees of intensity and locations of epilepsy are associated with malformations of cortical development. Researchers suggest that approximately 40% of children diagnosed with drug-resistant epilepsy have some degree of cortical malformation.
Lissencephaly (to which pachygyria is most closely linked) is associated with severe mental retardation, epilepsy, and motor disability. Two characteristics of lissencephaly include its absence of convolutions (agyria) and decreased presence of convolutions (pachygyria). The types of seizures associated with lissencephaly include:
- Persisting spasms
- Focal seizures
- Tonic seizures
- Atypical seizures
- Atonic seizures
Other possible symptoms of lissencephaly include telecanthus, estropia, hypertelorism, varying levels of mental retardation, cerebellar hypoplasia, corpus callosum aplasia, and decreased muscle tone and tendon reflexes. Over 90% of children affected with lissencephaly have seizures.
Patients with subcortical band heterotopia (another disorder associated with pachygyria) typically have milder symptoms and their cognitive function is closely linked to the thickness of the subcortical band and the degree of pachygyria present.
# Classifications
The degree of cerebral cortex malformation caused by genetic mutations is classified by the degree of malposition and the extent of faulty grey matter differentiation.
Neuronal migration disorders are generally classified into three groups:
- lissencephaly/subcortical band heterotopia
- cobblestone
- ‘other’ heterotopias
The ‘other’ types are associated with corpus callosum agenesis or cerebellar hypoplasia while the cobblestone lissencephalies are associated with eye and muscle disorders.
Classical lissencephaly, also known as type I or generalized agyria-pachygyria, is a severe brain malformation of a smooth cerebral surface, abnormally thick (10-20mm) cortex with four layers, widespread neuronal heterotopia, enlarged ventricles, and agenesis or malformation of the corpus callosum. Classical lissencephaly can range from agyria to regional pachygyria and is usually present along with subcortical band heterotopia (known as ‘double cortex’ to describe the circumferential bands of heterotopic neurons located beneath the cortex). Subcortical band heterotopia is a malformation slightly different from lissencephaly that is now classified under the agyria-pachygyria-band spectrum because it consists of a gyral pattern consistent with broad convolutions and an increased cortical thickness.
The established classification scheme for lissencephaly is based on the severity (grades 1-6) and the gradient.
- Grade 1: generalized agyria
- Grade 2: variable degree of agyria
- Grade 3: variable degree of pachygyria
- Grade 4: generalized pachygyria
- Grade 5: mixed pachygyria and subcortical band heterotopia
- Grade 6: subcortical band heterotopia alone
- Gradient ‘a’: from posterior to anterior gradient
- Gradient ‘b’: from anterior to posterior gradient
Grade 1 and Grade 4 are very rare. Grade 2 is observed in children with Miller-Dieker syndrome (a combination of lissencephaly with dysmorphic facial features, visceral abnormalities, and polydactyly). The most common lissencephaly observed, consisting of frontotemporal pachygyria and posterior agyria, is Grade 3.
Another malformation worth mentioning because of its connections to pachygyria is polymicrogyria. Polymicrogyria is characterized by many small gyri separated by shallow sulci, slightly thin cortex, neuronal heterotopia and enlarged ventricle and is often superimposed on pachygyria.
# Causes
Pachygyria is caused by a breakdown in the fetal neuronal migration process due to genetic or possibly environmental influences. The cerebral cortex will typically have only four developed layers.
One of the best known and most common types of neuronal migration disorders is lissencephaly (a diffuse cortical malformation relating directly to agyria and pachygyria). Incomplete neuronal migration during the early fetal brain development is the precursor to lissencephaly.
Should neurons follow an abnormal migration during development possible cortical malformations include classical lissencephaly (as stated above) and subcortical band heterotopia with an agyria-pachygyria band spectrum.
## Normal Neuronal Migration
Normal neuronal migration involves the development of six cortical layers, each one performing distinct functions.
Normal cerebral development occurs in three dynamic and overlapping stages:
- First stage: stem cells proliferate and differentiate into neurons or glial cells within the forebrain and the ventricular and subventricular zones lining the cerebral cavity
- In humans this stage lasts from gestational weeks 5-6 to 6-20
- Second stage: migration away from the origin in a radial fashion along the glial fibers from the periventricular region of the ganglionic eminences towards the pial surface
The generations settle into a pattern within the cortical plate during this stage
In humans this stage lasts from gestational weeks 6-7 to 20-24
- The generations settle into a pattern within the cortical plate during this stage
- In humans this stage lasts from gestational weeks 6-7 to 20-24
- Third stage: apoptosis and synaptogenesis within the six cortical layers to develop correct cortical organization
In humans this stage lasts from gestational week 16 until long after birth
- In humans this stage lasts from gestational week 16 until long after birth
Most types of incomplete neuronal migration to the cortex occur during the third and fourth gestational months. The abnormal migration of the neurons causes them to not reach their proper final destinations which results in failure of the sulci and gyri to form.
The stage of cortical development at which migration is arrested is directly related to the level of structural malposition.
One of the most critical stages in brain development is when the post-mitotic neurons migrate from the ventricular zone to form the cortical plate. Migration arrested toward the latter part of development usually restricts the abnormal cell position to the cortex level.
## Neuronal migration disorder caused by genetic mutations
Several genetic mutations have been isolated and linked to specific malformations of the cerebral cortex. Genes shown to cause lissencephaly include both autosomal and X-linked genes. Below, the mutations of LIS1 or DCX genes are discussed as they are most commonly linked to neuronal migration disorders including lissencephaly-pachygyria and subcortical band heterotopia.
## LIS1
LIS1 is responsible for the autosomal form of lissencephaly. Mutations of the LIS1 gene are associated with about 80% of those affected with lissencephaly.
LIS1 was the first human neuronal migration gene to be cloned. It is responsible for encoding the alpha subunit of the intracellular Ib isoform of platelet-activating factor acetylhydrolase. It is located on chromosome 17p13.3 and has 11 exons with a coding region of 1233bp. LIS1 protein appears to interact with tubulin to suppress microtubule dynamics. The protein is highly conserved and studies have shown that it participates in cytoplasmic dynein-mediated nucleokinesis, somal translocation, cell motility, mitosis, and chromosome segregation. LIS1 encodes for a 45kDa protein called PAFAH1B1 that contains seven WD40 repeats required for proper neuronal migration. The LIS1 gene encodes for a protein similar to the β subunit of G proteins responsible for degrading bioactive lipid platelet-activating factor (PAF). This leads to theories that LIS1 might exert its effect on migration through microtubules. Specific concentrations of PAF may be necessary for optimal neuronal migration by influencing cell morphology adhesion properties. Studies have shown that addition of PAF or inhibition of platelet-activating factor acetylhydrolase (PAF-AH) decreases cerebellar granule cell migration in vitro. Addition of PAF to hippocampal cells have shown growth cone collapse and neurite retraction. LIS1 knockout homozygous null mice die during embryogenesis and heterozygous mice survive with delayed neuronal migration confirmed by in vitro and in vivo cell migration assays.
Most lissencephaly cases are associated with deletions of mutations of the LIS1 gene and the results are usually more severe in the posterior brain regions.
One study showed that of an isolated group of patients with lissencephaly, 40% resulted from an LIS1 deletion and another 25% resulted from an intragenic mutation of the gene. Patients with missense mutations tend to have less severe symptoms, pachygyria, and rare cases of subcortical band heterotopia. Truncated (shortened) mutations of LIS1 tend to cause severe lissencephaly.
## Doublecortin
Doublecortin (DCX or XLIS) mutations are responsible for X-linked disorders. While LIS1 mutations tend to cause severe malformations in the posterior brain, DCX mutations focus much of their destruction on anterior malformations and are linked to lissencephaly in males and subcortical band heterotopias in females. Women with DCX mutations tend to have an anteriorly-predominant subcortical band heterotopia and pachygyria.
DCX was the first known gene causing X-linked lissencephaly and subcortical band heterotopia. It is found on chromosome Xq22.3-q23 and has nine exons that code for 360 proteins. DCX is expressed exclusively in the fetal brain.
# Treatment
Because pachygyria is a structural defect no treatments are currently available other than symptomatic treatments, especially for associated seizures. Another common treatment is a gastrostomy (insertion of a feeding tube) to reduce possible poor nutrition and repeated aspiration pneumonia.
# Case Studies
Scientists at the Sanjay Postgraduate Institute of Medical Sciences in India discovered a rare situation, four siblings with neuronal migration disorders, which they studied and compared to other known cases in the field highlighting the need for revision of the current lissencephaly classification scheme. No family history of mental retardation was reported and all four siblings were born to nonconsanguineous parents. The first child had developmental delays and two non-recurrent tonic convulsions as an infant. An MRI performed at age five showed generalized pachygyria with only a few broad gyri in the frontal and temporal lobes. The second child also had developmental delays and mild retardation, but more infantile seizures. Her MRI revealed pachygyria of the frontal and temporal lobes. The third and fourth child (one female and one male) did not have imaging performed but showed developmental similarities to their siblings. The authors hypothesize that autosomal recessive pattern of inheritance is the cause because all four children of different sexes have similar neuronal migration abnormalities and are from the same non-afflicted parents. After they thoroughly reviewed other studies the authors suggested a new classification involving frontotemporal pachygyria with a normal head circumference which can be broken into subgroups based on the involved lobes and neurological features.
A study dedicated to describing congenital fibrosis of extraocular muscles (a complex strabismus syndrome typically occurring in isolation and resulting from dysfunction of all of part of cranial nerves III and IV) in a group of four patients noted one 12 year old male patient with a history of asphyxia, microcephaly and psychomotor retardation whose craniocerebral CT scan revealed symmetrical expansion of the ventricular system with enlargement of the subarachnoid area as well as pachygyria.
Two of 29 patients called to a study involving hippocampal sclerosis, a neuronal loss associated with febrile convulsions, had evidence of pachygyria in their imaging results
Pachygyria has not previously been reported as associated with non-ketotic hyperglycinaemia but has been recognized as a radiological feature in children with Zellweger syndrome. This study focused on the second child born to non-consanguineous Caucasian parents. At two days old the child became lethargic, hypotonic and difficult to rouse. The child was incubated and ventilated at the hospital once hypoventilation was noticed. A septic screen and a cerebral CT scan were performed and the CT scan results were abnormal, showing poor grey-white differentiation and prominent cerebral spinal fluid spaces. While the child’s head circumference was relatively normal her anterior fontanelle was notably small. Her small pupils did constrict in response to light. She did not breathe above the ventilator rate and experienced occasional hiccoughs. Doctors were able to produce a flexor withdrawal to pain from the lower limbs. She had occasional myoclonic jerks but no overt seizure activity. The CT scan revealed pachygyria and partial agenesis of the corpus callosum. Thirty-six hours after the child’s death urine analysis was used to give a diagnosis of non-ketotic hyperglycinaemia. Her urine glycine level was grossly elevated and the CSF glycine was at least 100μmol/L. When compared to other studies, agenesis of the corpus callosum was seen in 6 of the 15 patients in literature findings of the same diagnosis. Gyral abnormalities were reported in 6 of the patients but were not described in detail. Biochemical syndromes previously described as associated with pachygyria, polymicrogyria, and heterotopia include glutaric aciduria type II, multiple peroxisomal oxidative deficiency, Zellweger syndrome, and now include non-ketotic hyperglycinaemia.
Microcephalic osteodysplastic primordial dwarfism (MOPD) type II is an autosomal multisystem disorder including severe pre- and post-natal growth retardation, microcephaly with Seckel syndrome-like facial appearance, and distinctive skeletal alterations. Usually those affect have mild to moderate mental retardation. This female child is the first born of nonconsanguineous parents at 35 weeks gestation through a cesarean section due to intrauterine growth retardation. She had a retarded psychomotor development and was repeatedly hospitalized during her first six months of life due to reoccurring respiratory infections. Her electroencephalography, auditory brainstem response evaluation, and chromosomal analysis were relatively normal. A brain MRI revealed thickened cerebral cortices with few and large gyri prominently in the frontal and posterior temporal regions, incomplete development of the Sylvian fissures, and dilatation of the posterior horns of the lateral ventricles (colpocephaly). Usually only mild brain malformations are associated with MOPD type II. The imaging findings of this child’s brain most likely represent diffuse pachygyria, a mild form of lissencephaly. This child’s neuro-developmental findings were mild when compared to previous reports of a well-defined chromosome 17-linked and X-linked lissencephaly in a bedridden patient with severe developmental delays. | Pachygyria
Template:DiseaseDisorder infobox
# Overview
Pachygyria (from the Greek "pachy" meaning "thick" or "fat" gyri) is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy.
# Pathogenesis
Pachygyria, lissencephaly (smooth brain), and polymicrogyria (multiple small gyri) are all the results of abnormal cell migration. The abnormal migration is typically associated with a disorganized cellular architecture, failure to form six layers of cortical neurons (a four-layer cortex is common), and functional problems. The abnormal formation of the brain may be associated with seizures, developmental delay, and mental dysfunctions.
Normally, the brain cells begin to develop in the periventricular region (germinal matrix) and then migrate from medial to lateral, to form the cerebral cortex.
# Clinical Presentation
The term 'pachygyria' does not directly relate to a specific malformation but rather is used to generally describe physical characteristics of the brain in association with several neuronal migration disorders; most commonly disorders relating to varied degrees of lissencephaly. Lissencephaly is present in 1 of 85,470 births and the life span of those affected is short as only a few survive past the age of 20. [1]
Pachygyria is a condition identified by a type of cortical genetic malformation. Clinicians will subjectively determine the malformation based on the degree of malposition and the extent of thickened abnormal grey differentiation present. [2]
# Diagnosis
Different imaging modalities are commonly used for diagnosis. Computed tomography (CT) is a lower-resolution imaging modality available, however, cerebral cortex malformations are more easily visualized in vivo and classified using high-resolution magnetic resonance imaging (MRI) equipment. [3]
Diffuse pachygyria (a mild form of lissencephaly) can be seen on a MRI as thickened cerebral cortices with few and large gyri and incomplete development of the Sylvian fissures [4]
# Signs/Symptoms
Malformations of the cerebral cortex can cause:
- Fetal lethality
- Major developmental disabilities
- Reproductive damage
- Severe epilepsy [3]
- Reduced longevity
- Varying degrees of mental retardation
- Intractable epilepsy
- Spasticity [5]
A patient’s cognitive ability ranges correlate to the thickness of any subcortical band present and the degree of pachygyria. [1][5]
# Connections to Epilepsy, Lissencephaly, and Subcortical Band Heterotopia
Various degrees of intensity and locations of epilepsy are associated with malformations of cortical development. Researchers suggest that approximately 40% of children diagnosed with drug-resistant epilepsy have some degree of cortical malformation.[1][2]
Lissencephaly (to which pachygyria is most closely linked) is associated with severe mental retardation, epilepsy, and motor disability. Two characteristics of lissencephaly include its absence of convolutions (agyria) and decreased presence of convolutions (pachygyria). [2] The types of seizures associated with lissencephaly include:
- Persisting spasms
- Focal seizures
- Tonic seizures
- Atypical seizures
- Atonic seizures [1]
Other possible symptoms of lissencephaly include telecanthus, estropia, hypertelorism, varying levels of mental retardation, cerebellar hypoplasia, corpus callosum aplasia, and decreased muscle tone and tendon reflexes. [4] Over 90% of children affected with lissencephaly have seizures. [2]
Patients with subcortical band heterotopia (another disorder associated with pachygyria) typically have milder symptoms and their cognitive function is closely linked to the thickness of the subcortical band and the degree of pachygyria present. [2]
# Classifications
The degree of cerebral cortex malformation caused by genetic mutations is classified by the degree of malposition and the extent of faulty grey matter differentiation. [1]
Neuronal migration disorders are generally classified into three groups:
- lissencephaly/subcortical band heterotopia
- cobblestone
- ‘other’ heterotopias [4]
The ‘other’ types are associated with corpus callosum agenesis or cerebellar hypoplasia while the cobblestone lissencephalies are associated with eye and muscle disorders. [4]
Classical lissencephaly, also known as type I or generalized agyria-pachygyria, is a severe brain malformation of a smooth cerebral surface, abnormally thick (10-20mm) cortex with four layers, widespread neuronal heterotopia, enlarged ventricles, and agenesis or malformation of the corpus callosum. [6][7] Classical lissencephaly can range from agyria to regional pachygyria and is usually present along with subcortical band heterotopia (known as ‘double cortex’ to describe the circumferential bands of heterotopic neurons located beneath the cortex). [7] Subcortical band heterotopia is a malformation slightly different from lissencephaly that is now classified under the agyria-pachygyria-band spectrum because it consists of a gyral pattern consistent with broad convolutions and an increased cortical thickness. [1]
The established classification scheme for lissencephaly is based on the severity (grades 1-6) and the gradient. [5]
- Grade 1: generalized agyria
- Grade 2: variable degree of agyria
- Grade 3: variable degree of pachygyria
- Grade 4: generalized pachygyria
- Grade 5: mixed pachygyria and subcortical band heterotopia
- Grade 6: subcortical band heterotopia alone
- Gradient ‘a’: from posterior to anterior gradient
- Gradient ‘b’: from anterior to posterior gradient [5]
Grade 1 and Grade 4 are very rare. Grade 2 is observed in children with Miller-Dieker syndrome (a combination of lissencephaly with dysmorphic facial features, visceral abnormalities, and polydactyly). The most common lissencephaly observed, consisting of frontotemporal pachygyria and posterior agyria, is Grade 3. [6]
Another malformation worth mentioning because of its connections to pachygyria is polymicrogyria. Polymicrogyria is characterized by many small gyri separated by shallow sulci, slightly thin cortex, neuronal heterotopia and enlarged ventricle and is often superimposed on pachygyria. [6]
# Causes
Pachygyria is caused by a breakdown in the fetal neuronal migration process due to genetic or possibly environmental influences. The cerebral cortex will typically have only four developed layers.
One of the best known and most common types of neuronal migration disorders is lissencephaly (a diffuse cortical malformation relating directly to agyria and pachygyria). [6] Incomplete neuronal migration during the early fetal brain development is the precursor to lissencephaly. [5]
Should neurons follow an abnormal migration during development possible cortical malformations include classical lissencephaly (as stated above) and subcortical band heterotopia with an agyria-pachygyria band spectrum. [2]
## Normal Neuronal Migration
Normal neuronal migration involves the development of six cortical layers, each one performing distinct functions. [2]
Normal cerebral development occurs in three dynamic and overlapping stages:
- First stage: stem cells proliferate and differentiate into neurons or glial cells within the forebrain and the ventricular and subventricular zones lining the cerebral cavity
- In humans this stage lasts from gestational weeks 5-6 to 6-20
- Second stage: migration away from the origin in a radial fashion along the glial fibers from the periventricular region of the ganglionic eminences towards the pial surface
The generations settle into a pattern within the cortical plate during this stage
In humans this stage lasts from gestational weeks 6-7 to 20-24
- The generations settle into a pattern within the cortical plate during this stage
- In humans this stage lasts from gestational weeks 6-7 to 20-24
- Third stage: apoptosis and synaptogenesis within the six cortical layers to develop correct cortical organization
In humans this stage lasts from gestational week 16 until long after birth [2]
- In humans this stage lasts from gestational week 16 until long after birth [2]
Most types of incomplete neuronal migration to the cortex occur during the third and fourth gestational months. [6] The abnormal migration of the neurons causes them to not reach their proper final destinations which results in failure of the sulci and gyri to form. [2]
The stage of cortical development at which migration is arrested is directly related to the level of structural malposition. [1]
One of the most critical stages in brain development is when the post-mitotic neurons migrate from the ventricular zone to form the cortical plate. [7] Migration arrested toward the latter part of development usually restricts the abnormal cell position to the cortex level. [1]
## Neuronal migration disorder caused by genetic mutations
Several genetic mutations have been isolated and linked to specific malformations of the cerebral cortex. [1] Genes shown to cause lissencephaly include both autosomal and X-linked genes. [4] Below, the mutations of LIS1 or DCX genes are discussed as they are most commonly linked to neuronal migration disorders including lissencephaly-pachygyria and subcortical band heterotopia. [2]
## LIS1
LIS1 is responsible for the autosomal form of lissencephaly. [2] Mutations of the LIS1 gene are associated with about 80% of those affected with lissencephaly. [5]
LIS1 was the first human neuronal migration gene to be cloned. It is responsible for encoding the alpha subunit of the intracellular Ib isoform of platelet-activating factor acetylhydrolase. It is located on chromosome 17p13.3 and has 11 exons with a coding region of 1233bp. LIS1 protein appears to interact with tubulin to suppress microtubule dynamics. The protein is highly conserved and studies have shown that it participates in cytoplasmic dynein-mediated nucleokinesis, somal translocation, cell motility, mitosis, and chromosome segregation. [7] LIS1 encodes for a 45kDa protein called PAFAH1B1 that contains seven WD40 repeats required for proper neuronal migration. [5] The LIS1 gene encodes for a protein similar to the β subunit of G proteins responsible for degrading bioactive lipid platelet-activating factor (PAF). [2] This leads to theories that LIS1 might exert its effect on migration through microtubules. Specific concentrations of PAF may be necessary for optimal neuronal migration by influencing cell morphology adhesion properties. Studies have shown that addition of PAF or inhibition of platelet-activating factor acetylhydrolase (PAF-AH) decreases cerebellar granule cell migration in vitro. Addition of PAF to hippocampal cells have shown growth cone collapse and neurite retraction. LIS1 knockout homozygous null mice die during embryogenesis and heterozygous mice survive with delayed neuronal migration confirmed by in vitro and in vivo cell migration assays. [5]
Most lissencephaly cases are associated with deletions of mutations of the LIS1 gene and the results are usually more severe in the posterior brain regions. [2]
One study showed that of an isolated group of patients with lissencephaly, 40% resulted from an LIS1 deletion and another 25% resulted from an intragenic mutation of the gene. Patients with missense mutations tend to have less severe symptoms, pachygyria, and rare cases of subcortical band heterotopia. Truncated (shortened) mutations of LIS1 tend to cause severe lissencephaly. [2]
## Doublecortin
Doublecortin (DCX or XLIS) mutations are responsible for X-linked disorders. [2] While LIS1 mutations tend to cause severe malformations in the posterior brain, DCX mutations focus much of their destruction on anterior malformations and are linked to lissencephaly in males and subcortical band heterotopias in females. [5][2] Women with DCX mutations tend to have an anteriorly-predominant subcortical band heterotopia and pachygyria. [1]
[2] DCX was the first known gene causing X-linked lissencephaly and subcortical band heterotopia. It is found on chromosome Xq22.3-q23 and has nine exons that code for 360 proteins. DCX is expressed exclusively in the fetal brain. [7]
# Treatment
Because pachygyria is a structural defect no treatments are currently available other than symptomatic treatments, especially for associated seizures. Another common treatment is a gastrostomy (insertion of a feeding tube) to reduce possible poor nutrition and repeated aspiration pneumonia. [6]
# Case Studies
Scientists at the Sanjay Postgraduate Institute of Medical Sciences in India discovered a rare situation, four siblings with neuronal migration disorders, which they studied and compared to other known cases in the field highlighting the need for revision of the current lissencephaly classification scheme. No family history of mental retardation was reported and all four siblings were born to nonconsanguineous parents. The first child had developmental delays and two non-recurrent tonic convulsions as an infant. An MRI performed at age five showed generalized pachygyria with only a few broad gyri in the frontal and temporal lobes. The second child also had developmental delays and mild retardation, but more infantile seizures. Her MRI revealed pachygyria of the frontal and temporal lobes. The third and fourth child (one female and one male) did not have imaging performed but showed developmental similarities to their siblings. The authors hypothesize that autosomal recessive pattern of inheritance is the cause because all four children of different sexes have similar neuronal migration abnormalities and are from the same non-afflicted parents. After they thoroughly reviewed other studies the authors suggested a new classification involving frontotemporal pachygyria with a normal head circumference which can be broken into subgroups based on the involved lobes and neurological features. [4]
A study dedicated to describing congenital fibrosis of extraocular muscles (a complex strabismus syndrome typically occurring in isolation and resulting from dysfunction of all of part of cranial nerves III and IV) in a group of four patients noted one 12 year old male patient with a history of asphyxia, microcephaly and psychomotor retardation whose craniocerebral CT scan revealed symmetrical expansion of the ventricular system with enlargement of the subarachnoid area as well as pachygyria. [3]
Two of 29 patients called to a study involving hippocampal sclerosis, a neuronal loss associated with febrile convulsions, had evidence of pachygyria in their imaging results [8]
Pachygyria has not previously been reported as associated with non-ketotic hyperglycinaemia but has been recognized as a radiological feature in children with Zellweger syndrome. This study focused on the second child born to non-consanguineous Caucasian parents. At two days old the child became lethargic, hypotonic and difficult to rouse. The child was incubated and ventilated at the hospital once hypoventilation was noticed. A septic screen and a cerebral CT scan were performed and the CT scan results were abnormal, showing poor grey-white differentiation and prominent cerebral spinal fluid spaces. While the child’s head circumference was relatively normal her anterior fontanelle was notably small. Her small pupils did constrict in response to light. She did not breathe above the ventilator rate and experienced occasional hiccoughs. Doctors were able to produce a flexor withdrawal to pain from the lower limbs. She had occasional myoclonic jerks but no overt seizure activity. The CT scan revealed pachygyria and partial agenesis of the corpus callosum. Thirty-six hours after the child’s death urine analysis was used to give a diagnosis of non-ketotic hyperglycinaemia. Her urine glycine level was grossly elevated and the CSF glycine was at least 100μmol/L. When compared to other studies, agenesis of the corpus callosum was seen in 6 of the 15 patients in literature findings of the same diagnosis. Gyral abnormalities were reported in 6 of the patients but were not described in detail. Biochemical syndromes previously described as associated with pachygyria, polymicrogyria, and heterotopia include glutaric aciduria type II, multiple peroxisomal oxidative deficiency, Zellweger syndrome, and now include non-ketotic hyperglycinaemia. [9]
Microcephalic osteodysplastic primordial dwarfism (MOPD) type II is an autosomal multisystem disorder including severe pre- and post-natal growth retardation, microcephaly with Seckel syndrome-like facial appearance, and distinctive skeletal alterations. Usually those affect have mild to moderate mental retardation. This female child is the first born of nonconsanguineous parents at 35 weeks gestation through a cesarean section due to intrauterine growth retardation. She had a retarded psychomotor development and was repeatedly hospitalized during her first six months of life due to reoccurring respiratory infections. Her electroencephalography, auditory brainstem response evaluation, and chromosomal analysis were relatively normal. A brain MRI revealed thickened cerebral cortices with few and large gyri prominently in the frontal and posterior temporal regions, incomplete development of the Sylvian fissures, and dilatation of the posterior horns of the lateral ventricles (colpocephaly). Usually only mild brain malformations are associated with MOPD type II. The imaging findings of this child’s brain most likely represent diffuse pachygyria, a mild form of lissencephaly. This child’s neuro-developmental findings were mild when compared to previous reports of a well-defined chromosome 17-linked and X-linked lissencephaly in a bedridden patient with severe developmental delays. [10] | https://www.wikidoc.org/index.php/Pachygyria | |
b7d2f53738ca30571029f9d4333827d9e0aa7f56 | wikidoc | Pediatrics | Pediatrics
# Overview
Pediatrics (also spelt paediatrics) is the branch of medicine that deals with the medical care of infants, children, and adolescents. The upper age limit ranges from age 14 to 21, depending on the country.
A medical practitioner who specializes in this area is thus known as a pediatrician (also spelt paediatrician); They may be either a DO (Doctor of Osteopathy) or MD (medical doctor).
The word pediatrics and its cognates mean healer of children; they derive from two Greek words: παῖς (pais = child) and ιατρός (iatros = doctor or healer).
# Differences between adult and pediatric medicine
Pediatrics differs from adult medicine in many respects. The obvious body size differences are paralleled by maturational changes. The smaller body of an infant or neonate is substantially different physiologically from that of an adult. Congenital defects, genetic variance, and a host of other issues are of greater concern to pediatricians than they often are to adult physicians.
Some diseases, such as sickle cell anemia and cystic fibrosis are more often treated by pediatricians because only recently did the majority of these patients survive into adulthood. Issues revolving around infectious diseases and immunizations are also dealt with primarily by pediatricians. Put simply, treating a child is not like treating a miniature adult.
Childhood is the period of greatest growth, development and maturation of the various organ systems in the body. Years of training and experience (above and beyond basic medical training) goes into recognizing the difference between normal variants and what is actually pathological.
Another major difference between pediatrics and adult medicine is that children are minors and, in most jurisdictions, cannot make decisions for themselves. The issues of guardianship, privacy, legal responsibility and informed consent must always be considered in every pediatric procedure. In a sense, pediatricians often have to treat the parents and sometimes, the family, rather than just the child. Adolescents are in their own legal class, having rights to their own health care decisions in certain circumstances only, though this is in legal flux and varies by region.
# History of pediatrics
In the 10th century, the famous Persian physician Rhazes (Muhammad ibn Zakarīya Rāzi) wrote The Diseases of Children, the first book to deal with pediatrics as an independent field of medicine. For this reason, some medical historians consider him the father of pediatrics. His teacher Ali ibn Sahl Rabban al-Tabari was also a pioneer in the field of child development, which he earlier discussed in his Firdous al-Hikmah. The first work on pediatrics in the Western world was the Book of Children, written circa 1530 by Thomas Phaer, who was inspired by the works of Rhazes and Avicenna.
Pediatrics as a separate area of medical practice in the Western world largely began in the nineteenth century. The Hospital for Sick Children, Great Ormond Street (London) was founded in 1852, and is probably the oldest such children's hospital in the English-speaking world. Great Ormond Street is adjacent to Coram's Fields, the site of the much earlier Foundling Hospital. The emigrant German physician, Abraham Jacobi, worked in the same period and is often considered the father of American pediatrics.
# Training of pediatricians
The training of pediatricians varies considerably across the world.
Like other physicians, pediatricians begin their training with an entry-level medical education: a tertiary-level course, undertaken at a medical school attached to a university. Depending on jurisdiction and university, this course may be either undergraduate-entry or graduate-entry. The former commonly takes five or six years. Entrants to graduate-entry courses, usually lasting four or five years, have previously completed a three- or four-year university degree, commonly but by no means always in sciences. Medical graduates hold a degree specific to the country and university in and from which they graduated. This degree qualifies that medical practitioner to become licensed or registered under the laws of that particular country, and sometimes of several countries, subject to requirements for "internship" or "conditional registration".
Pediatricians must undertake further training in their chosen field. This may take from three to six or more years, depending on jurisdiction and the degree of specialization. The training for a primary care physician, including primary care pediatricians, is generally not as lengthy as for a hospital-based medical specialist.
In most jurisdictions, entry-level degrees are common to all branches of the medical profession, but in some jurisdictions, specialization in pediatrics may begin before completion of this degree. In some jurisdictions, pediatric training is begun immediately following completion of entry-level training. In other jurisdictions, junior medical doctors must undertake generalist (unstreamed) training for a number of years before commencing pediatric (or any other) specialization. Specialist training is often largely under the control of pediatric organizations (see below) rather than universities, with varying degrees of government input, depending on jurisdiction.
# "Pediatrician" versus "Paediatrician"
There is a slight semantic difference associated with the difference in spelling. In the USA, a pediatrician (US spelling) is commonly a primary care physician, or general practitioner, who specializes in children. A similar situation exists in Germany: a kinderarzt is commonly a primary care pediatrician.
In the Commonwealth and in much of the rest of the world, a paediatrician (British spelling) is normally a specialist physician not in primary general practice: he or she sees patients who are either urgently admitted to a hospital or who are referred by general practitioners. A paediatrician in this sense could fairly be described as an internist who has subspecialized in infants & children, and usually had longer post-graduate training in child health than a primary care pediatrician.
# Subspecialists in pediatrics
Specialist pediatricians may undergo further training in sub-specialties. Practising a subspecialty in pediatrics is similar in some respects to practising the relevant adult specialty, but a major difference is in the pattern of disease. Typically, diseases commonly seen in children are rare in adults (eg bronchiolitis, rotavirus infection), and those seen in adults are rare in children (eg coronary artery disease, deep vein thrombosis). Hence, pediatric cardiologists deal with the heart conditions of children, particularly congenital heart defects, and pediatric oncologists most often treat types of cancer that are relatively common in children (eg certain leukemias, lymphomas and sarcomas), but which are rarely seen in adults. Every subspecialty of adult medicine exists in pediatrics (with the obvious exception of geriatrics).
Adolescent medicine is a growing sub-specialty. The pattern of diseases in adolescents in part resembles that seen in older adults, and specialists or sub-specialists in adolescent medicine are also drawn from practitioners of internal medicine or family medicine. Another major sub-specialty, which is unique to pediatrics, is neonatology: the medical care of newborn babies.
# Pediatric organizations
Most pediatricians are members of a national body. Examples are the American Academy of Pediatrics, the Canadian Paediatric Society, the Royal College Of Paediatrics and Child Health, Norsk barnelegeforening (The Norwegian society of pediatricians) or the Indian Academy of Pediatrics. In Australia and New Zealand, paediatricians are fellows of the Royal Australasian College of Physicians, which covers both nations and which has adult & paediatric sections. This was the situation in the UK until the late 1990s, where specialist paediatricians were Members or Fellows of either the Royal College of Physicians or of the fraternal colleges in Scotland. In 1996, British paediatricians were granted a royal charter to form their own college, the Royal College of Paediatrics and Child Health.
# Social role of pediatricians
Like other physicians, pediatricians are traditionally considered to be members of a learned profession, because of the extensive training requirements, and also because of the occupation's special ethical and legal duties.
Pediatricians commonly enjoy high social status, often combined with expectations of a high and stable income and job security. However, medical practitioners in general often work long and inflexible hours, with shifts at unsociable times, and may earn less than other professionals whose education is of comparable length. Neonatologists or general pediatricians in hospital practice are often on call at unsociable times for perinatal problems in particular — such as for Caesarean section or other high risk births, and for the care of ill newborn infants.
The U.S. Bureau of Labor Statistics estimates that general pediatricians earned an average of $141,440 in 2006. | Pediatrics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Otheruses4
# Overview
Pediatrics (also spelt paediatrics) is the branch of medicine that deals with the medical care of infants, children, and adolescents. The upper age limit ranges from age 14 to 21, depending on the country.
A medical practitioner who specializes in this area is thus known as a pediatrician (also spelt paediatrician); They may be either a DO (Doctor of Osteopathy) or MD (medical doctor).
The word pediatrics and its cognates mean healer of children; they derive from two Greek words: παῖς (pais = child) and ιατρός (iatros = doctor or healer).
# Differences between adult and pediatric medicine
Pediatrics differs from adult medicine in many respects. The obvious body size differences are paralleled by maturational changes. The smaller body of an infant or neonate is substantially different physiologically from that of an adult. Congenital defects, genetic variance, and a host of other issues are of greater concern to pediatricians than they often are to adult physicians.
Some diseases, such as sickle cell anemia and cystic fibrosis are more often treated by pediatricians because only recently did the majority of these patients survive into adulthood. Issues revolving around infectious diseases and immunizations are also dealt with primarily by pediatricians. Put simply, treating a child is not like treating a miniature adult.
Childhood is the period of greatest growth, development and maturation of the various organ systems in the body. Years of training and experience (above and beyond basic medical training) goes into recognizing the difference between normal variants and what is actually pathological.
Another major difference between pediatrics and adult medicine is that children are minors and, in most jurisdictions, cannot make decisions for themselves. The issues of guardianship, privacy, legal responsibility and informed consent must always be considered in every pediatric procedure. In a sense, pediatricians often have to treat the parents and sometimes, the family, rather than just the child. Adolescents are in their own legal class, having rights to their own health care decisions in certain circumstances only, though this is in legal flux and varies by region.
# History of pediatrics
In the 10th century, the famous Persian physician Rhazes (Muhammad ibn Zakarīya Rāzi) wrote The Diseases of Children, the first book to deal with pediatrics as an independent field of medicine. For this reason, some medical historians consider him the father of pediatrics.[1] His teacher Ali ibn Sahl Rabban al-Tabari was also a pioneer in the field of child development, which he earlier discussed in his Firdous al-Hikmah.[2] The first work on pediatrics in the Western world was the Book of Children, written circa 1530 by Thomas Phaer, who was inspired by the works of Rhazes and Avicenna.[3]
Pediatrics as a separate area of medical practice in the Western world largely began in the nineteenth century. The Hospital for Sick Children, Great Ormond Street (London) was founded in 1852, and is probably the oldest such children's hospital in the English-speaking world. Great Ormond Street is adjacent to Coram's Fields, the site of the much earlier Foundling Hospital. The emigrant German physician, Abraham Jacobi, worked in the same period and is often considered the father of American pediatrics.
# Training of pediatricians
The training of pediatricians varies considerably across the world.
Like other physicians, pediatricians begin their training with an entry-level medical education: a tertiary-level course, undertaken at a medical school attached to a university. Depending on jurisdiction and university, this course may be either undergraduate-entry or graduate-entry. The former commonly takes five or six years. Entrants to graduate-entry courses, usually lasting four or five years, have previously completed a three- or four-year university degree, commonly but by no means always in sciences. Medical graduates hold a degree specific to the country and university in and from which they graduated. This degree qualifies that medical practitioner to become licensed or registered under the laws of that particular country, and sometimes of several countries, subject to requirements for "internship" or "conditional registration".
Pediatricians must undertake further training in their chosen field. This may take from three to six or more years, depending on jurisdiction and the degree of specialization. The training for a primary care physician, including primary care pediatricians, is generally not as lengthy as for a hospital-based medical specialist.
In most jurisdictions, entry-level degrees are common to all branches of the medical profession, but in some jurisdictions, specialization in pediatrics may begin before completion of this degree. In some jurisdictions, pediatric training is begun immediately following completion of entry-level training. In other jurisdictions, junior medical doctors must undertake generalist (unstreamed) training for a number of years before commencing pediatric (or any other) specialization. Specialist training is often largely under the control of pediatric organizations (see below) rather than universities, with varying degrees of government input, depending on jurisdiction.
# "Pediatrician" versus "Paediatrician"
There is a slight semantic difference associated with the difference in spelling. In the USA, a pediatrician (US spelling) is commonly a primary care physician, or general practitioner, who specializes in children. A similar situation exists in Germany: a kinderarzt is commonly a primary care pediatrician.
In the Commonwealth and in much of the rest of the world, a paediatrician (British spelling) is normally a specialist physician not in primary general practice: he or she sees patients who are either urgently admitted to a hospital or who are referred by general practitioners. A paediatrician in this sense could fairly be described as an internist who has subspecialized in infants & children, and usually had longer post-graduate training in child health than a primary care pediatrician.
# Subspecialists in pediatrics
Specialist pediatricians may undergo further training in sub-specialties. Practising a subspecialty in pediatrics is similar in some respects to practising the relevant adult specialty, but a major difference is in the pattern of disease. Typically, diseases commonly seen in children are rare in adults (eg bronchiolitis, rotavirus infection), and those seen in adults are rare in children (eg coronary artery disease, deep vein thrombosis). Hence, pediatric cardiologists deal with the heart conditions of children, particularly congenital heart defects, and pediatric oncologists most often treat types of cancer that are relatively common in children (eg certain leukemias, lymphomas and sarcomas), but which are rarely seen in adults. Every subspecialty of adult medicine exists in pediatrics (with the obvious exception of geriatrics).
Adolescent medicine is a growing sub-specialty. The pattern of diseases in adolescents in part resembles that seen in older adults, and specialists or sub-specialists in adolescent medicine are also drawn from practitioners of internal medicine or family medicine. Another major sub-specialty, which is unique to pediatrics, is neonatology: the medical care of newborn babies.
# Pediatric organizations
Most pediatricians are members of a national body. Examples are the American Academy of Pediatrics, the Canadian Paediatric Society, the Royal College Of Paediatrics and Child Health, Norsk barnelegeforening (The Norwegian society of pediatricians) or the Indian Academy of Pediatrics. In Australia and New Zealand, paediatricians are fellows of the Royal Australasian College of Physicians, which covers both nations and which has adult & paediatric sections. This was the situation in the UK until the late 1990s, where specialist paediatricians were Members or Fellows of either the Royal College of Physicians or of the fraternal colleges in Scotland. In 1996, British paediatricians were granted a royal charter to form their own college, the Royal College of Paediatrics and Child Health.
# Social role of pediatricians
Like other physicians, pediatricians are traditionally considered to be members of a learned profession, because of the extensive training requirements, and also because of the occupation's special ethical and legal duties.
Pediatricians commonly enjoy high social status, often combined with expectations of a high and stable income and job security. However, medical practitioners in general often work long and inflexible hours, with shifts at unsociable times, and may earn less than other professionals whose education is of comparable length. Neonatologists or general pediatricians in hospital practice are often on call at unsociable times for perinatal problems in particular — such as for Caesarean section or other high risk births, and for the care of ill newborn infants.
The U.S. Bureau of Labor Statistics estimates that general pediatricians earned an average of $141,440 in 2006. | https://www.wikidoc.org/index.php/Paediatric | |
b37fb1c9320b00b58f53d562ec9e013ed2fe3cbe | wikidoc | Pagophagia | Pagophagia
Pagophagia is the compulsive consumption of ice.
It has been shown to respond to iron supplementation, leading some investigators to postulate that pica is the result, not the cause, of nutritional deficiency (specifically, deficiencies of iron, zinc, magnesium, and phosphorus).
Folk wisdom (and some early investigators) maintained that pica reflected an appetite to compensate for some problem. Ice probably helps relieve some of the symptoms of low iron, including inflammation of the tongue and stomach.
Later research, however, has demonstrated no evidence that the substances ingested provide any nutrient or mineral in which patients are deficient. | Pagophagia
Pagophagia is the compulsive consumption of ice.
It has been shown to respond to iron supplementation, leading some investigators to postulate that pica is the result, not the cause, of nutritional deficiency (specifically, deficiencies of iron, zinc, magnesium, and phosphorus).
Folk wisdom (and some early investigators) maintained that pica reflected an appetite to compensate for some problem. Ice probably helps relieve some of the symptoms of low iron, including inflammation of the tongue and stomach.
Later research, however, has demonstrated no evidence that the substances ingested provide any nutrient or mineral in which patients are deficient.
Template:Disease-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Pagophagia | |
1db6b12ec00d0b27935a9af806cdfee6434705d0 | wikidoc | Palifermin | Palifermin
# 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
Palifermin is a mucocutaneous epithelial human growth factor that is FDA approved for the treatment of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Common adverse reactions include rash, fever, elevated serum amylase (Grade 3/4), pruritus, erythema, and edema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Kepivance is 60 mcg/kg/day, administered as an intravenous bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy, for a total of 6 doses.
- Administer the first 3 doses prior to myelotoxic therapy. Administer the third dose 24 to 48 hours prior to beginning myelotoxic therapy.
- Administer the last 3 doses after myelotoxic therapy is complete; Administer the first of these doses on the day of hematopoietic stem cell infusion after the infusion is completed, and more than 4 days after the most recent administration of Kepivance.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Palifermin in adult patients.
### Non–Guideline-Supported Use
- Palifermin 40 mcg/kg/day by intravenous bolus on days 1 to 3.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Palifermin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Palifermin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Palifermin in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Potential for Stimulation of Tumor Growth
- The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies. The effects of Kepivance on stimulation of KGF receptor-expressing, non-hematopoietic tumors in patients are not known. Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell line growth in a human carcinoma xenograft model.
# 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 data described in Table 1 and the discussion below reflect exposure to Kepivance in 409 patients with hematologic malignancies who were enrolled in 3 randomized, placebo-controlled clinical trials and a pharmacokinetic study. Patients received Kepivance either before, or before and after, regimens of myelotoxic chemotherapy, with or without total body irradiation (TBI), followed by hematopoietic stem cell support. Kepivance was administered in daily doses ranging from 5 to 80 mcg/kg/day. The total dose of Kepivance ranged from 15 to 480 mcg/kg with a median of 360 mcg/kg. The population had a median age of 48 years (range: 41 to 60 years), 62% were male and 83% were White with 7.4 % Black and 6.2 % Hispanic. Non Hodgkin's lymphoma (NHL) was the most common malignancy followed by Hodgkin's disease, multiple myeloma, and leukemia.
- The most common serious adverse reaction attributed to Kepivance was skin rash, reported in less than 1% (3/409) of patients treated. Grade 3 skin rashes occurred in 3% of patients (9/409) receiving Kepivance and 2% (5/241) receiving placebo.
- Cataracts: In a postmarketing safety study, the incidence of cataracts was numerically higher among patients receiving Kepivance than in the control population.
- Laboratory Test Findings: Reversible elevations in serum lipase and amylase, which did not require treatment, were reported in 28% and 62% of patients receiving Kepivance and 23% and 54%of patients receiving placebo. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of hematopoietic stem cell infusion. Amylase was mainly salivary in origin.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Kepivance in the stem cell transplant setting. 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.
- Vaginal edema and erythema;
- Palmar plantar erythrodysesthesia syndrome (also known as “hand-foot syndrome”)
# Drug Interactions
- In vitro and in vivo data showed that palifermin interacts with unfractionated as well as low molecular weight heparins. Heparin co-administration resulted in a 5-fold increase in palifermin systemic exposure. Avoid co-administration of palifermin with heparin. If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after Kepivance administration.
- Do not administer Kepivance within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. In a clinical trial, administration of Kepivance within 24 hours of chemotherapy resulted in increased severity and duration of oral mucositis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of Kepivance in pregnant woman. Palifermin is embryotoxic in rabbits and rats. In reproductive toxicology studies, increased post-implantation loss and decrease in fetal body weight were observed in both rabbit (2.5 times the maximum recommended human dose , adjusted for body weight) and rat (8 times the MRHD, on a mcg/kg basis). Kepivance should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Palifermin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Palifermin during labor and delivery.
### Nursing Mothers
- It is not known whether Kepivance is secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Kepivance, 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
- Information on the dosing and safety of Kepivance in the pediatric population is limited. However, use of Kepivance in pediatric patients ages 1 to 16 years is supported by evidence from adequate and well-controlled studies of Kepivance in adults and a phase 1 study that included 27 pediatric patients with acute leukemia undergoing hematopoietic stem cell transplant. Three age groups were studied: ages 1 to 2 (n=9), ages 3 to 11 (n=9), and ages 12 to 16 (n=9); 56% were male, 26% were Caucasian, 63% Hispanic; 81% ALL, 19% AML. The patients received high-dose cytotoxic therapy consisting of fractionated total body irradiation (TBI) (12 Gy total dose), high dose etoposide (1500 mg/m2), and high dose cyclophosphamide (120 mg/kg) followed by allogeneic hematopoietic stem cell support. The dose intensity of this preparative regimen is comparable to the dose intensity of the Study 1 preparative regimen. Kepivance was administered as a daily intravenous injection for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. Three dose levels, 40, 60, and 80 mcg/kg/dose, were evaluated. There was no dose limiting toxicity identified at any dose level. Adverse events were similar to those reported in adult studies. The incidence of palifermin related adverse events was highest in the 80 μg/kg cohort. The overall incidence of WHO grade 3 and 4 oral mucositis was 10/27 (37%).
- The pharmacokinetics of Kepivance was evaluated in the phase 1 study. Age (1 to 16 years) did not affect the pharmacokinetics of palifermin over the dose range (40 to 80 mcg/kg). Palifermin concentrations declined in the first 30 minutes after dosing. An increase in palifermin concentrations occurred at around 2 to 4 hours post-dose for some subjects, which was followed by a second, slow decline phase. A similar trend has been observed in adult patients. The mean half-life range was 2.6 to 5.6 hours in pediatric patients following the first 60 mcg/kg dose of Kepivance. No accumulation was observed following 3 consecutive doses of Kepivance. Palifermin exposure did not increase linearly with increasing doses. The first dose AUC0-inf (mean) of Kepivance 60 mcg/kg/day in adult patients (18 to 63 years) was 38.2 ng*hr/mL compared to 46.1 ng*hr/mL (range of means: 22.8 to 81.6) for pediatric patients (1 to 16 years). The mean clearance was 1730 mL/hr/kg for adults and 2481 mL/hr/kg (range of means: 1700 to 3460) in pediatric patients.
### Geriatic Use
- Clinical studies of Kepivance did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently from younger subjects.
### Gender
There is no FDA guidance on the use of Palifermin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Palifermin with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended for patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Palifermin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Palifermin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Palifermin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Administer Kepivance by intravenous bolus injection. If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after Kepivance administration.
- The reconstituted solution contains no preservatives and is intended for single use only. Discard any unused portion.
- Following reconstitution, it is recommended that the product be used immediately. If not used immediately, the reconstituted solution of Kepivance may be stored refrigerated in its carton at 2° to 8°C (36° to 46°F) for up to 24 hours.
- Prior to injection, allow Kepivance to reach room temperature for a maximum of 1 hour protected from light. Discard Kepivance left at room temperature for more than 1 hour.
### Monitoring
There is limited information regarding Monitoring of Palifermin in the drug label.
# IV Compatibility
- Prepare the solution for infusion, using aseptic technique, as follows:
- Reconstitute Kepivance lyophilized powder with Sterile Water for Injection, USP (not supplied) by slowly injecting 1.2 mL of Sterile Water for Injection, USP to yield a final concentration of 5 mg/mL.
- Swirl the contents gently during dissolution. Do not shake or vigorously agitate the vial. Dissolution of Kepivance can take up to 3 minutes.
- Visually inspect the solution for discoloration and particulate matter before administration. The reconstituted solution should be clear and colorless. Do not administer Kepivance if discoloration or particulates are observed. Do not filter the reconstituted solution during preparation or administration. Do not freeze the reconstituted solution. Protect from light.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Palifermin in the drug label.
# Pharmacology
## Mechanism of Action
- KGF is an endogenous protein in the fibroblast growth factor (FGF) family that binds to the KGF receptor. Binding of KGF to its receptor has been reported to result in proliferation, differentiation, and migration of epithelial cells. The KGF receptor, one of four receptors in the FGF family, has been reported to be present on epithelial cells in many tissues examined including the tongue, buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, skin (hair follicles and sebaceous gland), and the lens of the eye. The KGF receptor has been reported to not be present on cells of the hematopoietic lineage. Endogenous KGF is produced by mesenchymal cells and is upregulated in response to epithelial tissue injury.
- In mice and rats, Kepivance enhanced proliferation of epithelial cells (as measured by Ki67 immunohistochemical staining and BrDU uptake) and demonstrated an increase in tissue thickness of the tongue, buccal mucosa, and gastrointestinal tract. Kepivance has been studied in murine models of chemotherapy and radiation-induced gastrointestinal injury. In such models, administration of Kepivance prior to and/or after the cytotoxic insult improved survival and reduced weight loss compared to control animals.
- Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro at concentrations ≥ 10 mcg/mL (> 15-fold higher than average therapeutic concentrations in humans). In nude mouse xenograft models, three consecutive daily treatments of Kepivance at doses of 1,500 and 4,000 mcg/kg (25- and 67-fold higher than the recommended human dose, respectively) repeated weekly for 4 to 6 weeks were associated with a dose-dependent increase in the growth rate of 1 of 7 KGF receptor-expressing human tumor cell lines.
## Structure
- Kepivance (palifermin) is a truncated human KGF produced by recombinant DNA technology in E coli. Kepivance is a water soluble, 140 amino acid protein with a molecular weight of 16.3 kilodaltons. It differs from endogenous human KGF in that the first 23 N terminal amino acids have been deleted to improve protein stability.
- Kepivance is supplied as a sterile, white, preservative-free, lyophilized powder for intravenous injection after reconstitution with 1.2 mL of Sterile Water for Injection, USP. Reconstitution yields a clear, colorless solution of Kepivance (5 mg/mL) with a pH of 6.5. Each single use vial of Kepivance contains palifermin (6.25 mg),with L histidine (1.94 mg), mannitol (50 mg), polysorbate 20 (0.13 mg or 0.01% w/v), and sucrose (25 mg).
## Pharmacodynamics
- Epithelial cell proliferation was assessed by Ki67 immunohistochemical staining in healthy subjects. A 3-fold or greater increase in Ki67 staining was observed in buccal biopsies from 3 of 6 healthy subjects given Kepivance at 40 mcg/kg/day intravenously for 3 days, when measured 24 hours after the third dose. Dose-dependent epithelial cell proliferation was observed in healthy subjects given single intravenous doses of 120 to 250 mcg/kg 48 hours post-dosing.
## Pharmacokinetics
- The pharmacokinetics of Kepivance were studied in healthy subjects and patients with hematologic malignancies. After single intravenous doses of 20 to 250 mcg/kg in healthy subjects and 60 mcg/kg in cancer patients, Kepivance concentrations declined over 95% in the first 30 minutes post-dose. A slight increase or plateau in concentration occurred at approximately 1 to 4 hours, followed by a terminal decline phase. Kepivance exhibited linear pharmacokinetics with extravascular distribution. In cancer patients compared with healthy subjects, after a 60 mcg/kg single dose of Kepivance the average total body clearance (CL) was 2- to 4-fold higher, and volume of distribution at steady state (Vss) was 2-fold higher. The elimination half-life was similar between healthy subjects and cancer patients (average 4.5 hours with a range of 3.3 to 5.7 hours). No accumulation of Kepivance occurred after 3 consecutive daily doses of 20 and 40 mcg/kg in healthy subjects or 60 mcg/kg in cancer patients. Age (1 to 16 years) did not affect the pharmacokinetics of palifermin over the dose range of 40 to 80 mcg/kg.
- Drug Interactions
- Co-administration with Heparin
- The potential pharmacokinetic interaction between palifermin and heparin was evaluated in a single-dose study in 27 healthy subjects receiving palifermin (60 mcg/kg) co-administered with and without therapeutic levels of unfractionated heparin. This co-administration resulted in a 5-fold increase in palifermin AUC and an 80% decrease in the mean CL. There was no significant effect of palifermin on heparin activity with respect to activated partial thromboplastin time (aPTT). The clinical relevance of this observed increase in palifermin systemic exposure is unclear.
- Pharmacokinetics in Specific Populations
- Renal Impairment
- Results from a pharmacokinetics study in 24 subjects with varying degrees of renal impairment demonstrated that renal impairment has little or no influence on Kepivance pharmacokinetics.
- Elderly
- In a single-dose study, subjects received a 180-mcg/kg or 90-mcg/kg dose of palifermin administered by intravenous bolus injection. Subjects over the age of 65 (n=8) had an approximately 30% lower rate of CL on average than those 65 and younger (n=19). No dose adjustment is recommended for the geriatric population.
## Nonclinical Toxicology
- Carcinogenicity: No treatment-related increase in the incidence of neoplastic lesions occurred in transgenic rasH2 mice treated with 9 weekly intravenous doses of palifermin, at 167-fold higher than the recommended human dose (on a mcg/kg basis).
- Mutagenicity: No clastogenic or mutagenic effects of palifermin were observed in mammalian chromosomal aberration or Ames genotoxicity assays.
- Impairment of Fertility: Reproductive performance, fertility, and sperm assessment parameters were not affected when palifermin was administered intravenously to male and female rats prior to and during mating at doses up to 100 mcg/kg/day. Decreased epididymal sperm counts, and increased post-implantation losses were observed at doses ≥ 300 mcg/kg/day (5-fold higher than the recommended human dose, on a mcg/kg basis). Increased pre-implantation loss and a decreased fertility index were observed at a palifermin dose of 1000 mcg/kg/day.
- In animal reproductive toxicity studies, palifermin is embryotoxic at doses that are 2.5 times (rabbits) and 5 to > 8 times (rats) the MRHD, based on body weight (mcg/kg). Pregnant rabbits received intravenous palifermin during organogenesis at doses equivalent to 1.0 and 2.5 times the MRHD, based on body weight (mcg/kg). Increased post-implantation loss and decreased fetal body weights occurred along with maternal toxicity (clinical signs and reductions in body weight gain/food consumption) at doses 2.5 times the MRHD.
- In pregnant rats, animals received intravenous palifermin during organogenesis at doses of 5 to >8 times the MRHD based on body weight (mcg/kg). Increased post-implantation loss, decreased fetal body weight, and/or increased skeletal variations occurred in the presence of maternal toxicity at doses > 8 times the MRHD.
# Clinical Studies
- The safety and efficacy of Kepivance in decreasing the incidence and duration of severe oral mucositis in patients with hematologic malignancies (NHL, Hodgkin's disease, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, or multiple myeloma) receiving myelotoxic therapy requiring hematopoietic stem cell support, were established in a randomized placebo-controlled clinical trial of 212 patients (Study 1) and a randomized, schedule-ranging, placebo-controlled clinical trial of 169 patients (Study 2).
- In Study 1, patients received high-dose cytotoxic therapy consisting of fractionated total-body irradiation (TBI) (12 Gy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (100 mg/kg) followed by hematopoietic stem cell support. Patients were randomized to receive either Kepivance (n = 106) or placebo (n = 106). Kepivance 60 mcg/kg was administered as a daily intravenous injection for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. The major efficacy outcome was the number of days during which patients experienced severe oral mucositis (Grade 3/4 on the WHO scale)1. Other analyses included the incidence, duration, and severity of oral mucositis and the use of opioid analgesia. There was no evidence of a delay in time to hematopoietic recovery in patients who received Kepivance as compared to patients who received placebo. The results of Study 1 are presented in Table 2 and Figure 1.
- Study 2 was a randomized, multi-center, placebo-controlled trial comparing varying schedules of Kepivance. All patients received high-dose cytotoxic therapy consisting of fractionated TBI (12cGy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (75—100 mg/kg) followed by hematopoietic stem cell support. The results for Study 1 were supported by results observed in the subset of patients in Study 2 who received the same dose and schedule of Kepivance administered in Study 1. One arm of Study 2 that included patients who received Kepivance for 3 consecutive days prior to initiation of cytotoxic therapy, a dose given on the last day of TBI prior to etoposide, and for 3 consecutive days following infusion of hematopoietic stem cells was prematurely closed by the Safety Committee for lack of efficacy and a trend towards increased severity and duration of oral mucositis as compared to placebo-treated patients. The Safety Committee attributed the safety finding to Kepivance having been administered within 24 hours of chemotherapy, which resulted in an increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period .
- In a post approval study, Study 3, designed to determine the efficacy of Kepivance with a high dose melphalan preparative regimen, patients with multiple myeloma were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The conditioning regimen was melphalan (200 mg/m2) on day -2 followed by autologous hematopoietic stem cell support. A total of 281 patients were randomized to 3 arms: Kepivance before melphalan on days -6, -5, -4 and after melphalan on days 0, 1, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57).
- The main outcome of the study was maximum severity of WHO oral mucositis. The median age of enrolled patients was 57 years (range 32-69), and 55% were male. The results are presented in Figure 2. The prespecified primary analysis was a comparison between the Kepivance pre-post and pre arms to placebo. The incidence of WHO Grade 3 and 4 in the Kepivance pre-post arm was 38%, compared to 37% in the placebo arm. There were no significant differences between either of the Kepivance regimens and the placebo arm in the incidence of severe oral mucositis.
- A subset of subjects enrolled in the multiple myeloma study were included in an evaluation for the risk of cataract development in patients receiving Kepivance treatment. Ophthalmologic examinations were performed on 101 patients enrolled in a double-blind, randomized, placebo-controlled study of two different schedules of Kepivance (pre and post chemotherapy and pre chemotherapy only) for reduction in severity of oral mucositis in subjects with multiple myeloma receiving high dose melphalan followed by autologous peripheral blood stem cell transplantation. For the primary cataract endpoint of incidence of cataract development or cataract progression at Month 12, there was a greater proportion of subjects that experienced cataract development in the Kepivance group: 48% (25/52) compared with the placebo group: 29% (4/14) (difference of 17 ).
# How Supplied
- Kepivance is supplied as a lyophilized powder in single use vials containing 6.25 mg of palifermin.
- Kepivance vials are supplied in:
- a dispensing pack containing 3 vials (NDC 66658-112-03)
- a dispensing pack containing 6 vials (NDC 66658-112-06)
- a distribution case containing 4 dispensing packs (NDC 66658-112-24) .
- Store Kepivance vials in the dispensing pack in its carton refrigerated at 2° to 8°C (36° to 46°F) until time of use. Protect from light.
## Storage
There is limited information regarding Palifermin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to report the following to healthcare providers:
- Rashes and reddening of skin
- Itchiness
- Swelling of tongue
- Changes in mouth and tongue sensation
- Alteration in taste
- Inform patients
- That the safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies
- Of the evidence of tumor growth and stimulation in cell culture and in animal models of non-hematopoietic human tumors.
# Precautions with Alcohol
- Alcohol-Palifermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KEPIVANCE®
# Look-Alike Drug Names
There is limited information regarding Palifermin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Palifermin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Palifermin is a mucocutaneous epithelial human growth factor that is FDA approved for the treatment of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Common adverse reactions include rash, fever, elevated serum amylase (Grade 3/4), pruritus, erythema, and edema.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Kepivance is 60 mcg/kg/day, administered as an intravenous bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy, for a total of 6 doses.
- Administer the first 3 doses prior to myelotoxic therapy. Administer the third dose 24 to 48 hours prior to beginning myelotoxic therapy.
- Administer the last 3 doses after myelotoxic therapy is complete; Administer the first of these doses on the day of hematopoietic stem cell infusion after the infusion is completed, and more than 4 days after the most recent administration of Kepivance.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Palifermin in adult patients.
### Non–Guideline-Supported Use
- Palifermin 40 mcg/kg/day by intravenous bolus on days 1 to 3.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Palifermin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Palifermin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Palifermin in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Potential for Stimulation of Tumor Growth
- The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies. The effects of Kepivance on stimulation of KGF receptor-expressing, non-hematopoietic tumors in patients are not known. Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell line growth in a human carcinoma xenograft model.
# 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 data described in Table 1 and the discussion below reflect exposure to Kepivance in 409 patients with hematologic malignancies who were enrolled in 3 randomized, placebo-controlled clinical trials and a pharmacokinetic study. Patients received Kepivance either before, or before and after, regimens of myelotoxic chemotherapy, with or without total body irradiation (TBI), followed by hematopoietic stem cell support. Kepivance was administered in daily doses ranging from 5 to 80 mcg/kg/day. The total dose of Kepivance ranged from 15 to 480 mcg/kg with a median of 360 mcg/kg. The population had a median age of 48 years (range: 41 to 60 years), 62% were male and 83% were White with 7.4 % Black and 6.2 % Hispanic. Non Hodgkin's lymphoma (NHL) was the most common malignancy followed by Hodgkin's disease, multiple myeloma, and leukemia.
- The most common serious adverse reaction attributed to Kepivance was skin rash, reported in less than 1% (3/409) of patients treated. Grade 3 skin rashes occurred in 3% of patients (9/409) receiving Kepivance and 2% (5/241) receiving placebo.
- Cataracts: In a postmarketing safety study, the incidence of cataracts was numerically higher among patients receiving Kepivance than in the control population.
- Laboratory Test Findings: Reversible elevations in serum lipase and amylase, which did not require treatment, were reported in 28% and 62% of patients receiving Kepivance and 23% and 54%of patients receiving placebo. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of hematopoietic stem cell infusion. Amylase was mainly salivary in origin.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Kepivance in the stem cell transplant setting. 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.
- Vaginal edema and erythema;
- Palmar plantar erythrodysesthesia syndrome (also known as “hand-foot syndrome”)
# Drug Interactions
- In vitro and in vivo data showed that palifermin interacts with unfractionated as well as low molecular weight heparins. Heparin co-administration resulted in a 5-fold increase in palifermin systemic exposure. Avoid co-administration of palifermin with heparin. If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after Kepivance administration.
- Do not administer Kepivance within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. In a clinical trial, administration of Kepivance within 24 hours of chemotherapy resulted in increased severity and duration of oral mucositis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of Kepivance in pregnant woman. Palifermin is embryotoxic in rabbits and rats. In reproductive toxicology studies, increased post-implantation loss and decrease in fetal body weight were observed in both rabbit (2.5 times the maximum recommended human dose [MRHD], adjusted for body weight) and rat (8 times the MRHD, on a mcg/kg basis). Kepivance should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Palifermin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Palifermin during labor and delivery.
### Nursing Mothers
- It is not known whether Kepivance is secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Kepivance, 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
- Information on the dosing and safety of Kepivance in the pediatric population is limited. However, use of Kepivance in pediatric patients ages 1 to 16 years is supported by evidence from adequate and well-controlled studies of Kepivance in adults and a phase 1 study that included 27 pediatric patients with acute leukemia undergoing hematopoietic stem cell transplant. Three age groups were studied: ages 1 to 2 (n=9), ages 3 to 11 (n=9), and ages 12 to 16 (n=9); 56% were male, 26% were Caucasian, 63% Hispanic; 81% ALL, 19% AML. The patients received high-dose cytotoxic therapy consisting of fractionated total body irradiation (TBI) (12 Gy total dose), high dose etoposide (1500 mg/m2), and high dose cyclophosphamide (120 mg/kg) followed by allogeneic hematopoietic stem cell support. The dose intensity of this preparative regimen is comparable to the dose intensity of the Study 1 preparative regimen. Kepivance was administered as a daily intravenous injection for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. Three dose levels, 40, 60, and 80 mcg/kg/dose, were evaluated. There was no dose limiting toxicity identified at any dose level. Adverse events were similar to those reported in adult studies. The incidence of palifermin related adverse events was highest in the 80 μg/kg cohort. The overall incidence of WHO grade 3 and 4 oral mucositis was 10/27 (37%).
- The pharmacokinetics of Kepivance was evaluated in the phase 1 study. Age (1 to 16 years) did not affect the pharmacokinetics of palifermin over the dose range (40 to 80 mcg/kg). Palifermin concentrations declined in the first 30 minutes after dosing. An increase in palifermin concentrations occurred at around 2 to 4 hours post-dose for some subjects, which was followed by a second, slow decline phase. A similar trend has been observed in adult patients. The mean half-life range was 2.6 to 5.6 hours in pediatric patients following the first 60 mcg/kg dose of Kepivance. No accumulation was observed following 3 consecutive doses of Kepivance. Palifermin exposure did not increase linearly with increasing doses. The first dose AUC0-inf (mean) of Kepivance 60 mcg/kg/day in adult patients (18 to 63 years) was 38.2 ng*hr/mL compared to 46.1 ng*hr/mL (range of means: 22.8 to 81.6) for pediatric patients (1 to 16 years). The mean clearance was 1730 mL/hr/kg for adults and 2481 mL/hr/kg (range of means: 1700 to 3460) in pediatric patients.
### Geriatic Use
- Clinical studies of Kepivance did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently from younger subjects.
### Gender
There is no FDA guidance on the use of Palifermin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Palifermin with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended for patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Palifermin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Palifermin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Palifermin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Administer Kepivance by intravenous bolus injection. If heparin is used to maintain an intravenous line, rinse the line with saline prior to and after Kepivance administration.
- The reconstituted solution contains no preservatives and is intended for single use only. Discard any unused portion.
- Following reconstitution, it is recommended that the product be used immediately. If not used immediately, the reconstituted solution of Kepivance may be stored refrigerated in its carton at 2° to 8°C (36° to 46°F) for up to 24 hours.
- Prior to injection, allow Kepivance to reach room temperature for a maximum of 1 hour protected from light. Discard Kepivance left at room temperature for more than 1 hour.
### Monitoring
There is limited information regarding Monitoring of Palifermin in the drug label.
# IV Compatibility
- Prepare the solution for infusion, using aseptic technique, as follows:
- Reconstitute Kepivance lyophilized powder with Sterile Water for Injection, USP (not supplied) by slowly injecting 1.2 mL of Sterile Water for Injection, USP to yield a final concentration of 5 mg/mL.
- Swirl the contents gently during dissolution. Do not shake or vigorously agitate the vial. Dissolution of Kepivance can take up to 3 minutes.
- Visually inspect the solution for discoloration and particulate matter before administration. The reconstituted solution should be clear and colorless. Do not administer Kepivance if discoloration or particulates are observed. Do not filter the reconstituted solution during preparation or administration. Do not freeze the reconstituted solution. Protect from light.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Palifermin in the drug label.
# Pharmacology
## Mechanism of Action
- KGF is an endogenous protein in the fibroblast growth factor (FGF) family that binds to the KGF receptor. Binding of KGF to its receptor has been reported to result in proliferation, differentiation, and migration of epithelial cells. The KGF receptor, one of four receptors in the FGF family, has been reported to be present on epithelial cells in many tissues examined including the tongue, buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, skin (hair follicles and sebaceous gland), and the lens of the eye. The KGF receptor has been reported to not be present on cells of the hematopoietic lineage. Endogenous KGF is produced by mesenchymal cells and is upregulated in response to epithelial tissue injury.
- In mice and rats, Kepivance enhanced proliferation of epithelial cells (as measured by Ki67 immunohistochemical staining and BrDU uptake) and demonstrated an increase in tissue thickness of the tongue, buccal mucosa, and gastrointestinal tract. Kepivance has been studied in murine models of chemotherapy and radiation-induced gastrointestinal injury. In such models, administration of Kepivance prior to and/or after the cytotoxic insult improved survival and reduced weight loss compared to control animals.
- Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro at concentrations ≥ 10 mcg/mL (> 15-fold higher than average therapeutic concentrations in humans). In nude mouse xenograft models, three consecutive daily treatments of Kepivance at doses of 1,500 and 4,000 mcg/kg (25- and 67-fold higher than the recommended human dose, respectively) repeated weekly for 4 to 6 weeks were associated with a dose-dependent increase in the growth rate of 1 of 7 KGF receptor-expressing human tumor cell lines.
## Structure
- Kepivance (palifermin) is a truncated human KGF produced by recombinant DNA technology in E coli. Kepivance is a water soluble, 140 amino acid protein with a molecular weight of 16.3 kilodaltons. It differs from endogenous human KGF in that the first 23 N terminal amino acids have been deleted to improve protein stability.
- Kepivance is supplied as a sterile, white, preservative-free, lyophilized powder for intravenous injection after reconstitution with 1.2 mL of Sterile Water for Injection, USP. Reconstitution yields a clear, colorless solution of Kepivance (5 mg/mL) with a pH of 6.5. Each single use vial of Kepivance contains palifermin (6.25 mg),with L histidine (1.94 mg), mannitol (50 mg), polysorbate 20 (0.13 mg or 0.01% w/v), and sucrose (25 mg).
## Pharmacodynamics
- Epithelial cell proliferation was assessed by Ki67 immunohistochemical staining in healthy subjects. A 3-fold or greater increase in Ki67 staining was observed in buccal biopsies from 3 of 6 healthy subjects given Kepivance at 40 mcg/kg/day intravenously for 3 days, when measured 24 hours after the third dose. Dose-dependent epithelial cell proliferation was observed in healthy subjects given single intravenous doses of 120 to 250 mcg/kg 48 hours post-dosing.
## Pharmacokinetics
- The pharmacokinetics of Kepivance were studied in healthy subjects and patients with hematologic malignancies. After single intravenous doses of 20 to 250 mcg/kg in healthy subjects and 60 mcg/kg in cancer patients, Kepivance concentrations declined over 95% in the first 30 minutes post-dose. A slight increase or plateau in concentration occurred at approximately 1 to 4 hours, followed by a terminal decline phase. Kepivance exhibited linear pharmacokinetics with extravascular distribution. In cancer patients compared with healthy subjects, after a 60 mcg/kg single dose of Kepivance the average total body clearance (CL) was 2- to 4-fold higher, and volume of distribution at steady state (Vss) was 2-fold higher. The elimination half-life was similar between healthy subjects and cancer patients (average 4.5 hours with a range of 3.3 to 5.7 hours). No accumulation of Kepivance occurred after 3 consecutive daily doses of 20 and 40 mcg/kg in healthy subjects or 60 mcg/kg in cancer patients. Age (1 to 16 years) did not affect the pharmacokinetics of palifermin over the dose range of 40 to 80 mcg/kg.
- Drug Interactions
- Co-administration with Heparin
- The potential pharmacokinetic interaction between palifermin and heparin was evaluated in a single-dose study in 27 healthy subjects receiving palifermin (60 mcg/kg) co-administered with and without therapeutic levels of unfractionated heparin. This co-administration resulted in a 5-fold increase in palifermin AUC and an 80% decrease in the mean CL. There was no significant effect of palifermin on heparin activity with respect to activated partial thromboplastin time (aPTT). The clinical relevance of this observed increase in palifermin systemic exposure is unclear.
- Pharmacokinetics in Specific Populations
- Renal Impairment
- Results from a pharmacokinetics study in 24 subjects with varying degrees of renal impairment demonstrated that renal impairment has little or no influence on Kepivance pharmacokinetics.
- Elderly
- In a single-dose study, subjects received a 180-mcg/kg or 90-mcg/kg dose of palifermin administered by intravenous bolus injection. Subjects over the age of 65 (n=8) had an approximately 30% lower rate of CL on average than those 65 and younger (n=19). No dose adjustment is recommended for the geriatric population.
## Nonclinical Toxicology
- Carcinogenicity: No treatment-related increase in the incidence of neoplastic lesions occurred in transgenic rasH2 mice treated with 9 weekly intravenous doses of palifermin, at 167-fold higher than the recommended human dose (on a mcg/kg basis).
- Mutagenicity: No clastogenic or mutagenic effects of palifermin were observed in mammalian chromosomal aberration or Ames genotoxicity assays.
- Impairment of Fertility: Reproductive performance, fertility, and sperm assessment parameters were not affected when palifermin was administered intravenously to male and female rats prior to and during mating at doses up to 100 mcg/kg/day. Decreased epididymal sperm counts, and increased post-implantation losses were observed at doses ≥ 300 mcg/kg/day (5-fold higher than the recommended human dose, on a mcg/kg basis). Increased pre-implantation loss and a decreased fertility index were observed at a palifermin dose of 1000 mcg/kg/day.
- In animal reproductive toxicity studies, palifermin is embryotoxic at doses that are 2.5 times (rabbits) and 5 to > 8 times (rats) the MRHD, based on body weight (mcg/kg). Pregnant rabbits received intravenous palifermin during organogenesis at doses equivalent to 1.0 and 2.5 times the MRHD, based on body weight (mcg/kg). Increased post-implantation loss and decreased fetal body weights occurred along with maternal toxicity (clinical signs and reductions in body weight gain/food consumption) at doses 2.5 times the MRHD.
- In pregnant rats, animals received intravenous palifermin during organogenesis at doses of 5 to >8 times the MRHD based on body weight (mcg/kg). Increased post-implantation loss, decreased fetal body weight, and/or increased skeletal variations occurred in the presence of maternal toxicity at doses > 8 times the MRHD.
# Clinical Studies
- The safety and efficacy of Kepivance in decreasing the incidence and duration of severe oral mucositis in patients with hematologic malignancies (NHL, Hodgkin's disease, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, or multiple myeloma) receiving myelotoxic therapy requiring hematopoietic stem cell support, were established in a randomized placebo-controlled clinical trial of 212 patients (Study 1) and a randomized, schedule-ranging, placebo-controlled clinical trial of 169 patients (Study 2).
- In Study 1, patients received high-dose cytotoxic therapy consisting of fractionated total-body irradiation (TBI) (12 Gy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (100 mg/kg) followed by hematopoietic stem cell support. Patients were randomized to receive either Kepivance (n = 106) or placebo (n = 106). Kepivance 60 mcg/kg was administered as a daily intravenous injection for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. The major efficacy outcome was the number of days during which patients experienced severe oral mucositis (Grade 3/4 on the WHO [World Health Organization] scale)1. Other analyses included the incidence, duration, and severity of oral mucositis and the use of opioid analgesia. There was no evidence of a delay in time to hematopoietic recovery in patients who received Kepivance as compared to patients who received placebo. The results of Study 1 are presented in Table 2 and Figure 1.
- Study 2 was a randomized, multi-center, placebo-controlled trial comparing varying schedules of Kepivance. All patients received high-dose cytotoxic therapy consisting of fractionated TBI (12cGy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (75—100 mg/kg) followed by hematopoietic stem cell support. The results for Study 1 were supported by results observed in the subset of patients in Study 2 who received the same dose and schedule of Kepivance administered in Study 1. One arm of Study 2 that included patients who received Kepivance for 3 consecutive days prior to initiation of cytotoxic therapy, a dose given on the last day of TBI prior to etoposide, and for 3 consecutive days following infusion of hematopoietic stem cells was prematurely closed by the Safety Committee for lack of efficacy and a trend towards increased severity and duration of oral mucositis as compared to placebo-treated patients. The Safety Committee attributed the safety finding to Kepivance having been administered within 24 hours of chemotherapy, which resulted in an increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period [see Dosage and Administration (2.1) and Drug Interactions (7)].
- In a post approval study, Study 3, designed to determine the efficacy of Kepivance with a high dose melphalan preparative regimen, patients with multiple myeloma were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The conditioning regimen was melphalan (200 mg/m2) on day -2 followed by autologous hematopoietic stem cell support. A total of 281 patients were randomized to 3 arms: Kepivance before melphalan on days -6, -5, -4 and after melphalan on days 0, 1, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57).
- The main outcome of the study was maximum severity of WHO oral mucositis. The median age of enrolled patients was 57 years (range 32-69), and 55% were male. The results are presented in Figure 2. The prespecified primary analysis was a comparison between the Kepivance pre-post and pre arms to placebo. The incidence of WHO Grade 3 and 4 in the Kepivance pre-post arm was 38%, compared to 37% in the placebo arm. There were no significant differences between either of the Kepivance regimens and the placebo arm in the incidence of severe oral mucositis.
- A subset of subjects enrolled in the multiple myeloma study were included in an evaluation for the risk of cataract development in patients receiving Kepivance treatment. Ophthalmologic examinations were performed on 101 patients enrolled in a double-blind, randomized, placebo-controlled study of two different schedules of Kepivance (pre and post chemotherapy and pre chemotherapy only) for reduction in severity of oral mucositis in subjects with multiple myeloma receiving high dose melphalan followed by autologous peripheral blood stem cell transplantation. For the primary cataract endpoint of incidence of cataract development or cataract progression at Month 12, there was a greater proportion of subjects that experienced cataract development in the Kepivance group: 48% (25/52) compared with the placebo group: 29% (4/14) (difference of 17 [95% CI: -11, 46]).
# How Supplied
- Kepivance is supplied as a lyophilized powder in single use vials containing 6.25 mg of palifermin.
- Kepivance vials are supplied in:
- a dispensing pack containing 3 vials (NDC 66658-112-03)
- a dispensing pack containing 6 vials (NDC 66658-112-06)
- a distribution case containing 4 dispensing packs (NDC 66658-112-24) [4 x 6 vial dispensing packs (24 x 6.25 mg/vial)].
- Store Kepivance vials in the dispensing pack in its carton refrigerated at 2° to 8°C (36° to 46°F) until time of use. Protect from light.
## Storage
There is limited information regarding Palifermin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to report the following to healthcare providers:
- Rashes and reddening of skin
- Itchiness
- Swelling of tongue
- Changes in mouth and tongue sensation
- Alteration in taste
- Inform patients
- That the safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies
- Of the evidence of tumor growth and stimulation in cell culture and in animal models of non-hematopoietic human tumors.
# Precautions with Alcohol
- Alcohol-Palifermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KEPIVANCE®[2]
# Look-Alike Drug Names
There is limited information regarding Palifermin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Palifermin | |
7ed75055d5e55a7a9210a715c5d97f039997ea8c | wikidoc | Palindrome | Palindrome
A palindrome is a word, phrase, number or other sequence of units that can be read the same way in either direction (the adjustment of punctuation and spaces between words is generally permitted). Composing literature in palindromes is an example of constrained writing.
The word "palindrome" was coined from Greek roots palin (Template:Polytonic; "back") and dromos (Template:Polytonic; "way, direction") by English writer Ben Jonson in the 1600s. The actual Greek phrase to describe the phenomenon is karkinikê epigrafê (Template:Polytonic; crab inscription), or simply karkiniêoi (Template:Polytonic; crabs), alluding to the backward movement of crabs, like an inscription which can be read backwards.
# History
Palindromes date back at least to 79 A.D., as the palindromic Latin word square "Sator Arepo Tenet Opera Rotas" was found as a graffito at Herculaneum, buried by ash in that year. This palindrome is remarkable for the fact that it also reproduces itself if one forms a word from the first letters, then the second letters and so forth. Hence it can be arranged into a word square that reads in four different ways: horizontally or vertically from top left to bottom right orpoertically from bottom right to top left. While some sources translate this as "The sower Arepo holds the wheels at work", translation is problematic as the word arepo is otherwise unknown; the square may have been a coded Christian signifier, with TENET forming a cross.
A palindrome with the same property is the Hebrew palindrome "We explained the glutton who is in the honey was burned and incinerated" (Template:Script/Hebrew; PRShNW R`BTN ShBDBSh NTB`R WNShRP or parasnu ra`avtan sheba'dvash nitba'er venisraf) by Ibn Ezra, referring to the halachic question as to whether a fly landing in honey makes the honey treif.
Another Latin palindrome, In girum imus nocte et consumimur igni ("We go wandering at night and are consumed by fire" — In girum ire is translated as "go wandering" instead of the literal "go in a circle", cf. Italian andare in giro, "go strolling or wandering around"), was said to describe the behavior of moths. It is likely from medieval rather than ancient times.
Byzantine Greeks often inscribed the palindrome "Wash my sins not only my face" (: Template:Polytonic; Modern: Template:Polytonic; Nipson anomēmata mē monan opsin, note ps is the single Greek letter psi (Ψ)) on baptismal fonts. This is round the font at St. Mary's Church, Nottingham and also the font in the basilica of St. Sophia, Constantinople, the font of St. Stephen d’Egres, Paris; at St. Menin’s Abbey, Orléans; at Dulwich College; and at the following churches: Worlingsworth (Suffolk), Harlow (Essex), Knapton (Norfolk), St Martin, Ludgate (London), and Hadleigh (Suffolk).
## Palindromes in Ancient Sanskrit
Palindromes of considerable complexity were experimented with in Sanskrit poetry. An example which has been called "the most complex and exquisite type of palindrome ever invented", appears in the 19th canto of the 8th century epic poem śiśupāla-vadha by Magha. It yields the same text if read forwards, backwards, down, or up:
(note: hyphen indicates continuation of same word). The last four lines are an inversion of the first four and are not part of the verse. They are only included here so that its properties can be more easily discerned, as the up-and-down reading depends on re-reading the text back up again in each column.
The stanza translates as:
# Types
## Characters
The most familiar palindromes, in English at least, are character-by-character: the written characters read the same backwards as forwards. Palindromic words exist, for example civic, level, rotator, rotor, kayak, and racecar.
Palindromes often consist of a phrase or sentence ("Was it a rat I saw?", "Step on no pets", "Sit on a potato pan, Otis", "Lisa Bonet ate no basil", "Satan, oscillate my metallic sonatas", "I roamed under it as a tired nude Maori"). Punctuation, capitalization, and spacing are usually ignored, although some (such as "Rats live on no evil star") include the spacing.
The three famous English palindromes are "Able was I ere I saw Elba" (which is also palindromic with respect to spacing), "A man, a plan, a canal, Panama!”, and “Madam, I'm Adam”.
Some people have names that are palindromes. Some changed their name in order to be a palindrome (one example is actor Robert Trebor), while others were given a palindromic name at birth (such as Neo-Nazi philologist Revilo Oliver and more than one man named Mike Kim).
## Words
Some palindromes use words as units rather than letters. Examples are "Fall leaves after leaves fall", "First Ladies rule the State and state the rule: ladies first" and "Girl, bathing on Bikini, eyeing boy, sees boy eyeing bikini on bathing girl". The command "Level, madam, level!", composed only of words that are themselves palindromes, is both a character-by-character and a word-by-word palindrome.
## Lines
Still other palindromes take the line as the unit. The poem Doppelganger, composed by James A. Lindon, is an example.
The dialogue "Crab Canon" in Douglas Hofstadter's Gödel, Escher, Bach is nearly a line-by-line palindrome. The second half of the dialog consists, with some very minor changes, of the same lines as the first half, but in reverse order and spoken by the opposite characters (i.e., lines spoken by Achilles in the first half are spoken by the Tortoise in the second, and vice versa). In the middle is a non-symmetrical line spoken by the Crab, who enters and spouts some nonsense, apparently triggering the reversal. The structure is modeled after the musical form known as crab canon, in particular the canon a 2 cancrizans of Johann Sebastian Bach's The Musical Offering.
## Molecular biology
Restriction enzymes recognize a specific sequence of nucleotides and produce a double-stranded cut in the DNA. While recognition sequences vary widely, with lengths between 4 and 8 nucleotides, many of them are palindromic, which correspond to nitrogenous base sequences that read the same backwards and forwards.
## Numbers
A palindromic number is a number whose digits, with decimal representation usually assumed, are the same read backwards, for example, 58285. They are studied in recreational mathematics where palindromic numbers with special properties are sought. A palindromic prime is a palindromic number that is a prime number.
## Dates
Palindromic dates are of interest to recreational mathematicians and numerologists, and sometimes generate comment in the general media. Whether or not a date is palindromic depends on the style in which it is written. For example, in the dd/mm/yyyy style, the 20th of February in 2002 (20-02-2002) was palindromic.
## Music
Joseph Haydn's Symphony No.47 in G is nicknamed the Palindrome. The third movement, minuet and trio is a musical palindrome. This clever piece goes forward twice and backwards twice and arrives back at the same place.
The interlude from Alban Berg's opera Lulu is a palindrome, as are sections and pieces, in arch form, by many other composers, including James Tenney, and most famously Béla Bartók. George Crumb also used musical palindrome to text paint the Federico Garcia Lorca poem "¿Porque nací?", the first movement of three in his fourth book of Madrigals. Igor Stravinsky's final composition, The Owl and the Pussy Cat, is a palindrome. British composer Robert Simpson also composed music in the palindrome or based on palindromic themes; the slow movement of his Symphony No. 2 is a palindrome, as is the slow movement of his String Quartet No. 1.
The music of Anton Webern is often imbued with palindromes. Webern, who had studied the music of the Renaissance composer Heinrich Issac, was extremely interested in symmetries in music, be they horizontal or vertical. For one of the most famous examples of horizontal or linear symmetry in Webern's music, one should look no further than the first phrase in the second movement of the Opus 21 Symphony. In one of the most striking examples of vertical symmetry, the second movement of the Opus 27 Piano Variations, Webern arranges every pitch of this dodecaphonic work around the central pitch axis of A4. From this, each downward reaching interval is replicated exactly in the opposite direction. For example, a G-sharp3 – 13 half-steps down from A4 – is replicated as a B-flat5 – 13 half-steps above.
In classical music, a crab canon is a canon in which one line of the melody is reversed in time and pitch from the other.
Hüsker Dü's concept album Zen Arcade contains the songs "Reoccurring Dreams" and "Dreams Reoccurring," the latter of which appears earlier on the album but is actually the intro of the former song played in reverse. Similarly, The Stone Roses' first album contains the songs "Waterfall" and "Don't Stop," the latter of which is essentially the former performed backwards.
The title track of the 1992 album entitled UFO Tofu by Béla Fleck and the Flecktones is said by its composer to be a musical palindrome.
In 2003 the city of San Diego, California commissioned sculptor Roman DeSalvo and composer Joseph Waters to create a public artwork in the form of a safety railing on the 25th Street overpass at F and 25th Streets. The result,Crab Carillon, is a set of 488 tuned chimes that can be played by pedestrians as they cross the overpass. Each chime is tuned to the note of a melody, composed by Waters. The melody is in the form of a palindrome, to accommodate walking in either direction.City of San Diego Public Art website.
The song "I Palindrome I", by They Might Be Giants, features palindromic lyrics and imagery. The 27-word bridge is word-symmetrical.
"Weird Al" Yankovic's song "Bob", from his 2003 album Poodle Hat, consists of rhyming palindromes and parodies the Bob Dylan song Subterranean Homesick Blues.
The 2007 re-release of Yoko Ono's song "No, No, No" is credited simply to "Ono", making the artist–title combination a palindrome.
Baby Gramps is known for songs where the lyrics are made up of palindromes.
The Fall of Troy made a song with the famous palindrome "A Man, A Plan, A Canal, Panama" as title.
The first and last tracks on Andrew Bird's album Noble Beast form a palindrome ("Oh No" and "On Ho!") and the seventh track is a palindrome in itself "Ouo". He has also mentioned palindromes in earlier music, giving his songs names like "11:11" "T'N'T" and "Fake Palindromes" (although the last title is not a palindrome itself). He also mentions palindromes in the lyrics of the song "I" and the "I" redux "Imitosis".
Starálfur, from Sigur Rós's Ágætis byrjun has the strings part palindrome.
## Acoustic
A palindrome in which a recorded phrase of speech sounds the same when it is played backwards was discovered by composer John Oswald in 1974 while he was working on audio tape versions of the cut-up technique using recorded readings by William S. Burroughs. Oswald discovered in repeated instances of Burroughs speaking the phrase "I got" that the recordings still sound like "I got" when played backwards.
# Long palindromes
## Single words
The longest palindromic word in the Oxford English Dictionary is the onomatopoeic tattarrattat, coined by James Joyce in Ulysses (1922) for a knock on the door. The Guinness Book of Records gives the title to detartrated, the past tense of detartrate, a somewhat contrived chemical term meaning to remove tartrates. Rotavator, a trademarked name for an agricultural machine, is often listed in dictionaries. The term redivider is used by some writers but appears to be an invented term — only redivide and redivision appear in the Shorter Oxford Dictionary. Malayalam, an Indian language, is of equal length (strictly, this name should be spelt either Malayaalam or Malayālam, as the next to last vowel is long). Another aspect of the word "malayalam" is that it stays a letter palindrome if it is written in any phonetic script like devanagari.
The Finnish word saippuakivikauppias (soap-stone vendor) is claimed to be the world's longest palindromic word in everyday use. A meaningful derivative from it is saippuakalasalakauppias (soapfish bootlegger). An even longer effort is saippuakuppinippukauppias (soapdish batch seller). Koortsmeetsysteemstrook (fever measuring system strip) is probably the longest palindrome in Dutch.
# Biological structures
In most genomes or sets of genetic instructions, palindromic motifs are found. However, the meaning of palindrome in the context of genetics is slightly different from the definition used for words and sentences. Since the DNA is formed by two paired strands of nucleotides, and the nucleotides always pair in the same way (Adenine (A) with Thymine (T), Cytosine (C) with Guanine (G)), a (single-stranded) sequence of DNA is said to be a palindrome if it is equal to its complementary sequence read backwards. For example, the sequence ACCTAGGT is palindromic because its complement is TGGATCCA, which is equal to the original sequence in reverse complement.
A palindromic DNA sequence can form a hairpin. Palindromic motifs are made by the order of the nucleotides that specify the complex chemicals (proteins) which, as a result of those genetic instructions, the cell is to produce. They have been specially researched in bacterial chromosomes and in the so-called Bacterial Interspersed Mosaic Elements (BIMEs) scattered over them. Recently a research genome sequencing project discovered that many of the bases on the Y chromosome are arranged as palindromes. A palindrome structure allows the Y chromosome to repair itself by bending over at the middle if one side is damaged.
It is believed that palindromes are also found frequently in proteins, but their role in the protein function is not clearly known. It is recently suggested that the prevalence existence of palindromes in peptides might be related to the prevalence of low-complexity regions in proteins, as palindromes are frequently associated with low-complexity sequences. Their prevalence might be also related to an alpha helical formation propensity of these sequences, or in formation of protein/protein complexes .
# Computation theory
In the automata theory, a set of all palindromes in a given alphabet is a typical example of a language which is context-free, but not regular. This means that it is theoretically impossible for a computer with a finite amount of memory to reliably test for palindromes. (For practical purposes with modern computers, this limitation would only apply to incredibly long letter-sequences.)
Additionally, the set of palindromes cannot be reliably tested by a deterministic pushdown automaton and is not LR(k) parseable. When reading a palindrome from left-to-right, it is essentially impossible to locate the “middle” until the entire word has been read.
# Semordnilaps
Semordnilap is a name coined for a word or phrase that spells a different word or phrase backwards. "Semordnilap" is itself "palindromes" spelled backwards. According to author O.V. Michaelsen, it was probably coined by logologist Dmitri A. Borgmann and appeared in Oddities and Curiosities, annotated by Martin Gardner, 1961. Semordnilaps are also known as volvograms, heteropalindromes, semi-palindromes, half-palindromes, reversgrams, mynoretehs, reversible anagrams, word reversals, or anadromes. They have also sometimes been called antigrams, though this term now usually refers to anagrams with opposing meanings.
These words are very useful in constructing palindromes; together, each pair forms a palindrome, and they can be added on either side of a shorter palindrome in order to extend it.
The longest single-word instance in English is probably stratagem / mega tarts, which consists of nine letters. There are many examples containing eight letters, such as:
- stressed / desserts
- samaroid (resembling a samara) / dioramas
- rewarder / redrawer
- departer / retraped (construction based on the fact that verb trape is recorded as an alternative spelling of traipse)
- reporter / retroper (construction based on the fact that trope is recorded as a verb, meaning "to furnish with tropes")
Other examples include:
- gateman / nametag
- deliver / reviled
- lamina / animal
- dennis / sinned
- straw / warts
- star / rats
- stop / pots
- snap / pans
- pins / snip
- lived / devil
- diaper / repaid
- smart / trams
- spit / tips
- live / evil
- dog / god
- gut / tug
- maps / spam
- war / raw
- was / saw
- trap / part
# Non-English palindromes
Palindromes in languages that use an alphabetic writing system work in essentially the same way as English palindromes. In languages that use a writing system other than an alphabet (such as Chinese), a palindrome is still a sequence of characters from that writing system that remains the same when reversed, though the characters now represent words rather than letters.
The treatment of diacritics varies. In languages such as Czech and Spanish, letters with diacritics or accents (except tildes) are not given a separate place in the alphabet, and thus preserve the palindrome whether or not the repeated letter has an ornamentation. However, in Danish and other Nordic languages, A and A with a ring (Å) are distinct letters and must be mirrored exactly to be considered a true palindrome.
# More examples of English palindromes
- Step on no pets.
- Dammit, I'm mad!
- Rise to vote, sir.
- Never odd or even
- If I had a hi-fi
- Yo, banana boy!
- Do geese see God?
- No devil lived on.
- Ah, Satan sees Natasha.
- Lewd did I live & evil I did dwel!
- Was it a car or a cat I saw?
- Are we not drawn onward, we few, drawn onward to new era?
- No lemon, no melon
- Now I see bees, I won.
- Ma is as selfless as I am.
- Nurse, I spy gypsies—run!
- Was it Eliot's toilet I saw?
- No, sir, away! A papaya war is on!
- Go hang a salami, I'm a lasagna hog.
- I, madam, I made radio! So I dared! Am I mad? Am I?
- Swap God for a janitor, rot in a jar of dog paws.
- Eva, can I see bees in a cave?
- So many dynamos!
- Red rum, sir, is murder.
- Never even
# Family
There is a certain warmth provided by palindromes perhaps coming from childhood.
Ironically many family nicknames, particularly in English, are palindromes:
Mom, Dad, Pop, Pap and Sis.
Likewise there are palindromes with a tag like: Momma, Poppa, Poppy, Pappy, Bubba, Nanna, Mamma,
Daddy and Sissa. Abba is the name for God the father. | Palindrome
A palindrome is a word, phrase, number or other sequence of units that can be read the same way in either direction (the adjustment of punctuation and spaces between words is generally permitted). Composing literature in palindromes is an example of constrained writing.
The word "palindrome" was coined from Greek roots palin (Template:Polytonic; "back") and dromos (Template:Polytonic; "way, direction") by English writer Ben Jonson in the 1600s. The actual Greek phrase to describe the phenomenon is karkinikê epigrafê (Template:Polytonic; crab inscription), or simply karkiniêoi (Template:Polytonic; crabs), alluding to the backward movement of crabs, like an inscription which can be read backwards.
Template:TOClimit
# History
Palindromes date back at least to 79 A.D., as the palindromic Latin word square "Sator Arepo Tenet Opera Rotas" was found as a graffito at Herculaneum, buried by ash in that year. This palindrome is remarkable for the fact that it also reproduces itself if one forms a word from the first letters, then the second letters and so forth. Hence it can be arranged into a word square that reads in four different ways: horizontally or vertically from top left to bottom right orpoertically from bottom right to top left. While some sources translate this as "The sower Arepo holds the wheels at work", translation is problematic as the word arepo is otherwise unknown; the square may have been a coded Christian signifier,[citation needed] with TENET forming a cross.
A palindrome with the same property is the Hebrew palindrome "We explained the glutton who is in the honey was burned and incinerated" (Template:Script/Hebrew; PRShNW R`BTN ShBDBSh NTB`R WNShRP or parasnu ra`avtan sheba'dvash nitba'er venisraf) by Ibn Ezra, referring to the halachic question as to whether a fly landing in honey makes the honey treif.
פ ר ש נ ו
ר ע ב ת ן
ש ב ד ב ש
נ ת ב ע ר
ו נ ש ר ף
Another Latin palindrome, In girum imus nocte et consumimur igni ("We go wandering at night and are consumed by fire" — In girum ire is translated as "go wandering" instead of the literal "go in a circle", cf. Italian andare in giro, "go strolling or wandering around"), was said to describe the behavior of moths. It is likely from medieval rather than ancient times.
Byzantine Greeks often inscribed the palindrome "Wash my sins not only my face" (: Template:Polytonic; Modern: Template:Polytonic; Nipson anomēmata mē monan opsin, note ps is the single Greek letter psi (Ψ)) on baptismal fonts. This is round the font at St. Mary's Church, Nottingham and also the font in the basilica of St. Sophia, Constantinople, the font of St. Stephen d’Egres, Paris; at St. Menin’s Abbey, Orléans; at Dulwich College; and at the following churches: Worlingsworth (Suffolk), Harlow (Essex), Knapton (Norfolk), St Martin, Ludgate (London), and Hadleigh (Suffolk).
## Palindromes in Ancient Sanskrit
Palindromes of considerable complexity were experimented with in Sanskrit poetry. An example which has been called "the most complex and exquisite type of palindrome ever invented",[1] appears in the 19th canto of the 8th century epic poem śiśupāla-vadha by Magha. It yields the same text if read forwards, backwards, down, or up:
(note: hyphen indicates continuation of same word). The last four lines are an inversion of the first four and are not part of the verse. They are only included here so that its properties can be more easily discerned, as the up-and-down reading depends on re-reading the text back up again in each column.
The stanza translates as:
# Types
## Characters
The most familiar palindromes, in English at least, are character-by-character: the written characters read the same backwards as forwards. Palindromic words exist, for example civic, level, rotator, rotor, kayak, and racecar.
Palindromes often consist of a phrase or sentence ("Was it a rat I saw?", "Step on no pets", "Sit on a potato pan, Otis", "Lisa Bonet ate no basil", "Satan, oscillate my metallic sonatas", "I roamed under it as a tired nude Maori"). Punctuation, capitalization, and spacing are usually ignored, although some (such as "Rats live on no evil star") include the spacing.[2]
The three famous English palindromes are "Able was I ere I saw Elba"[3] (which is also palindromic with respect to spacing), "A man, a plan, a canal, Panama!”,[4] and “Madam, I'm Adam”.
Some people have names that are palindromes. Some changed their name in order to be a palindrome (one example is actor Robert Trebor), while others were given a palindromic name at birth (such as Neo-Nazi philologist Revilo Oliver and more than one man named Mike Kim[5]).
## Words
Some palindromes use words as units rather than letters. Examples are "Fall leaves after leaves fall", "First Ladies rule the State and state the rule: ladies first" and "Girl, bathing on Bikini, eyeing boy, sees boy eyeing bikini on bathing girl". The command "Level, madam, level!", composed only of words that are themselves palindromes, is both a character-by-character and a word-by-word palindrome.
## Lines
Still other palindromes take the line as the unit. The poem Doppelganger, composed by James A. Lindon, is an example.
The dialogue "Crab Canon" in Douglas Hofstadter's Gödel, Escher, Bach is nearly a line-by-line palindrome. The second half of the dialog consists, with some very minor changes, of the same lines as the first half, but in reverse order and spoken by the opposite characters (i.e., lines spoken by Achilles in the first half are spoken by the Tortoise in the second, and vice versa). In the middle is a non-symmetrical line spoken by the Crab, who enters and spouts some nonsense, apparently triggering the reversal. The structure is modeled after the musical form known as crab canon, in particular the canon a 2 cancrizans of Johann Sebastian Bach's The Musical Offering.
## Molecular biology
Restriction enzymes recognize a specific sequence of nucleotides and produce a double-stranded cut in the DNA. While recognition sequences vary widely, with lengths between 4 and 8 nucleotides, many of them are palindromic, which correspond to nitrogenous base sequences that read the same backwards and forwards.
## Numbers
A palindromic number is a number whose digits, with decimal representation usually assumed, are the same read backwards, for example, 58285. They are studied in recreational mathematics where palindromic numbers with special properties are sought. A palindromic prime is a palindromic number that is a prime number.
## Dates
Palindromic dates are of interest to recreational mathematicians and numerologists, and sometimes generate comment in the general media.[6] Whether or not a date is palindromic depends on the style in which it is written. For example, in the dd/mm/yyyy style, the 20th of February in 2002 (20-02-2002) was palindromic.
## Music
Joseph Haydn's Symphony No.47 in G is nicknamed the Palindrome. The third movement, minuet and trio is a musical palindrome. This clever piece goes forward twice and backwards twice and arrives back at the same place.
The interlude from Alban Berg's opera Lulu is a palindrome, as are sections and pieces, in arch form, by many other composers, including James Tenney, and most famously Béla Bartók. George Crumb also used musical palindrome to text paint the Federico Garcia Lorca poem "¿Porque nací?", the first movement of three in his fourth book of Madrigals. Igor Stravinsky's final composition, The Owl and the Pussy Cat, is a palindrome. British composer Robert Simpson also composed music in the palindrome or based on palindromic themes; the slow movement of his Symphony No. 2 is a palindrome, as is the slow movement of his String Quartet No. 1.
The music of Anton Webern is often imbued with palindromes. Webern, who had studied the music of the Renaissance composer Heinrich Issac, was extremely interested in symmetries in music, be they horizontal or vertical. For one of the most famous examples of horizontal or linear symmetry in Webern's music, one should look no further than the first phrase in the second movement of the Opus 21 Symphony. In one of the most striking examples of vertical symmetry, the second movement of the Opus 27 Piano Variations, Webern arranges every pitch of this dodecaphonic work around the central pitch axis of A4. From this, each downward reaching interval is replicated exactly in the opposite direction. For example, a G-sharp3 – 13 half-steps down from A4 – is replicated as a B-flat5 – 13 half-steps above.
In classical music, a crab canon is a canon in which one line of the melody is reversed in time and pitch from the other.
Hüsker Dü's concept album Zen Arcade contains the songs "Reoccurring Dreams" and "Dreams Reoccurring," the latter of which appears earlier on the album but is actually the intro of the former song played in reverse. Similarly, The Stone Roses' first album contains the songs "Waterfall" and "Don't Stop," the latter of which is essentially the former performed backwards.
The title track of the 1992 album entitled UFO Tofu by Béla Fleck and the Flecktones is said by its composer to be a musical palindrome.
In 2003 the city of San Diego, California commissioned sculptor Roman DeSalvo and composer Joseph Waters to create a public artwork in the form of a safety railing on the 25th Street overpass at F and 25th Streets. The result,Crab Carillon, is a set of 488 tuned chimes that can be played by pedestrians as they cross the overpass. Each chime is tuned to the note of a melody, composed by Waters. The melody is in the form of a palindrome, to accommodate walking in either direction.City of San Diego Public Art website.
The song "I Palindrome I", by They Might Be Giants, features palindromic lyrics and imagery. The 27-word bridge is word-symmetrical.
"Weird Al" Yankovic's song "Bob", from his 2003 album Poodle Hat, consists of rhyming palindromes and parodies the Bob Dylan song Subterranean Homesick Blues.
The 2007 re-release of Yoko Ono's song "No, No, No" is credited simply to "Ono", making the artist–title combination a palindrome.
Baby Gramps is known for songs where the lyrics are made up of palindromes.
The Fall of Troy made a song with the famous palindrome "A Man, A Plan, A Canal, Panama" as title.
The first and last tracks on Andrew Bird's album Noble Beast form a palindrome ("Oh No" and "On Ho!") and the seventh track is a palindrome in itself "Ouo". He has also mentioned palindromes in earlier music, giving his songs names like "11:11" "T'N'T" and "Fake Palindromes" (although the last title is not a palindrome itself). He also mentions palindromes in the lyrics of the song "I" and the "I" redux "Imitosis".
Starálfur, from Sigur Rós's Ágætis byrjun has the strings part palindrome.
## Acoustic
A palindrome in which a recorded phrase of speech sounds the same when it is played backwards was discovered by composer John Oswald in 1974 while he was working on audio tape versions of the cut-up technique using recorded readings by William S. Burroughs. Oswald discovered in repeated instances of Burroughs speaking the phrase "I got" that the recordings still sound like "I got" when played backwards.[7][8]
# Long palindromes
## Single words
The longest palindromic word in the Oxford English Dictionary is the onomatopoeic tattarrattat, coined by James Joyce in Ulysses (1922) for a knock on the door. The Guinness Book of Records gives the title to detartrated, the past tense of detartrate, a somewhat contrived chemical term meaning to remove tartrates. Rotavator, a trademarked name for an agricultural machine, is often listed in dictionaries. The term redivider is used by some writers but appears to be an invented term — only redivide and redivision appear in the Shorter Oxford Dictionary. Malayalam, an Indian language, is of equal length (strictly, this name should be spelt either Malayaalam or Malayālam, as the next to last vowel is long). Another aspect of the word "malayalam" is that it stays a letter palindrome if it is written in any phonetic script like devanagari.
The Finnish word saippuakivikauppias (soap-stone vendor) is claimed to be the world's longest palindromic word in everyday use. A meaningful derivative from it is saippuakalasalakauppias (soapfish bootlegger). An even longer effort is saippuakuppinippukauppias (soapdish batch seller). Koortsmeetsysteemstrook (fever measuring system strip) is probably the longest palindrome in Dutch.
# Biological structures
In most genomes or sets of genetic instructions, palindromic motifs are found. However, the meaning of palindrome in the context of genetics is slightly different from the definition used for words and sentences. Since the DNA is formed by two paired strands of nucleotides, and the nucleotides always pair in the same way (Adenine (A) with Thymine (T), Cytosine (C) with Guanine (G)), a (single-stranded) sequence of DNA is said to be a palindrome if it is equal to its complementary sequence read backwards. For example, the sequence ACCTAGGT is palindromic because its complement is TGGATCCA, which is equal to the original sequence in reverse complement.
A palindromic DNA sequence can form a hairpin. Palindromic motifs are made by the order of the nucleotides that specify the complex chemicals (proteins) which, as a result of those genetic instructions, the cell is to produce. They have been specially researched in bacterial chromosomes and in the so-called Bacterial Interspersed Mosaic Elements (BIMEs) scattered over them. Recently a research genome sequencing project discovered that many of the bases on the Y chromosome are arranged as palindromes.[citation needed] A palindrome structure allows the Y chromosome to repair itself by bending over at the middle if one side is damaged.
It is believed that palindromes are also found frequently in proteins,[9][10] but their role in the protein function is not clearly known. It is recently [11] suggested that the prevalence existence of palindromes in peptides might be related to the prevalence of low-complexity regions in proteins, as palindromes are frequently associated with low-complexity sequences. Their prevalence might be also related to an alpha helical formation propensity of these sequences[11], or in formation of protein/protein complexes [12].
# Computation theory
In the automata theory, a set of all palindromes in a given alphabet is a typical example of a language which is context-free, but not regular. This means that it is theoretically impossible for a computer with a finite amount of memory to reliably test for palindromes. (For practical purposes with modern computers, this limitation would only apply to incredibly long letter-sequences.)
Additionally, the set of palindromes cannot be reliably tested by a deterministic pushdown automaton and is not LR(k) parseable. When reading a palindrome from left-to-right, it is essentially impossible to locate the “middle” until the entire word has been read.
# Semordnilaps
Semordnilap is a name coined for a word or phrase that spells a different word or phrase backwards. "Semordnilap" is itself "palindromes" spelled backwards. According to author O.V. Michaelsen, it was probably coined by logologist Dmitri A. Borgmann and appeared in Oddities and Curiosities, annotated by Martin Gardner, 1961. Semordnilaps are also known as volvograms,[13] heteropalindromes, semi-palindromes, half-palindromes, reversgrams, mynoretehs, reversible anagrams,[14] word reversals, or anadromes.[15] They have also sometimes been called antigrams,[15] though this term now usually refers to anagrams with opposing meanings.
These words are very useful in constructing palindromes; together, each pair forms a palindrome, and they can be added on either side of a shorter palindrome in order to extend it.
The longest single-word instance in English is probably stratagem / mega tarts, which consists of nine letters. There are many examples containing eight letters, such as:
- stressed / desserts
- samaroid (resembling a samara) / dioramas
- rewarder / redrawer
- departer / retraped (construction based on the fact that verb trape is recorded as an alternative spelling of traipse[16])
- reporter / retroper (construction based on the fact that trope is recorded as a verb, meaning "to furnish with tropes"[16])
Other examples include:
- gateman / nametag
- deliver / reviled
- lamina / animal
- dennis / sinned
- straw / warts
- star / rats
- stop / pots
- snap / pans
- pins / snip
- lived / devil
- diaper / repaid
- smart / trams
- spit / tips
- live / evil
- dog / god
- gut / tug
- maps / spam
- war / raw
- was / saw
- trap / part
# Non-English palindromes
Palindromes in languages that use an alphabetic writing system work in essentially the same way as English palindromes. In languages that use a writing system other than an alphabet (such as Chinese), a palindrome is still a sequence of characters from that writing system that remains the same when reversed, though the characters now represent words rather than letters.
The treatment of diacritics varies. In languages such as Czech and Spanish, letters with diacritics or accents (except tildes) are not given a separate place in the alphabet, and thus preserve the palindrome whether or not the repeated letter has an ornamentation. However, in Danish and other Nordic languages, A and A with a ring (Å) are distinct letters and must be mirrored exactly to be considered a true palindrome.
# More examples of English palindromes
- Step on no pets.
- Dammit, I'm mad!
- Rise to vote, sir.
- Never odd or even
- If I had a hi-fi
- Yo, banana boy!
- Do geese see God?
- No devil lived on.
- Ah, Satan sees Natasha.
- Lewd did I live & evil I did dwel!
- Was it a car or a cat I saw?
- Are we not drawn onward, we few, drawn onward to new era?
- No lemon, no melon
- Now I see bees, I won.
- Ma is as selfless as I am.
- Nurse, I spy gypsies—run!
- Was it Eliot's toilet I saw?
- No, sir, away! A papaya war is on!
- Go hang a salami, I'm a lasagna hog.
- I, madam, I made radio! So I dared! Am I mad? Am I?
- Swap God for a janitor, rot in a jar of dog paws.
- Eva, can I see bees in a cave?
- So many dynamos!
- Red rum, sir, is murder.
- Never even
# Family
There is a certain warmth provided by palindromes perhaps coming from childhood.
Ironically many family nicknames, particularly in English, are palindromes:
Mom, Dad, Pop, Pap and Sis.
Likewise there are palindromes with a tag like: Momma, Poppa, Poppy, Pappy, Bubba, Nanna, Mamma,
Daddy and Sissa. Abba is the name for God the father. | https://www.wikidoc.org/index.php/Palindrome | |
bb655de3cbb461551c152074b2a80cfb8c23141f | wikidoc | Panama Red | Panama Red
Panama Red is a legendary cannabis sativa cultivar of the 1960s and 1970s, popular amongst cannabis afficiandos. Panama Red is genetically related to Columbian Red.Its name comes from the fact that it originated in the country of Panama, with much of it being produced in the Pearl Islands. It is known for causing a racy, paranoia-inducing, psychedelic high. Cannabis culture died off in Panama with the rise of cocaine trafficking. Today, there are still Panama Red seeds available from collectors, but this strain is very rare.
"Panama Red" was a song played by Jerry Garcia with Peter Rowan in Old and in the Way in 1973. It was also recorded and played by the New Riders of the Purple Sage (after Jerry had stopped playing with them). This particular type of cannabis is also mentioned in the song "Amsterdam" by Van Halen. During the seminal Vietnam War film Apocalypse Now, the character "Chef" specifically requests "Panama Red" cannabis from a military quartermaster.
Columbian Red is a cannabis sativa cultivar genetically related to Panama Red.
# Reference
- "SongFacts - Panama Red". Retrieved November 26, 2006..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} | Panama Red
Template:Tfd
Panama Red is a legendary cannabis sativa cultivar of the 1960s and 1970s, popular amongst cannabis afficiandos. Panama Red is genetically related to Columbian Red.Its name comes from the fact that it originated in the country of Panama, with much of it being produced in the Pearl Islands.[citation needed] It is known for causing a racy, paranoia-inducing, psychedelic high. Cannabis culture died off in Panama with the rise of cocaine trafficking. Today, there are still Panama Red seeds available from collectors, but this strain is very rare.[citation needed]
"Panama Red" was a song played by Jerry Garcia with Peter Rowan in Old and in the Way in 1973. It was also recorded and played by the New Riders of the Purple Sage (after Jerry had stopped playing with them). This particular type of cannabis is also mentioned in the song "Amsterdam" by Van Halen. During the seminal Vietnam War film Apocalypse Now, the character "Chef" specifically requests "Panama Red" cannabis from a military quartermaster.
Columbian Red is a cannabis sativa cultivar genetically related to Panama Red.
# Reference
- "SongFacts - Panama Red". Retrieved November 26, 2006..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Template:Cannabis resources
Template:Hallucinogen-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Panama_Red | |
1ffedb1e24ecdc940af152325a7a81f331c8e7a5 | wikidoc | Pancreatin | Pancreatin
# Overview
Pancreatin is a mixture of several digestive enzymes produced by the exocrine cells of the pancreas. It is composed of amylase, lipase and protease. This mixture is used to treat conditions in which pancreatic secretions are deficient, such as surgical pancreatectomy, pancreatitis and cystic fibrosis. It has been claimed to help with food allergies, celiac disease, autoimmune disease, cancer and weight loss. Pancreatin is sometimes called "pancreatic acid", although it is neither a single chemical substance nor an acid.
Pancreatin contains the pancreatic enzymes trypsin, amylase and lipase. A similar mixture of enzymes is sold as pancrelipase, which contains more active lipase enzyme than does pancreatin. The trypsin found in pancreatin works to hydrolyze proteins into oligopeptides; amylase hydrolyzes starches into oligosaccharides and the disaccharide maltose; and lipase hydrolyzes triglycerides into fatty acids and glycerols. Pancreatin is an effective enzyme supplement for replacing missing pancreatic enzymes, and aids in the digestion of foods in cases of pancreatic insufficiency.
Pancreatin reduces the absorption of iron from food in the duodenum during digestion
Some contact lens cleaning solutions contain porcine pancreatin extractives to assist in the intended protein-removal process. | Pancreatin
Template:Seealso
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pancreatin is a mixture of several digestive enzymes produced by the exocrine cells of the pancreas. It is composed of amylase, lipase and protease. This mixture is used to treat conditions in which pancreatic secretions are deficient, such as surgical pancreatectomy, pancreatitis and cystic fibrosis. It has been claimed to help with food allergies, celiac disease, autoimmune disease, cancer and weight loss. Pancreatin is sometimes called "pancreatic acid", although it is neither a single chemical substance nor an acid.
Pancreatin contains the pancreatic enzymes trypsin, amylase and lipase. A similar mixture of enzymes is sold as pancrelipase, which contains more active lipase enzyme than does pancreatin. The trypsin found in pancreatin works to hydrolyze proteins into oligopeptides; amylase hydrolyzes starches into oligosaccharides and the disaccharide maltose; and lipase hydrolyzes triglycerides into fatty acids and glycerols. Pancreatin is an effective enzyme supplement for replacing missing pancreatic enzymes, and aids in the digestion of foods in cases of pancreatic insufficiency.
Pancreatin reduces the absorption of iron from food in the duodenum during digestion [1]
Some contact lens cleaning solutions contain porcine pancreatin extractives to assist in the intended protein-removal process. | https://www.wikidoc.org/index.php/Pancreatin | |
9006ed9b16a69a5cd2e716eaf7bc77b8f2b545e6 | wikidoc | Pantethine | Pantethine
# Overview
Pantethine (bis-pantethine or co-enzyme pantethine) is a dimeric form of pantothenic acid (vitamin B5). It is composed of two molecules of pantothenic acid linked by cysteamine bridging groups. The monomer of this compound is known as pantetheine and is an intermediate in the production of Coenzyme A by the body. Pantethine is considered the more biologically active form of vitamin B5, but it is less stable, decomposing over time if it is not kept refrigerated. Most vitamin B5 supplements are therefore in the form of calcium pantothenate, a salt of pantothenic acid.
# Dietary supplementation
Pantethine is available as a dietary supplement because of evidence of its health benefits. In multiple clinical trials of patients with elevated cholesterol and triglycerides, total and LDL cholesterol were decreased by 12%, triglycerides decreased by 18%, and HDL cholesterol was increased by 9%. These clinical trials were conducted with daily intakes ranging from 600 to 1200 mg/day. Within this dose range there is no evidence of a dose-effect relationship, i.e. changes in lipid concentrations overlapped across the range of doses. Direct dose-response evidence is not available because no trial tested more than one dose. A few trials tested 300 mg/day with more modest but still statistically significant results.
# Physiological effects
Although pantethine can serve as a precursor for generation of vitamin B5, this is not thought to be the mechanism of action. Vitamin B5 requirements are on the order of 5 mg/day. Effective pantethine intakes are in the range of 600 to 1200 mg/day. Mega-dosing of vitamin B5 does not have the same lipid consequences as pantethine.
Two mechanisms of action are proposed for pantethine. In the first, pantethine serves as the precursor for synthesis of coenzyme A. In the second, pantethine is converted to two pantetheine molecules which are in turn metabolized to form two pantethenic acid and two cysteamine molecules. Cysteamine is theorized to bind to and thus inactivate sulfer-containing amino acids in liver enzymes involved in the production of cholesterol and triglycerides. | Pantethine
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pantethine (bis-pantethine or co-enzyme pantethine) is a dimeric form of pantothenic acid (vitamin B5). It is composed of two molecules of pantothenic acid linked by cysteamine bridging groups. The monomer of this compound is known as pantetheine and is an intermediate in the production of Coenzyme A by the body. Pantethine is considered the more biologically active form of vitamin B5, but it is less stable, decomposing over time if it is not kept refrigerated. Most vitamin B5 supplements are therefore in the form of calcium pantothenate, a salt of pantothenic acid.
# Dietary supplementation
Pantethine is available as a dietary supplement because of evidence of its health benefits. In multiple clinical trials of patients with elevated cholesterol and triglycerides, total and LDL cholesterol were decreased by 12%, triglycerides decreased by 18%, and HDL cholesterol was increased by 9%.[citation needed] These clinical trials were conducted with daily intakes ranging from 600 to 1200 mg/day. Within this dose range there is no evidence of a dose-effect relationship, i.e. changes in lipid concentrations overlapped across the range of doses. Direct dose-response evidence is not available because no trial tested more than one dose. A few trials tested 300 mg/day with more modest but still statistically significant results.[citation needed]
# Physiological effects
Although pantethine can serve as a precursor for generation of vitamin B5, this is not thought to be the mechanism of action. Vitamin B5 requirements are on the order of 5 mg/day. Effective pantethine intakes are in the range of 600 to 1200 mg/day. Mega-dosing of vitamin B5 does not have the same lipid consequences as pantethine.[citation needed]
Two mechanisms of action are proposed for pantethine.[1] In the first, pantethine serves as the precursor for synthesis of coenzyme A. In the second, pantethine is converted to two pantetheine molecules which are in turn metabolized to form two pantethenic acid and two cysteamine molecules. Cysteamine is theorized to bind to and thus inactivate sulfer-containing amino acids in liver enzymes involved in the production of cholesterol and triglycerides. | https://www.wikidoc.org/index.php/Pantethine | |
f629cee0b7c36bdc87d5fe9692c808c299835c58 | wikidoc | Papaverine | Papaverine
# 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
Papaverine is a phosphodiesterase inhibitor that is FDA approved for the treatment of vascular spasm associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral vascular disease, peripheral and pulmonary embolism. Common adverse reactions include general discomfort, nausea, abdominal discomfort, anorexia, skin rash, malaise, vertigo and headache..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Papaverine is recommended in various conditions accompanied by spasm of smooth muscle, such as vascular spasm associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral and pulmonary embolism, peripheral vascular disease in which there is a vasospastic element, or certain cerebral angiospastic states; and visceral spasm, as in ureteral, biliary, or gastrointestinal colic.
- Dosage
- Papaverine Hydrochloride may be administered intravenously or intramuscularly. The intravenous route is recommended when an immediate effect is desired, but the drug must be injected slowly over the course of 1 or 2 minutes to avoid uncomfortable or alarming side effects.
- Parenteral administration of papaverine hydrochloride in doses of 1 to 4 mL is repeated every 3 hours as indicated. In the treatment of cardiac extrasystoles, 2 doses may be given 10 minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Papaverine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Papaverine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Papaverine in pediatric patients.
# Contraindications
- Intravenous injection of papaverine is contraindicated in the presence of complete atrioventricular heart block. When conduction is depressed, the drug may produce transient ectopic rhythms of ventricular origin, either premature beats or paroxysmal tachycardia.
- Papaverine Hydrochloride is not indicated for the treatment of impotence by intracorporeal injection. The intracorporeal injection of papaverine hydrochloride has been reported to have resulted in persistent priapism requiring medical and surgical intervention.
# Warnings
### Precautions
- Papaverine Hydrochloride Injection, USP, should not be added to Lactated Ringer’s Injection, because precipitation would result.
- Papaverine Hydrochloride should be used with caution in patients with glaucoma. The medication should be discontinued if hepatic hypersensitivity with gastrointestinal symptoms, jaundice, or eosinophilia becomes evident or if liver function test values become altered.
- Drug dependence resulting from the abuse of many of the selective depressants, including papaverine hydrochloride, has been reported.
# Adverse Reactions
## Clinical Trials Experience
- The following side effects have been reported: general discomfort, nausea, abdominal discomfort, anorexia, constipation or diarrhea, skin rash, malaise, vertigo, headache, intensive flushing of the face, perspiration, increase in the depth of respiration, increase in heart rate, a slight rise in blood pressure, and excessive sedation.
- Hepatitis, probably related to an immune mechanism, has been reported infrequently. Rarely, this has progressed to cirrhosis.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Papaverine in the drug label.
# Drug Interactions
There is limited information regarding Papaverine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- No teratogenic effects were observed in rats when papaverine hydrochloride was administered subcutaneously as a single agent. It is not known whether papaverine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. *Papaverine Hydrochloride should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Papaverine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Papaverine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when papaverine hydrochloride is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Papaverine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Papaverine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Papaverine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Papaverine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Papaverine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Papaverine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Papaverine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenously or Intramuscularly
### Monitoring
There is limited information regarding Monitoring of Papaverine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Papaverine in the drug label.
# Overdosage
- The symptoms of toxicity from papaverine hydrochloride often result from vasomotor instability and include nausea, vomiting, weakness, central nervous system depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and sinus tachycardia.
- In large overdoses, papaverine is a potent inhibitor of cellular respiration and a weak calcium antagonist.
- Following an oral overdose of 15 g, metabolic acidosis with hyperventilation, hyperglycemia, and hypokalemia have been reported. No information on toxic serum concentrations is available.
- Following intravenous overdosing in animals, seizures, tachyarrhythmias, and ventricular fibrillation have been reported. The oral median lethal dose in rats is 360 mg/kg.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- No specific antidote is known.
- Treatment should be symptomatic and supportive.
- Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor vital signs, blood gases, blood chemistry values, and other variables.
- If convulsions occur, consider diazepam, phenytoin, or phenobarbital. If the seizures are refractory, general anesthesia with thiopental or halothane and paralysis with a neuromuscular blocking agent may be necessary.
- For hypotension, consider intravenous fluids, elevation of the legs, and an inotropic vasopressor, such as dopamine or norepinephrine (levarterenol). Theoretically, calcium gluconate may be helpful in treating some of the toxic cardiovascular effects of papaverine; monitor the ECG and plasma calcium concentrations.
- Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of papaverine hydrochloride.
# Pharmacology
## Mechanism of Action
- The most characteristic effect of papaverine is relaxation of the tonus of all smooth muscle, especially when it has been spasmodically contracted. Papaverine Hydrochloride apparently acts directly on the muscle itself. This relaxation is noted in the vascular system and bronchial musculature and in the gastrointestinal, biliary and urinary tracts.
- The main actions of papaverine are exerted on cardiac and smooth muscle. Papaverine relaxes various smooth muscles, especially those of larger arteries; this relaxation may be prominent if spasm exists. The antispasmodic effect is a direct one and unrelated to muscle innervation, and the muscle still responds to drugs and other stimuli causing contraction. Papaverine has minimal actions on the central nervous system, although very large doses tend to produce some sedation and sleepiness in some patients. In certain circumstances, mild respiratory stimulation can be observed, but this is therapeutically inconsequential. Papaverine stimulates respiration by acting on carotid and aortic body chemoreceptors.
- Papaverine relaxes the smooth musculature of the larger blood vessels, including the coronary, cerebral, peripheral, and pulmonary arteries. This action is particularly evident when such vessels are in spasm, induced reflexly or by drugs, and it provides the basis for the clinical use of papaverine in peripheral or pulmonary arterial embolism.
- Experimentally in dogs, the alkaloid has been shown to cause fairly marked and long-lasting coronary vasodilatation and an increase in coronary blood flow. However, it also appears to have a direct inotropic effect and, when increased mechanical activity coincides with decreased systemic pressure, increases in coronary blood flow may not be sufficient to prevent brief periods of hypoxic myocardial depression.
## Structure
- Papaverine Hydrochloride, USP, is the hydrochloride of an alkaloid obtained from opium or prepared synthetically. It belongs to the benzylisoquinoline group of alkaloids. It does not contain a phenanthrene group as do morphine and codeine.
- Papaverine Hydrochloride, USP, is 6,7-dimethoxy-1- veratrylisoquinoline hydrochloride and contains, on the dried basis, not less than 98.5% of C20H21NO4HCI. The molecular weight is 375.85. The structural formula is as shown.
- Papaverine Hydrochloride occurs as white crystals or white crystalline powder. One gram dissolves in about 30 mL of water and in 120 mL of alcohol. It is soluble in chloroform and practically insoluble in ether.
- Papaverine Hydrochloride Injection, USP, is a clear, colorless to pale-yellow solution.
- Papaverine Hydrochloride, for parenteral administration, is a smooth-muscle relaxant that is available in vials containing 30 mg/mL. Each vial also contains edetate disodium 0.005%. The 10 mL vials also contain chlorobutanol 0.5% as a preservative. pH may be adjusted with sodium citrate and/or citric acid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Papaverine in the drug label.
## Pharmacokinetics
- Papaverine is effective by all routes of administration. A considerable fraction of the drug localizes in fat deposits and in the liver, with the remainder being distributed throughout the body. *It is metabolized in the liver. About 90% of the drug is bound to plasma protein. Although estimates of its biologic half-life vary widely, reasonably constant plasma levels can be maintained with oral administration at 6 hour intervals. The drug is excreted in the urine in an inactive form.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Papaverine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Papaverine in the drug label.
# How Supplied
- Papaverine Hydrochloride Injection, USP, 30 mg/mL
- 0517-4002-25 2 mL Vial packaged in boxes of 25
- 0517-4010-01 10 mL Multiple Dose Vial- packaged individually
- The 10 mL Multiple Dose Vial contains chlorobutanol 0.5% as a preservative.
## Storage
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature).
- PROTECT FROM LIGHT. RETAIN IN CARTON UNTIL TIME OF USE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Papaverine in the drug label.
# Precautions with Alcohol
- Alcohol-Papaverine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Papacon
- Para-Time S.R.
- Pavacot
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Papaverine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Papaverine is a phosphodiesterase inhibitor that is FDA approved for the treatment of vascular spasm associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral vascular disease, peripheral and pulmonary embolism. Common adverse reactions include general discomfort, nausea, abdominal discomfort, anorexia, skin rash, malaise, vertigo and headache..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Papaverine is recommended in various conditions accompanied by spasm of smooth muscle, such as vascular spasm associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral and pulmonary embolism, peripheral vascular disease in which there is a vasospastic element, or certain cerebral angiospastic states; and visceral spasm, as in ureteral, biliary, or gastrointestinal colic.
- Dosage
- Papaverine Hydrochloride may be administered intravenously or intramuscularly. The intravenous route is recommended when an immediate effect is desired, but the drug must be injected slowly over the course of 1 or 2 minutes to avoid uncomfortable or alarming side effects.
- Parenteral administration of papaverine hydrochloride in doses of 1 to 4 mL is repeated every 3 hours as indicated. In the treatment of cardiac extrasystoles, 2 doses may be given 10 minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Papaverine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in children have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Papaverine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Papaverine in pediatric patients.
# Contraindications
- Intravenous injection of papaverine is contraindicated in the presence of complete atrioventricular heart block. When conduction is depressed, the drug may produce transient ectopic rhythms of ventricular origin, either premature beats or paroxysmal tachycardia.
- Papaverine Hydrochloride is not indicated for the treatment of impotence by intracorporeal injection. The intracorporeal injection of papaverine hydrochloride has been reported to have resulted in persistent priapism requiring medical and surgical intervention.
# Warnings
### Precautions
- Papaverine Hydrochloride Injection, USP, should not be added to Lactated Ringer’s Injection, because precipitation would result.
- Papaverine Hydrochloride should be used with caution in patients with glaucoma. The medication should be discontinued if hepatic hypersensitivity with gastrointestinal symptoms, jaundice, or eosinophilia becomes evident or if liver function test values become altered.
- Drug dependence resulting from the abuse of many of the selective depressants, including papaverine hydrochloride, has been reported.
# Adverse Reactions
## Clinical Trials Experience
- The following side effects have been reported: general discomfort, nausea, abdominal discomfort, anorexia, constipation or diarrhea, skin rash, malaise, vertigo, headache, intensive flushing of the face, perspiration, increase in the depth of respiration, increase in heart rate, a slight rise in blood pressure, and excessive sedation.
- Hepatitis, probably related to an immune mechanism, has been reported infrequently. Rarely, this has progressed to cirrhosis.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Papaverine in the drug label.
# Drug Interactions
There is limited information regarding Papaverine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- No teratogenic effects were observed in rats when papaverine hydrochloride was administered subcutaneously as a single agent. It is not known whether papaverine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. *Papaverine Hydrochloride should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Papaverine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Papaverine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when papaverine hydrochloride is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Papaverine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Papaverine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Papaverine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Papaverine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Papaverine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Papaverine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Papaverine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenously or Intramuscularly
### Monitoring
There is limited information regarding Monitoring of Papaverine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Papaverine in the drug label.
# Overdosage
- The symptoms of toxicity from papaverine hydrochloride often result from vasomotor instability and include nausea, vomiting, weakness, central nervous system depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and sinus tachycardia.
- In large overdoses, papaverine is a potent inhibitor of cellular respiration and a weak calcium antagonist.
- Following an oral overdose of 15 g, metabolic acidosis with hyperventilation, hyperglycemia, and hypokalemia have been reported. No information on toxic serum concentrations is available.
- Following intravenous overdosing in animals, seizures, tachyarrhythmias, and ventricular fibrillation have been reported. The oral median lethal dose in rats is 360 mg/kg.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- No specific antidote is known.
- Treatment should be symptomatic and supportive.
- Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor vital signs, blood gases, blood chemistry values, and other variables.
- If convulsions occur, consider diazepam, phenytoin, or phenobarbital. If the seizures are refractory, general anesthesia with thiopental or halothane and paralysis with a neuromuscular blocking agent may be necessary.
- For hypotension, consider intravenous fluids, elevation of the legs, and an inotropic vasopressor, such as dopamine or norepinephrine (levarterenol). Theoretically, calcium gluconate may be helpful in treating some of the toxic cardiovascular effects of papaverine; monitor the ECG and plasma calcium concentrations.
- Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of papaverine hydrochloride.
# Pharmacology
## Mechanism of Action
- The most characteristic effect of papaverine is relaxation of the tonus of all smooth muscle, especially when it has been spasmodically contracted. Papaverine Hydrochloride apparently acts directly on the muscle itself. This relaxation is noted in the vascular system and bronchial musculature and in the gastrointestinal, biliary and urinary tracts.
- The main actions of papaverine are exerted on cardiac and smooth muscle. Papaverine relaxes various smooth muscles, especially those of larger arteries; this relaxation may be prominent if spasm exists. The antispasmodic effect is a direct one and unrelated to muscle innervation, and the muscle still responds to drugs and other stimuli causing contraction. Papaverine has minimal actions on the central nervous system, although very large doses tend to produce some sedation and sleepiness in some patients. In certain circumstances, mild respiratory stimulation can be observed, but this is therapeutically inconsequential. Papaverine stimulates respiration by acting on carotid and aortic body chemoreceptors.
- Papaverine relaxes the smooth musculature of the larger blood vessels, including the coronary, cerebral, peripheral, and pulmonary arteries. This action is particularly evident when such vessels are in spasm, induced reflexly or by drugs, and it provides the basis for the clinical use of papaverine in peripheral or pulmonary arterial embolism.
- Experimentally in dogs, the alkaloid has been shown to cause fairly marked and long-lasting coronary vasodilatation and an increase in coronary blood flow. However, it also appears to have a direct inotropic effect and, when increased mechanical activity coincides with decreased systemic pressure, increases in coronary blood flow may not be sufficient to prevent brief periods of hypoxic myocardial depression.
## Structure
- Papaverine Hydrochloride, USP, is the hydrochloride of an alkaloid obtained from opium or prepared synthetically. It belongs to the benzylisoquinoline group of alkaloids. It does not contain a phenanthrene group as do morphine and codeine.
- Papaverine Hydrochloride, USP, is 6,7-dimethoxy-1- veratrylisoquinoline hydrochloride and contains, on the dried basis, not less than 98.5% of C20H21NO4•HCI. The molecular weight is 375.85. The structural formula is as shown.
- Papaverine Hydrochloride occurs as white crystals or white crystalline powder. One gram dissolves in about 30 mL of water and in 120 mL of alcohol. It is soluble in chloroform and practically insoluble in ether.
- Papaverine Hydrochloride Injection, USP, is a clear, colorless to pale-yellow solution.
- Papaverine Hydrochloride, for parenteral administration, is a smooth-muscle relaxant that is available in vials containing 30 mg/mL. Each vial also contains edetate disodium 0.005%. The 10 mL vials also contain chlorobutanol 0.5% as a preservative. pH may be adjusted with sodium citrate and/or citric acid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Papaverine in the drug label.
## Pharmacokinetics
- Papaverine is effective by all routes of administration. A considerable fraction of the drug localizes in fat deposits and in the liver, with the remainder being distributed throughout the body. *It is metabolized in the liver. About 90% of the drug is bound to plasma protein. Although estimates of its biologic half-life vary widely, reasonably constant plasma levels can be maintained with oral administration at 6 hour intervals. The drug is excreted in the urine in an inactive form.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Papaverine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Papaverine in the drug label.
# How Supplied
- Papaverine Hydrochloride Injection, USP, 30 mg/mL
- 0517-4002-25 2 mL Vial packaged in boxes of 25
- 0517-4010-01 10 mL Multiple Dose Vial* packaged individually
- The 10 mL Multiple Dose Vial contains chlorobutanol 0.5% as a preservative.
## Storage
- Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature).
- PROTECT FROM LIGHT. RETAIN IN CARTON UNTIL TIME OF USE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Papaverine in the drug label.
# Precautions with Alcohol
- Alcohol-Papaverine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Papacon
- Para-Time S.R.
- Pavacot
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Papaverine | |
edfa94901d3c650ec0793fb3055e05747091afc3 | wikidoc | Parahumans | Parahumans
A parahuman or para-human is a human-animal hybrid. Scientists have done extensive research into the combination of genes from different species, e.g. adding human (and other animal) genes to bacteria and farm animals to mass-produce insulin and spider silk proteins. Note that individual genes can be transplanted between species without the transplantation of whole cells.
# Human-animal hybrids
Parahumans are also referred to as "human-animal hybrids". The term parahuman is not used in scientific publications. The term is sometimes used to sensationalize research that involves mixing biological materials from humans and other species. It was used in a National Geographic article to describe an experiment in 2003, during which Chinese scientists at the Shanghai Second Medical University successfully fused human cells with rabbit eggs.
# Rationale
There are several possible reasons that parahumans or chimeras might be created. The current forms of chimera exist for medical and industrial purposes, e.g., production of drugs and of organs suitable for organ transplantation. Other experiments aim to reveal knowledge about the function of the human body, e.g., by creating mice with a human-like immune system to study AIDS or with a brain incorporating human nerve cells. Restrictions on cloning and stem cell research makes chimera research a more attractive alternative in some researchers' eyes.
If parahumans are created using germline engineering, they breed true, and are different enough from ordinary humans to be unable to breed with them, this would qualify them as being a distinct species. Parahumans created using only somatic genetic engineering would have "normal" children. Another key difference is that a germ-line parahuman would most likely be modified before birth, while a somatic parahuman could be an adult human who chooses to be modified. The latter is sometimes seen as more ethical because the changes are made with informed consent; a counterargument is that no harm is done to a person born with modified genes because the person had no control over their genetics in the first place.
# Human-animal hybrids for scientific research
January, 2004
Scientists in Britain have been granted permission to create human-animal hybrid embryos by injecting human DNA into cows' eggs for stem cell research. Researchers from Newcastle University and King's College London submitted the application to the Human Fertilization and Embryology Authority (HFEA), an independent regulatory body that oversees embryo research and fertility treatment in Britain. The scientists said the hybrid human-bovine embryos could prove useful in pursuing treatments to prevent Parkinson's disease and Alzheimer's, as well as spinal cord injuries, diabetes and arthritis. However we have come to believe from recent scientfic research, that combining a human egg from a female donor and sperm from a cow; it is possible to create a cow-human hybrid. Instead of using human eggs, the researchers will remove the nuclei from cows' eggs and replace them with cells from the patients to create cloned stem cell lines that contain the same genetic mutation that results in these neurological disorders. This is groundbreaking research that will result in animal-human offspring later in the year 0f 2010.
"We feel that the development of disease-specific human embryonic stem cell lines from individuals suffering from genetic forms of neurodegenerative disorders will stimulate both basic research and the development of new treatments for devastating brain diseases," Dr. Stephen Minger, of the stem cell biology laboratory at King's College London, said in a release.
Minger cited the short supply of human eggs left over from in vitro fertilization, which have been used for stem cell research but have to be acquired through surgery on the women. "The hybrid embryo would be 99.9 percent human. The only bovine element would be found in DNA outside the nucleus of the cell."
The proposal has appalled critics of stem cell research, who criticize the idea of creating so-called "chimera" (see: Chimera (genetics)) embryos as an unethical and potentially dangerous practice.
# Ethics
There is no scientific field of parahuman research. Ethical, moral, and legal issues of parahuman research are speculative extensions of existing issues that arise in actual research. Some individuals see the creation of chimeras to devalue the uniqueness of human life or to be tampering with a divine plan.
In contrast, some transhumanists see this technology as one of many ways to overcome fundamental human limitations, such as disease and aging, and point out the many potential commercial and medical benefits. The debate can also be seen in terms of individual freedom to use germinal choice technology or reprogenetics.
Other ethical issues (shared with genetic engineering in general) involve the legal and moral status of a hybrid individual or race, whether the decision-making power over its creation should lie with governments or individuals, whether a distinction should be drawn between strictly medical treatments (restoring lost function) and those enhancing humans above some "normal" standard, whether medical ethics allow doctors to offer parahuman-related treatments, and whether xenotransplantation poses risks of cross-species disease transfer.
The developmental biologist Stuart Newman applied for a patent on a human-nonhuman chimera in 1997 as a challenge to the U.S. Patent and Trademark Office and the U.S. Congress on the patentability of organisms.
# Parahumans in fiction
Science fiction authors sometimes use the term parahuman to refer to distinct "races" of human-like creatures created through genetic engineering. A parahuman created starting from a nonhuman-animal template could be considered a biological uplift, as in the works of David Brin, while a parahuman based more closely on the human form and genome might also be called posthuman or transhuman. The role-playing game Transhuman Space and the related book "GURPS Bio-Tech" use the term parahuman interchangeably with variant human to refer to a wide array of heavily modified racial templates. These range from a "Gilgamesh-Series" resembling normal humans but with increased lifespan; a "Lepus-Series" resembling anthropomorphic rabbits; to a "Tek Rat" described as a mix of human, raccoon, and possum. The television series Dark Angel (TV series)|Dark Angel featured a group of parahumans (referred to in the series as "transgenics") with animal DNA selected to enhance their abilities to serve as supersoldiers. In Chapterhouse: Dune, by Frank Herbert, there is a species called Futar; they are a genetically engineered human/feline hybrid trained to kill the Honored Matres.
Parahumans are a useful concept for the science fiction writer, because they offer ways to explore issues such as racism, alienation, religion, and freedom and to justify colonization of exotic environments such as the ocean or planets with non-Earthlike properties.
One famous work involving parahumans (though not referred to as such) is The Island of Doctor Moreau]] by has explored the subject of parahumans in a number of science fiction stories, including The Dry Salvages (novella)|The Dry Salvages, "Riding the White Bull", and "Faces in Revolving Souls". John Crowley, in his novel Beasts (John Crowley)|Beasts, centered his plot around lion-human hybrids, with a lone fox-human hybrid acting as a kingmaker.
Humor authors such as Lewis Carroll in English language|English and Sukumar Ray in Bangla have had parahuman characters in their writings. More recently, Teenage Mutant Ninja Turtles, Maximum Ride and Full Metal Alchemist are themed around human-animal hybrids. | Parahumans
A parahuman or para-human is a human-animal hybrid. Scientists have done extensive research into the combination of genes from different species, e.g. adding human (and other animal) genes to bacteria and farm animals to mass-produce insulin and spider silk proteins. Note that individual genes can be transplanted between species without the transplantation of whole cells.
# Human-animal hybrids
Parahumans are also referred to as "human-animal hybrids". The term parahuman is not used in scientific publications. The term is sometimes used to sensationalize research that involves mixing biological materials from humans and other species. It was used in a National Geographic article to describe an experiment in 2003, during which Chinese scientists at the Shanghai Second Medical University successfully fused human cells with rabbit eggs.[1]
# Rationale
There are several possible reasons that parahumans or chimeras might be created. The current forms of chimera exist for medical and industrial purposes, e.g., production of drugs and of organs suitable for organ transplantation. Other experiments aim to reveal knowledge about the function of the human body, e.g., by creating mice with a human-like immune system to study AIDS or with a brain incorporating human nerve cells. Restrictions on cloning and stem cell research makes chimera research a more attractive alternative in some researchers' eyes.
If parahumans are created using germline engineering, they breed true, and are different enough from ordinary humans to be unable to breed with them, this would qualify them as being a distinct species. Parahumans created using only somatic genetic engineering would have "normal" children. Another key difference is that a germ-line parahuman would most likely be modified before birth, while a somatic parahuman could be an adult human who chooses to be modified. The latter is sometimes seen as more ethical because the changes are made with informed consent; a counterargument is that no harm is done to a person born with modified genes because the person had no control over their genetics in the first place.
# Human-animal hybrids for scientific research
January, 2004
Scientists in Britain have been granted permission to create human-animal hybrid embryos by injecting human DNA into cows' eggs for stem cell research.[2][3][4][1] Researchers from Newcastle University and King's College London submitted the application to the Human Fertilization and Embryology Authority (HFEA), an independent regulatory body that oversees embryo research and fertility treatment in Britain. The scientists said the hybrid human-bovine embryos could prove useful in pursuing treatments to prevent Parkinson's disease and Alzheimer's, as well as spinal cord injuries, diabetes and arthritis. However we have come to believe from recent scientfic research, that combining a human egg from a female donor and sperm from a cow; it is possible to create a cow-human hybrid. Instead of using human eggs, the researchers will remove the nuclei from cows' eggs and replace them with cells from the patients to create cloned stem cell lines that contain the same genetic mutation that results in these neurological disorders. This is groundbreaking research that will result in animal-human offspring later in the year 0f 2010.
"We feel that the development of disease-specific human embryonic stem cell lines from individuals suffering from genetic forms of neurodegenerative disorders will stimulate both basic research and the development of new treatments for devastating brain diseases," Dr. Stephen Minger, of the stem cell biology laboratory at King's College London, said in a release.
Minger cited the short supply of human eggs left over from in vitro fertilization, which have been used for stem cell research but have to be acquired through surgery on the women. "The hybrid embryo would be 99.9 percent human. The only bovine element would be found in DNA outside the nucleus of the cell."
The proposal has appalled critics of stem cell research, who criticize the idea of creating so-called "chimera" (see: Chimera (genetics)) embryos as an unethical and potentially dangerous practice.
# Ethics
There is no scientific field of parahuman research. Ethical, moral, and legal issues of parahuman research are speculative extensions of existing issues that arise in actual research. Some individuals see the creation of chimeras to devalue the uniqueness of human life or to be tampering with a divine plan.
In contrast, some transhumanists see this technology as one of many ways to overcome fundamental human limitations, such as disease and aging, and point out the many potential commercial and medical benefits.[5] The debate can also be seen in terms of individual freedom to use germinal choice technology or reprogenetics.
Other ethical issues (shared with genetic engineering in general) involve the legal and moral status of a hybrid individual or race, whether the decision-making power over its creation should lie with governments or individuals, whether a distinction should be drawn between strictly medical treatments (restoring lost function) and those enhancing humans above some "normal" standard, whether medical ethics allow doctors to offer parahuman-related treatments, and whether xenotransplantation poses risks of cross-species disease transfer.
The developmental biologist Stuart Newman applied for a patent on a human-nonhuman chimera in 1997 as a challenge to the U.S. Patent and Trademark Office and the U.S. Congress on the patentability of organisms.[6]
# Parahumans in fiction
Science fiction authors sometimes use the term parahuman to refer to distinct "races" of human-like creatures created through genetic engineering. A parahuman created starting from a nonhuman-animal template could be considered a biological uplift, as in the works of David Brin, while a parahuman based more closely on the human form and genome might also be called posthuman or transhuman. The role-playing game Transhuman Space and the related book "GURPS Bio-Tech" use the term parahuman interchangeably with variant human to refer to a wide array of heavily modified racial templates. These range from a "Gilgamesh-Series" resembling normal humans but with increased lifespan; a "Lepus-Series" resembling anthropomorphic rabbits; to a "Tek Rat" described as a mix of human, raccoon, and possum. The television series Dark Angel (TV series)|Dark Angel featured a group of parahumans (referred to in the series as "transgenics") with animal DNA selected to enhance their abilities to serve as supersoldiers. In Chapterhouse: Dune, by Frank Herbert, there is a species called Futar; they are a genetically engineered human/feline hybrid trained to kill the Honored Matres.
Parahumans are a useful concept for the science fiction writer, because they offer ways to explore issues such as racism, alienation, religion, and freedom and to justify colonization of exotic environments such as the ocean or planets with non-Earthlike properties.
One famous work involving parahumans (though not referred to as such) is The Island of Doctor Moreau]] by [[H.G. Wells. During the Golden Age of Science Fiction, Cordwainer Smith's parahuman underpeople (humans derived from animal stock) were an important part of his Instrumentality stories. More recently, Caitlín R. Kiernan, who has described herself as a parahumanist,[citation needed] has explored the subject of parahumans in a number of science fiction stories, including The Dry Salvages (novella)|The Dry Salvages, "Riding the White Bull", and "Faces in Revolving Souls". John Crowley, in his novel Beasts (John Crowley)|Beasts, centered his plot around lion-human hybrids, with a lone fox-human hybrid acting as a kingmaker.
Humor authors such as Lewis Carroll in English language|English and Sukumar Ray in Bangla have had parahuman characters in their writings. More recently, Teenage Mutant Ninja Turtles, Maximum Ride and Full Metal Alchemist are themed around human-animal hybrids. | https://www.wikidoc.org/index.php/Parahumans | |
3e2d10ee8a55bdfe524307c730474c9abeb6d771 | wikidoc | Paranormal | Paranormal
Paranormal is a general term that describes unusual experiences that lack a scientific explanation, or phenomena alleged to be outside of science's current ability to explain or measure. In parapsychology, it is used to describe the potentially psychic phenomena of telepathy, extra-sensory perception, psychokinesis, ghosts, and hauntings. The term is also applied to UFOs, some creatures that fall under the scope of cryptozoology, purported phenomena surrounding the Bermuda Triangle, and other non-psychic subjects. Stories relating to paranormal phenomena are found in popular culture and folklore, but the scientific community, as referenced in statements made by organization such as the United States National Science Foundation, contends that scientific evidence does not support paranormal beliefs.
# Paranormal research
Approaching the paranormal from a research perspective is often difficult because of the lack of acceptance of the physical reality of most of the purported phenonema. By definition, the paranormal does not conform to conventional expectations of the natural. Despite this challenge, studies on the paranormal are periodically conducted by researchers all from various disciplines. Some researchers study just the beliefs in the paranormal regardless of whether the phenomena are considered to objectively exist. This section deals with various approaches to the paranormal: anecdotal, experimental, and participant-observer approaches, the skeptical investigation approach and the survey approach.
## Anecdotal approach
An anecdotal approach to the paranormal involves the collection of stories told about the paranormal. Such collections, lacking the rigour of empirical evidence, are not amenable to be subjected to scientific investigation. The anecdotal approach is not a scientific approach to the paranormal because it leaves verification dependent on the credibility of the party presenting the evidence. It is also subject to such logical fallacies as cognitive bias, inductive reasoning, lack of falsifiability, and other fallacies that may prevent the anecdote from having meaningful information to impart. Nevertheless, it is a common approach to paranormal phenomena.
Charles Fort (1874-1932) is perhaps the best known collector of paranormal anecdotes. Fort is said to have compiled as many as 40,000 notes on unexplained paranormal experiences, though there were no doubt many more than these. These notes came from what he called "the orthodox conventionality of Science", which were odd events originally reported in magazines and newspapers such as The Times and scientific journals such as Scientific American, Nature and Science. From this research Fort wrote seven books, though only four survive. These are: The Book of the Damned (1919), New Lands (1923), Lo! (1931) and Wild Talents (1932); one book was written between New Lands and Lo! but it was abandoned and absorbed into Lo!.
Reported events that he collected include teleportation (a term Fort is generally credited with coining); poltergeist events, falls of frogs, fishes, inorganic materials of an amazing range; crop circles; unaccountable noises and explosions; spontaneous fires; levitation; ball lightning (a term explicitly used by Fort); unidentified flying objects; mysterious appearances and disappearances; giant wheels of light in the oceans; and animals found outside their normal ranges (see phantom cat). He offered many reports of OOPArts, abbreviation for "out of place" artifacts: strange items found in unlikely locations. He also is perhaps the first person to explain strange human appearances and disappearances by the hypothesis of alien abduction, and was an early proponent of the extraterrestrial hypothesis.
Fort is considered by many as the father of modern paranormalism, which is the study of the paranormal.
The magazine Fortean Times continues Charles Fort's approach, regularly reporting anecdotal accounts of the paranormal.
## Parapsychology
Experimental investigation of the paranormal has been conducted by parapsychologists. Although parapsychology has its roots in earlier research, it began using the experimental approach in the 1930s under the direction of J. B. Rhine (1895 – 1980). Rhine popularized the now famous methodology of using card-guessing and dice-rolling experiments in a laboratory in the hopes of finding a statistical validation of extra-sensory perception.
In 1957, the Parapsychological Association was formed as the preeminent society for parapsychologists. In 1969, they became affiliated with the American Association for the Advancement of Science. That affiliation, along with a general openness to psychic and occult phenomena in the 1970s, led to a decade of increased parapsychological research. During this time, other notable organizations were also formed, including the Academy of Parapsychology and Medicine (1970), the Institute of Parascience (1971), the Academy of Religion and Psychical Research, the Institute for Noetic Sciences (1973), and the International Kirlian Research Association (1975). Each of these groups performed experiments on paranormal subjects to varying degrees. Parapsychological work was also conducted at the Stanford Research Institute during this time.
With the increase in parapsychological investigation, there came an increase in opposition to both the findings of parapsychologists and the granting of any formal recognition of the field. Criticisms of the field were focused in the founding of the Committee for the Scientific Investigation of Claims of the Paranormal (1976), now called the Committee for Skeptical Inquiry, and its periodical, Skeptical Inquirer. Eventually, more mainstream scientists became critical of parapsychology as an endeavor, and statements by the National Academies of Science and the National Science Foundation cast a pall on the claims of evidence for parapsychology. Today, many cite parapsychology as an example of a pseudoscience.
Though there are still some parapsychologists active today, interest and activity has waned considerably since the 1970s. To date there have been no experimental results that have gained wide acceptance in the scientific community as valid evidence of the paranormal.
## Participant-observer approach
While parapsychologists look for quantitative evidence of the paranormal in laboratories, a great number of people immerse themselves in qualitative research through participant-observer approaches to the paranormal. Participant-observer methodologies have overlaps with other essentially qualitative approaches as well, including phenomenological research that seeks largely to describe subjects as they are experienced, rather than to explain them.
Participant-observation suggests that by immersing oneself in the subject being studied, a researcher is presumed to gain understanding of the subject. Criticisms of participant-observation as a data-gathering technique are similar to criticisms of other approaches to the paranormal, but also include an increased threat to the objectivity of the researcher, unsystematic gathering of data, reliance on subjective measurement, and possible observer effects (observation may distort the observed behavior). Specific data gathering methods, such as recording EMF readings at haunted locations have their own criticisms beyond those attributed to the participant-observation approach itself.
The participant-observer approach to the paranormal has gained increased visibility and popularity through reality-based television shows like Ghost Hunters, and the formation of independent ghost hunting groups which advocate immersive research at alleged paranormal locations. One popular website for ghost hunting enthusiasts lists over 300 of these organizations throughout the United States and the United Kingdom.
## Skeptical scientific investigation
Scientific skeptics advocate critical investigation of claims of paranormal phenomena: applying the scientific method to reach a rational, scientific explanation of the phenomena to account for the paranormal claims, taking into account that alleged paranormal abilities and occurrences are sometimes hoaxes or misinterpretations of natural phenomena. A way of summarizing this method is by the application of Occam's razor, which suggests that the simplest solution is usually the correct one. The standard scientific models gives an explanation for what appears to be paranormal phenomena is usually a misinterpretation, misunderstanding, or anomalous variation of natural phenomena, rather than an actual paranormal phenomenon.
The Committee for Skeptical Inquiry, formerly the Committee for the Scientific Investigation of Claims of the Paranormal (CSICOP), is an organisation that aims to publicise the scientific, skeptical approach. It carries out investigations aimed at understanding paranormal reports in terms of scientific understanding, and publishes its results in its journal, the Skeptical Inquirer.
Former stage magician, James Randi, is a well-known investigator of paranormal claims and a prominent member of CSICOP. As an investigator with a background in illusion, Randi feels that the simplest explanation for those claiming paranormal abilities is often trickery, illustrated by demonstrating that the spoon bending abilities of psychic Uri Geller can easily be duplicated by trained magicians. He is also the founder of the James Randi Educational Foundation and its famous million dollar challenge offering a prize of US $1,000,000 to anyone who can demonstrate evidence of any paranormal, supernatural or occult power or event, under test conditions agreed to by both parties.
### Anomalistics
Anomalistics works on the premise that paranormal phenomena may be hoaxes, understood within current scientific models, or else be rationalized using an as yet unexplored avenue of science.
# Belief polls
While the validity of the existence of paranormal phenomena is controversial and debated passionately by both proponents of the paranormal and by skeptics, surveys are useful in determining the beliefs of people in regards to paranormal phenomena. These opinions, while not constituting scientific evidence for or against, may give an indication of the mindset of a certain portion of the population (at least among those who answered the polls).
One survey of the beliefs of the general United States population regarding paranormal topics was conducted by the Gallup Organization in 2005. The survey found that 73 percent of those polled believed in at least one of the ten paranormal items presented in the survey. The ten items included in the survey were: Extrasensory perception (41% held this belief), haunted houses (37%), ghosts (32%), telepathy (31%), clairvoyance (26%), astrology (25%), communication with the dead (21%), witches (21%), reincarnation (20%), and channeling spiritual entities (9%). These items were selected as they "require the belief that humans have more than the 'normal' five senses." Only one percent of respondents believed in all ten items.
Another survey conducted in 2006 by researchers from Australia's Monash University sought to determine what types of phenomena people claim to have experienced and the effects these experiences have had on their lives. The study was conducted as an online survey with over 2,000 respondents from around the world participating. The results revealed that around 70% of the respondents believe to have had an unexplained paranormal event that changed their life, mostly in a positive way. About 70% also claimed to have seen, heard, or been touched by an animal or person that they knew was not there; 80% have reported having a premonition, and almost 50% stated they recalled a previous life.
Polls were conducted by Bryan Farha at Oklahoma City University and Gary Steward of the University of Central Oklahoma in 2006, and compared to the results of a Gallup poll in 2001. They found fairly consistent results.
Other surveys by different organizations at different times have found very similar results. A 2001 Gallup Poll found that the general public embraced the following: 54% of people believed in psychic/spiritual healing, 42% believed in haunted houses, 41% believed in satanic possession, 36% in telepathy, 25% in reincarnation, and 15% in channeling. A survey by Jeffrey S. Levin, associate professor at
Eastern Virginia Medical School, Norfolk found that over 2/3 of the U.S. population reported having at least one mystical experience.
A 1996 Gallup poll estimated that 71% of the people in the United States believed that the government was covering up information about UFOs. A 2002 Roper poll conducted for the Sci Fi channel reported that 56% thought UFOs were real craft and 48% that aliens had visited the Earth.
A 2001 National Science Foundation survey found that 9 percent of people polled thought astrology was very scientific, and 31 percent thought it was somewhat scientific. About 32% of Americans surveyed stated that some numbers were lucky, while 46% of Europeans agreed with that claim. About 60% of all people polled believed in some form of Extra-sensory perception and 30% thought that "some of the unidentified flying objects that have been reported are really space vehicles from other civilizations."
# Paranormal subjects
This section explores the notable paranormal beliefs that appear in popular culture.
## Ghosts
For believers, ghosts are generally seen to be the spirit or soul of a deceased person. Alternative theories expand on that idea and include belief in the ghosts of deceased animals. Sometimes the term "ghost" is used synonymously with any spirit or demon, however in popular usage the term typically refers to a deceased person.
The belief in ghosts as souls of the departed is closely tied to the concept of animism, an ancient belief which attributed souls to everything in nature. As the nineteenth-century anthropologist James Frazer explained in his classic work, The Golden Bough, souls were seen as the creature within that animated the body. Although the human soul was sometimes symbolically or literally depicted in ancient cultures as a bird or other animal, it was widely held that the soul was an exact reproduction of the body in every feature, even down to clothing the person wore. This is depicted in artwork from various ancient cultures, including such works as the Egyptian Book of the Dead, which shows deceased people in the afterlife appearing much as they did before death, including the style of dress.
A widespread belief concerning ghosts is that they are composed of a misty, airy, or subtle material. Anthropologists speculate that this may also stem from early beliefs that ghosts were the person within the person, most noticeable in ancient cultures as a person's breath, which upon exhaling in colder climates appears visibly as a white mist. This belief may have also fostered the metaphorical meaning of "breath" in certain languages, such as the Latin spiritus and the Greek pneuma, which by analogy became extended to mean the soul. In the Bible, God is depicted as animating Adam with a breath.
Numerous theories have been proposed by scientists to provide non-paranormal explanations for ghosts sightings. Although the evidence for ghosts is largely anecdotal, the belief in ghosts throughout history has remained widespread and persistent.
## UFOs
The possibility of extraterrestrial life is not, by itself, a paranormal subject. Many scientists are actively engaged in the search for unicellular life within the solar system, carrying out studies on the surface of Mars and examining meteors that have fallen to Earth. Projects such as SETI are conducting an astronomical search for radio activity that would show evidence of intelligent life outside the solar system. Scientific theories of how life developed on Earth allow for the possibility that life developed on other planets as well. The paranormal aspect of extraterrestrial life centers largely around the belief in unidentified flying objects and the phenomena said to be associated with them.
Early in the history of UFO culture, believers divided themselves into two camps. The first held a rather conservative view of the phenomena, interpreting it as unexplained occurrences that merited serious study. They began calling themselves "ufologists" in the 1950s and felt that logical analysis of sighting reports would validate the notion of extraterrestrial visitation.
The second camp consisted of individuals who coupled ideas of extraterrestrial visitation with beliefs from existing quasi-religious movements. These individuals typically were enthusiasts of occultism and the paranormal. Many had backgrounds as active Theosophists, Spiritualists, or were followers of other esoteric doctrines. In contemporary times, many of these beliefs have coalesced into New Age spiritual movements.
Both secular and spiritual believers describe UFOs as having abilities beyond what is considered possible according to aerodynamics and physical laws. The transitory events surrounding many UFO sightings also limits the opportunity for repeat testing required by the scientific method. Acceptance of UFO theories by the larger scientific community is further hindered by the many possible hoaxes associated with UFO culture.
# Paranormal challenges
In 1922, Scientific American offered two US $2,500 offers: (1) for the first authentic spirit photograph made under test conditions, and (2) for the first psychic to produce a "visible psychic manifestation." Harry Houdini was a member of the investigating committee. The first medium to be tested was George Valiantine, who claimed that in his presence spirits would speak through a trumpet that floated around a darkened room. For the test, Valiantine was placed in a room, the lights were extinguished, but unbeknownst to him his chair had been rigged to light a signal in an adjoining room if he ever left his seat. Because the light signals were tripped during his performance, Valiantine did not collect the award. The last to be examined by Scientific American was Mina Crandon in 1924.
Since then, many individuals and groups have offered similar monetary awards for proof of the paranormal in an observed setting. These prizes have a combined value of over $2.4 million dollars.
The James Randi Educational Foundation offers a prize of a million dollars to a person who can prove that they have supernatural or paranormal abilities under appropriate test conditions. No famous psychic has gone through with taking the challenge.
# Etymology
The word “paranormal” has been in the English language since at least 1920. It consists of two parts: para and normal. In most definitions of the word paranormal, it is described as anything that is beyond or contrary to what is deemed scientifically possible. The definition implies that the scientific explanation of the world around us is the 'normal' part of the word and 'para' makes up the above, beyond, beside, contrary, or against part of the meaning.
Para has a Greek and Latin origin. Its most common meaning (the Greek usage) is 'similar to' or 'near to', as in paragraph. In Latin, para means 'above,' against,' 'counter,' 'outside,' or 'beyond'. For example, parapluie in French means 'counter-rain' – an umbrella. It can be construed, then, that the term paranormal is derived from the Latin use of the prefix 'para', meaning 'against, counter, outside or beyond the norm.' | Paranormal
Template:Paranormal
Paranormal is a general term that describes unusual experiences that lack a scientific explanation,[1] or phenomena alleged to be outside of science's current ability to explain or measure.[2] In parapsychology, it is used to describe the potentially psychic phenomena of telepathy, extra-sensory perception, psychokinesis, ghosts, and hauntings. The term is also applied to UFOs, some creatures that fall under the scope of cryptozoology, purported phenomena surrounding the Bermuda Triangle, and other non-psychic subjects.[3] Stories relating to paranormal phenomena are found in popular culture and folklore, but the scientific community, as referenced in statements made by organization such as the United States National Science Foundation, contends that scientific evidence does not support paranormal beliefs.[4]
# Paranormal research
Approaching the paranormal from a research perspective is often difficult because of the lack of acceptance of the physical reality of most of the purported phenonema. By definition, the paranormal does not conform to conventional expectations of the natural. Despite this challenge, studies on the paranormal are periodically conducted by researchers all from various disciplines. Some researchers study just the beliefs in the paranormal regardless of whether the phenomena are considered to objectively exist. This section deals with various approaches to the paranormal: anecdotal, experimental, and participant-observer approaches, the skeptical investigation approach and the survey approach.
## Anecdotal approach
An anecdotal approach to the paranormal involves the collection of stories told about the paranormal. Such collections, lacking the rigour of empirical evidence, are not amenable to be subjected to scientific investigation. The anecdotal approach is not a scientific approach to the paranormal because it leaves verification dependent on the credibility of the party presenting the evidence. It is also subject to such logical fallacies as cognitive bias, inductive reasoning, lack of falsifiability, and other fallacies that may prevent the anecdote from having meaningful information to impart. Nevertheless, it is a common approach to paranormal phenomena.
Charles Fort (1874-1932) is perhaps the best known collector of paranormal anecdotes. Fort is said to have compiled as many as 40,000 notes on unexplained paranormal experiences, though there were no doubt many more than these. These notes came from what he called "the orthodox conventionality of Science", which were odd events originally reported in magazines and newspapers such as The Times and scientific journals such as Scientific American, Nature and Science. From this research Fort wrote seven books, though only four survive. These are: The Book of the Damned (1919), New Lands (1923), Lo! (1931) and Wild Talents (1932); one book was written between New Lands and Lo! but it was abandoned and absorbed into Lo!.
Reported events that he collected include teleportation (a term Fort is generally credited with coining); poltergeist events, falls of frogs, fishes, inorganic materials of an amazing range; crop circles; unaccountable noises and explosions; spontaneous fires; levitation; ball lightning (a term explicitly used by Fort); unidentified flying objects; mysterious appearances and disappearances; giant wheels of light in the oceans; and animals found outside their normal ranges (see phantom cat). He offered many reports of OOPArts, abbreviation for "out of place" artifacts: strange items found in unlikely locations. He also is perhaps the first person to explain strange human appearances and disappearances by the hypothesis of alien abduction, and was an early proponent of the extraterrestrial hypothesis.
Fort is considered by many as the father of modern paranormalism, which is the study of the paranormal.
The magazine Fortean Times continues Charles Fort's approach, regularly reporting anecdotal accounts of the paranormal.
## Parapsychology
Experimental investigation of the paranormal has been conducted by parapsychologists. Although parapsychology has its roots in earlier research, it began using the experimental approach in the 1930s under the direction of J. B. Rhine (1895 – 1980).[5] Rhine popularized the now famous methodology of using card-guessing and dice-rolling experiments in a laboratory in the hopes of finding a statistical validation of extra-sensory perception.[5]
In 1957, the Parapsychological Association was formed as the preeminent society for parapsychologists. In 1969, they became affiliated with the American Association for the Advancement of Science. That affiliation, along with a general openness to psychic and occult phenomena in the 1970s, led to a decade of increased parapsychological research.[5] During this time, other notable organizations were also formed, including the Academy of Parapsychology and Medicine (1970), the Institute of Parascience (1971), the Academy of Religion and Psychical Research, the Institute for Noetic Sciences (1973), and the International Kirlian Research Association (1975). Each of these groups performed experiments on paranormal subjects to varying degrees. Parapsychological work was also conducted at the Stanford Research Institute during this time.[5]
With the increase in parapsychological investigation, there came an increase in opposition to both the findings of parapsychologists and the granting of any formal recognition of the field. Criticisms of the field were focused in the founding of the Committee for the Scientific Investigation of Claims of the Paranormal (1976), now called the Committee for Skeptical Inquiry, and its periodical, Skeptical Inquirer.[5] Eventually, more mainstream scientists became critical of parapsychology as an endeavor, and statements by the National Academies of Science and the National Science Foundation cast a pall on the claims of evidence for parapsychology. Today, many cite parapsychology as an example of a pseudoscience.
Though there are still some parapsychologists active today, interest and activity has waned considerably since the 1970s.[6] To date there have been no experimental results that have gained wide acceptance in the scientific community as valid evidence of the paranormal. [6]
## Participant-observer approach
While parapsychologists look for quantitative evidence of the paranormal in laboratories, a great number of people immerse themselves in qualitative research through participant-observer approaches to the paranormal. Participant-observer methodologies have overlaps with other essentially qualitative approaches as well, including phenomenological research that seeks largely to describe subjects as they are experienced, rather than to explain them.[7]
Participant-observation suggests that by immersing oneself in the subject being studied, a researcher is presumed to gain understanding of the subject. Criticisms of participant-observation as a data-gathering technique are similar to criticisms of other approaches to the paranormal, but also include an increased threat to the objectivity of the researcher, unsystematic gathering of data, reliance on subjective measurement, and possible observer effects (observation may distort the observed behavior).[8] Specific data gathering methods, such as recording EMF readings at haunted locations have their own criticisms beyond those attributed to the participant-observation approach itself.
The participant-observer approach to the paranormal has gained increased visibility and popularity through reality-based television shows like Ghost Hunters, and the formation of independent ghost hunting groups which advocate immersive research at alleged paranormal locations. One popular website for ghost hunting enthusiasts lists over 300 of these organizations throughout the United States and the United Kingdom.[9]
## Skeptical scientific investigation
Scientific skeptics advocate critical investigation of claims of paranormal phenomena: applying the scientific method to reach a rational, scientific explanation of the phenomena to account for the paranormal claims, taking into account that alleged paranormal abilities and occurrences are sometimes hoaxes or misinterpretations of natural phenomena. A way of summarizing this method is by the application of Occam's razor, which suggests that the simplest solution is usually the correct one.[10] The standard scientific models gives an explanation for what appears to be paranormal phenomena is usually a misinterpretation, misunderstanding, or anomalous variation of natural phenomena, rather than an actual paranormal phenomenon.
The Committee for Skeptical Inquiry, formerly the Committee for the Scientific Investigation of Claims of the Paranormal (CSICOP), is an organisation that aims to publicise the scientific, skeptical approach. It carries out investigations aimed at understanding paranormal reports in terms of scientific understanding, and publishes its results in its journal, the Skeptical Inquirer.
Former stage magician, James Randi, is a well-known investigator of paranormal claims[11] and a prominent member of CSICOP. As an investigator with a background in illusion, Randi feels that the simplest explanation for those claiming paranormal abilities is often trickery, illustrated by demonstrating that the spoon bending abilities of psychic Uri Geller can easily be duplicated by trained magicians.[12] He is also the founder of the James Randi Educational Foundation and its famous million dollar challenge offering a prize of US $1,000,000 to anyone who can demonstrate evidence of any paranormal, supernatural or occult power or event, under test conditions agreed to by both parties.[13]
### Anomalistics
Anomalistics works on the premise that paranormal phenomena may be hoaxes, understood within current scientific models, or else be rationalized using an as yet unexplored avenue of science.[14][15]
[16]
# Belief polls
While the validity of the existence of paranormal phenomena is controversial and debated passionately by both proponents of the paranormal and by skeptics, surveys are useful in determining the beliefs of people in regards to paranormal phenomena. These opinions, while not constituting scientific evidence for or against, may give an indication of the mindset of a certain portion of the population (at least among those who answered the polls).
One survey of the beliefs of the general United States population regarding paranormal topics was conducted by the Gallup Organization in 2005.[17] The survey found that 73 percent of those polled believed in at least one of the ten paranormal items presented in the survey. The ten items included in the survey were: Extrasensory perception (41% held this belief), haunted houses (37%), ghosts (32%), telepathy (31%), clairvoyance (26%), astrology (25%), communication with the dead (21%), witches (21%), reincarnation (20%), and channeling spiritual entities (9%). These items were selected as they "require the belief that humans have more than the 'normal' five senses." Only one percent of respondents believed in all ten items.
Another survey conducted in 2006 by researchers from Australia's Monash University[18] sought to determine what types of phenomena people claim to have experienced and the effects these experiences have had on their lives. The study was conducted as an online survey with over 2,000 respondents from around the world participating. The results revealed that around 70% of the respondents believe to have had an unexplained paranormal event that changed their life, mostly in a positive way. About 70% also claimed to have seen, heard, or been touched by an animal or person that they knew was not there; 80% have reported having a premonition, and almost 50% stated they recalled a previous life.[18]
Polls were conducted by Bryan Farha at Oklahoma City University and Gary Steward of the University of Central Oklahoma in 2006, and compared to the results of a Gallup poll in 2001.[19] They found fairly consistent results.
Other surveys by different organizations at different times have found very similar results. A 2001 Gallup Poll found that the general public embraced the following: 54% of people believed in psychic/spiritual healing, 42% believed in haunted houses, 41% believed in satanic possession, 36% in telepathy, 25% in reincarnation, and 15% in channeling.[20] A survey by Jeffrey S. Levin, associate professor at
Eastern Virginia Medical School, Norfolk found that over 2/3 of the U.S. population reported having at least one mystical experience.[21][19]
A 1996 Gallup poll estimated that 71% of the people in the United States believed that the government was covering up information about UFOs. A 2002 Roper poll conducted for the Sci Fi channel reported that 56% thought UFOs were real craft and 48% that aliens had visited the Earth.[19]
A 2001 National Science Foundation survey found that 9 percent of people polled thought astrology was very scientific, and 31 percent thought it was somewhat scientific. About 32% of Americans surveyed stated that some numbers were lucky, while 46% of Europeans agreed with that claim. About 60% of all people polled believed in some form of Extra-sensory perception and 30% thought that "some of the unidentified flying objects that have been reported are really space vehicles from other civilizations."[22]
# Paranormal subjects
This section explores the notable paranormal beliefs that appear in popular culture.
## Ghosts
For believers, ghosts are generally seen to be the spirit or soul of a deceased person.[23] Alternative theories expand on that idea and include belief in the ghosts of deceased animals. Sometimes the term "ghost" is used synonymously with any spirit or demon[24], however in popular usage the term typically refers to a deceased person.
The belief in ghosts as souls of the departed is closely tied to the concept of animism, an ancient belief which attributed souls to everything in nature.[5] As the nineteenth-century anthropologist James Frazer explained in his classic work, The Golden Bough, souls were seen as the creature within that animated the body.[25] Although the human soul was sometimes symbolically or literally depicted in ancient cultures as a bird or other animal, it was widely held that the soul was an exact reproduction of the body in every feature, even down to clothing the person wore. This is depicted in artwork from various ancient cultures, including such works as the Egyptian Book of the Dead, which shows deceased people in the afterlife appearing much as they did before death, including the style of dress.
A widespread belief concerning ghosts is that they are composed of a misty, airy, or subtle material. Anthropologists speculate that this may also stem from early beliefs that ghosts were the person within the person, most noticeable in ancient cultures as a person's breath, which upon exhaling in colder climates appears visibly as a white mist.[5] This belief may have also fostered the metaphorical meaning of "breath" in certain languages, such as the Latin spiritus and the Greek pneuma, which by analogy became extended to mean the soul. In the Bible, God is depicted as animating Adam with a breath.
Numerous theories have been proposed by scientists to provide non-paranormal explanations for ghosts sightings.[5] Although the evidence for ghosts is largely anecdotal, the belief in ghosts throughout history has remained widespread and persistent.
## UFOs
The possibility of extraterrestrial life is not, by itself, a paranormal subject. Many scientists are actively engaged in the search for unicellular life within the solar system, carrying out studies on the surface of Mars and examining meteors that have fallen to Earth.[26] Projects such as SETI are conducting an astronomical search for radio activity that would show evidence of intelligent life outside the solar system.[27] Scientific theories of how life developed on Earth allow for the possibility that life developed on other planets as well. The paranormal aspect of extraterrestrial life centers largely around the belief in unidentified flying objects and the phenomena said to be associated with them.
Early in the history of UFO culture, believers divided themselves into two camps. The first held a rather conservative view of the phenomena, interpreting it as unexplained occurrences that merited serious study. They began calling themselves "ufologists" in the 1950s and felt that logical analysis of sighting reports would validate the notion of extraterrestrial visitation.[5]
The second camp consisted of individuals who coupled ideas of extraterrestrial visitation with beliefs from existing quasi-religious movements. These individuals typically were enthusiasts of occultism and the paranormal. Many had backgrounds as active Theosophists, Spiritualists, or were followers of other esoteric doctrines. In contemporary times, many of these beliefs have coalesced into New Age spiritual movements.[5]
Both secular and spiritual believers describe UFOs as having abilities beyond what is considered possible according to aerodynamics and physical laws. The transitory events surrounding many UFO sightings also limits the opportunity for repeat testing required by the scientific method. Acceptance of UFO theories by the larger scientific community is further hindered by the many possible hoaxes associated with UFO culture.
# Paranormal challenges
In 1922, Scientific American offered two US $2,500 offers: (1) for the first authentic spirit photograph made under test conditions, and (2) for the first psychic to produce a "visible psychic manifestation." Harry Houdini was a member of the investigating committee. The first medium to be tested was George Valiantine, who claimed that in his presence spirits would speak through a trumpet that floated around a darkened room. For the test, Valiantine was placed in a room, the lights were extinguished, but unbeknownst to him his chair had been rigged to light a signal in an adjoining room if he ever left his seat. Because the light signals were tripped during his performance, Valiantine did not collect the award.[28] The last to be examined by Scientific American was Mina Crandon in 1924.
Since then, many individuals and groups have offered similar monetary awards for proof of the paranormal in an observed setting. These prizes have a combined value of over $2.4 million dollars.[29]
The James Randi Educational Foundation offers a prize of a million dollars to a person who can prove that they have supernatural or paranormal abilities under appropriate test conditions. No famous psychic has gone through with taking the challenge.
# Etymology
The word “paranormal” has been in the English language since at least 1920.[30][31] It consists of two parts: para and normal. In most definitions of the word paranormal, it is described as anything that is beyond or contrary to what is deemed scientifically possible.[32] The definition implies that the scientific explanation of the world around us is the 'normal' part of the word and 'para' makes up the above, beyond, beside, contrary, or against part of the meaning.
Para has a Greek and Latin origin. Its most common meaning (the Greek usage) is 'similar to' or 'near to', as in paragraph. In Latin, para means 'above,' against,' 'counter,' 'outside,' or 'beyond'. For example, parapluie in French means 'counter-rain' – an umbrella. It can be construed, then, that the term paranormal is derived from the Latin use of the prefix 'para', meaning 'against, counter, outside or beyond the norm.' | https://www.wikidoc.org/index.php/Paranormal | |
11a1ccece06bb375c30e61f24ecefc1102ccafe5 | wikidoc | Paraphilia | Paraphilia
Synonyms and keywords: Fetishism, Voyeurism, Zoophilia, Pedophilia, Sexual perversion, Zoophilism, Abnormal sexual activity
# Overview
Paraphilias are characterized by severe deviant sexual desire or urge resulting in actions that may cause significant impairment in functioning as well as distress (for oneself and/or others). Paraphilic behavior may occur intermittently or may persist for the entire life. To begin with, paraphilia occurs in the form of fantasy, and the paraphilic behavior manifests later in life. Mostly the individuals with this condition do not seek treatment themselves due to the pleasure they obtain from it and in some cases, the associated stigma. Paraphilias are not illegal but the resulting behaviors are. Timely treatment is important to prevent sexual offenses like pedophilia or serial rapes. Patients may have more than one type of paraphilia and therefore, it is essential to evaluate them thoroughly to provide optimal management.
# Historical Perspective
- The term 'Paraphilia' is Greek in origin and is derived from the words-'Para'(deviation) and 'philia'(attraction).
- From biblical times, human societies across the world, have placed restrictions on many types of sexual behaviors. The level of acceptability is based on cultural variations across the globe.
- There is controversy in what should be called sexual deviation, mainly based on various factors like the degree of consent, age of the involved individuals, degree of distress caused, location of sexual behavior, degree of unacceptable by others, etc.
- The term 'Sadism' originated from Marquis de Sade (1740-1814). He was placed in a lunatic asylum multiple times and ultimately, died there. His mental instability is considered to have resulted in this pattern of sexual behavior.
- The term 'Masochism' came from Baron Leopold von Sacher Masoch (1835-1895), who was of European origin.
- With the publication of Psychopathia Sexualis at the end of the nineteenth century, sexual deviance was considered a medical condition. Psychopathia Sexualis was written by a German psychiatrist Krafft-Ebing, who described the sexual murders in this publication.
# Classification
- Earlier the non-reproductive sexual behaviors were considered pathological and criminalized. However, over years the boundaries of pathology have been confined to the absence of sexual consent.
- The inclusion of the pathological classification of paraphilias in the DSM and ICD has been criticized for a long time. It is based on the thin line of difference between something that is a normal variation or just unusual, and something that is pathological.
- According to DSM-III, a patient could have more than one paraphilias but the extent of the multiplicity was not described until later editions.
- Till DSM-IV-TR, the diagnostic category of paraphilia was scrutinized for logic, clarity, and consistency.
- DSM-IV-TR included paraphilias in the chapter ‘Sexual and Gender Identity Disorders’.
- There were proposals to remove paraphilias as a diagnostic category from DSM-5. Some considered the concept of paraphilic disorder as more ideological than scientific.
- Despite the ongoing controversies, in DSM-5, the paraphilias have been assigned a separate chapter and are termed Paraphilic disorders.
- According to DSM-5, paraphilia as such does not require psychiatric intervention. Paraphilia causing harm to others or severe distress to oneself, is termed paraphilic disorder and needs treatment.
- It has been found that DSM-5 diagnostic criteria for paraphilias can increase the false-positive rates by diagnosing without assessing the underlying motivation (may not necessarily be paraphilic sexual arousal). As a result, attaining this diagnosis can produce many legal consequences.
- ICD-10 does not comprise a clear-cut definition of paraphilia. It simply refers to paraphilia as a disorder of sexual preference.
# Pathophysiology
## Monoamine Hypothesis
- Norepinephrine, serotonin, and dopamine are the monoamines involved in the physiology of sexual behavior.
- Side effects of certain medications like antidepressants and neuroleptics show that the alteration of monoamine levels can adversely affect sexuality.
- Monoamines modulate impulsivity, anxiety, depression, and antisocial behavior. Dysregulation of the neurotransmitters may also produce these conditions in patients with paraphilic disorders.
- The medications that act by increasing the serotonergic function have been found to suppress the paraphilic behavior. This further supports the monoamine hypothesis.
## Role of Testosterone
Sex-steroid genetics influences both antisocial traits, and sexual behavior. The relationship between testosterone and paraphilia is further evident by the positive response seen in these patients with antiandrogen therapy.
# Differential Diagnosis
It is important to differentiate paraphilias from others like
- Impulse disorder not otherwise specified (NOS)
- Bipolar affective disorder
- Cyclothymic disorder
- Substance-induced anxiety disorder
- Substance intoxication (like cocaine, or alcohol)
- Dissociative disorder
- Delusional disorder (erotomania)
- Gender identity disorder
- Obsessive-compulsive disorder
- Cognitive disorders like dementia
- Delirium
- Parkinson’s disease
- Other neurological disorders
# Epidemiology and Demographics
- The exact prevalence of Paraphilic Disorders is difficult to estimate.
- Only a few patients seek treatment and most of the data is obtained from the paraphilic cases caught up in the legal system.
## Age
- Although discrepancies in studies exist, on average no specific age group has been predisposed to develop Paraphilia.
- Literature has revealed that paraphilias mostly begin in childhood and are manifested later in adolescence.
## Gender
- Paraphilic behavior is seen mostly in men. However, there are studies that show no prominent gender-differences.
## Race
- Limited studies have been done about racial predilection.
- Most studies present mixed results and it can be concluded that no specific race is predisposed to develop paraphilia.
# Risk Factors
- Noxious child-rearing experiences, non-sexual and sexual both
- Childhood emotional abuse
- Childhood sexual abuse
# Natural History, Complications, and Prognosis
- Patients with paraphilias have high chances of relapse.
- After 15 years, pedophiles attracted to boys are likely to commit the crime again (35%) as compared to those attracted to girls (16%).
- Good prognostic factors are
Early treatment
Individuals with good ego strength and high motivation for treatment
Patients with normal adult sexual experiences
- Early treatment
- Individuals with good ego strength and high motivation for treatment
- Patients with normal adult sexual experiences
- Poor prognostic factors are
Coexisting mental disorders
Early-onset of paraphilic behaviors
Lack of remorse for their behaviors
Substance misuse
Pedophilia with a sexual interest in boys
- Coexisting mental disorders
- Early-onset of paraphilic behaviors
- Lack of remorse for their behaviors
- Substance misuse
- Pedophilia with a sexual interest in boys
- The risk of recurrence depends on
Static risk factors (history of sexual abuse) - The factors that do not change during treatment
Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy
- Static risk factors (history of sexual abuse) - The factors that do not change during treatment
- Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy
# Comorbidities
Various comorbid conditions exist with paraphilias like
- Major Depressive Disorder
- Anxiety disorders
- Substance abuse
- Erotomania
- Suicidality
- Gender identity disorder
- Autism Spectrum Disorder (ASD)
- Mental Retardation
- Antisocial Personality Disorder
- Personality change due to General Medical Condition
# Diagnosis
## DSM-5 Diagnostic Criteria
- Following conditions have been described in the chapter on Paraphilia
- Exhibitionistic Disorder
- Fetishistic Disorder
- Frotteuristic Disorder
- Paedophilic Disorder
- Sexual Masochism Disorder
- Sexual Sadism Disorder
- Voyeuristic Disorder
- Transvestic Disorder
- Other specified Paraphilic Disorder
- Unspecified Paraphilic Disorder
### Voyeuristic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from observing an unsuspected naked person.
- B. Action has been taken on the urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
- C. The individual is at least 18 years old.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Exhibitionistic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from exposure of one's genitals to an unsuspected person.
- B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify whether:
- Sexually aroused by exposing genitals to the prepubertal children.
- Sexually aroused by exposing genitals to physically mature individuals.
- Sexually aroused by exposing genitals to the prepubertal children as well as physically mature individuals.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Frotteuristic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from touching or rubbing against a non-consenting person, as manifested by fantasies, or behavior.
- B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Sexual Masochism Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from being beaten, bound, humiliated, or made to suffer; is manifested in the form of fantasies, urges, or behaviors.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify if:
With asphyxiophilia: If the individual experiences sexual arousal due to restriction of breathing.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Sexual Sadism Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from the psychological or physical suffering of another person; is manifested in the form of urges, fantasies, or behaviors.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Pedophilic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior involving sexual activity with a child or many children of age 13 or younger.
- B. Significant distress/ interpersonal difficulty is caused by these sexual urges or fantasies, or the individual has acted on these sexual urges.
- C. The individual is at least 16 years old and a minimum of 5 years older than the child.
Specify whether:
- Exclusive type (attracted to children only).
- Non-exclusive type.
Specify if:
- Sexually attracted to males only.
- Sexually attracted to females only.
- Sexually attracted to both.
Specify if:
- Limited to incest.
### Fetishistic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from the use of non-living objects, or a focus on non-genital body part/parts.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior.
- C. The fetish objects are not limited to clothing or objects designed for tactile genital stimulation.
Specify if:
- Body part/parts.
- Non-living object/objects.
- Other.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Transvestic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from cross-dressing.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior.
Specify if:
- With fetishism.
- With autogynephilia - Sexual arousal by thoughts or images of self as a female.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Other Specified Paraphilic Disorder
- Significant distress/ socio-occupational functioning impairment is caused by the symptoms characteristic of a paraphilic disorder but does not completely fulfill the criteria of any of the categories in the Paraphilic Disorders.
### Unspecified Paraphilic Disorder
- Used in the conditions where the clinician chooses not to mention the reason that the criteria are not fulfilled for a specific paraphilic disorder.
# Treatment
- A treatment plan comprising of psychotherapy, and/or pharmacotherapy is usually needed to suppress the paraphiliac fantasies and behaviors.
- The treatment depends on the intensity and frequency of paraphiliac sexual fantasies as well as the risk of sexual violence.
- The very severe conditions may lead to sexual offenses, like rape and it is necessary to manage such patients aggressively with hormonal intervention.
- The treatment regime consists of six levels with escalating degrees of medical intervention, based on the severity of the disorder.
## Pharmacotherapy
- Three main classes of medications used in paraphilias are antidepressants, hormones, and gonadotrophin-releasing hormone (GnRH) analogs.
- Treatment of comorbidities is very important to improve the quality of life.
- Treatment with antiandrogens has the drawback that it may increase psychotic symptoms and depression risk.
### Antidepressants
- Antidepressants are used to treat paraphilias because of their action on involved neurotransmitters. The mechanism of action is supported by the monoamine hypothesis.
- The comorbidities such as obsessive-compulsive spectrum disorders share the dysfunction of similar neurotransmitters. Therefore, antidepressants can treat both the disorders simultaneously.
- Antidepressants commonly used are
Selective Serotonin Reuptake Inhibitors(SSRI) such as Fluoxetine, Paroxetine, and Escitalopram act on serotonergic (5-HT2) receptors and have become the standard of care. Additionally, SSRIs treat the comorbid conditions like depression, OCD, or anxiety disorders.
Tricyclic Antidepressants(TCA) such as Imipramine, Clomipramine, and Desipramine.
- Selective Serotonin Reuptake Inhibitors(SSRI) such as Fluoxetine, Paroxetine, and Escitalopram act on serotonergic (5-HT2) receptors and have become the standard of care. Additionally, SSRIs treat the comorbid conditions like depression, OCD, or anxiety disorders.
- Tricyclic Antidepressants(TCA) such as Imipramine, Clomipramine, and Desipramine.
### Hormones
- Estrogen
- Steroid antiandrogens
Medroxyprogesterone- It is synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamic-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production.
Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone.
- Medroxyprogesterone- It is synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamic-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production.
- Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone.
### Gonadotrophin Releasing Hormone Analogue (GnRH Analogue)
- They reduce the circulating testosterone, in turn, reducing aggression and hypersexuality.
## Psychotherapy
- In subjects that are not at high risk of victimization, cognitive behavioral therapy(CBT) is the first-line treatment.
- CBT addresses the cognitive distortions, along with empathy training, relapse prevention, sexual impulse control training, and biofeedback.
## Combined Pharmacotherapy and Psychotherapy
- The combination therapy has a better response compared to either therapy used alone.
Very few evidence-based treatment options are available for a complex condition like paraphilia, and further research is warranted to effectively prevent the relapses. | Paraphilia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vatsala Sharma; M.B.B.S[2]
Synonyms and keywords: Fetishism, Voyeurism, Zoophilia, Pedophilia, Sexual perversion, Zoophilism, Abnormal sexual activity
# Overview
Paraphilias are characterized by severe deviant sexual desire or urge resulting in actions that may cause significant impairment in functioning as well as distress (for oneself and/or others). Paraphilic behavior may occur intermittently or may persist for the entire life. To begin with, paraphilia occurs in the form of fantasy, and the paraphilic behavior manifests later in life. Mostly the individuals with this condition do not seek treatment themselves due to the pleasure they obtain from it and in some cases, the associated stigma. Paraphilias are not illegal but the resulting behaviors are. Timely treatment is important to prevent sexual offenses like pedophilia or serial rapes. Patients may have more than one type of paraphilia and therefore, it is essential to evaluate them thoroughly to provide optimal management.
# Historical Perspective
- The term 'Paraphilia' is Greek in origin and is derived from the words-'Para'(deviation) and 'philia'(attraction).[1]
- From biblical times, human societies across the world, have placed restrictions on many types of sexual behaviors. The level of acceptability is based on cultural variations across the globe.
- There is controversy in what should be called sexual deviation, mainly based on various factors like the degree of consent, age of the involved individuals, degree of distress caused, location of sexual behavior, degree of unacceptable by others, etc. [2]
- The term 'Sadism' originated from Marquis de Sade (1740-1814). He was placed in a lunatic asylum multiple times and ultimately, died there. His mental instability is considered to have resulted in this pattern of sexual behavior. [2]
- The term 'Masochism' came from Baron Leopold von Sacher Masoch (1835-1895), who was of European origin.[2]
- With the publication of Psychopathia Sexualis at the end of the nineteenth century, sexual deviance was considered a medical condition. Psychopathia Sexualis was written by a German psychiatrist Krafft-Ebing, who described the sexual murders in this publication. [2][3]
# Classification
- Earlier the non-reproductive sexual behaviors were considered pathological and criminalized. However, over years the boundaries of pathology have been confined to the absence of sexual consent. [4]
- The inclusion of the pathological classification of paraphilias in the DSM and ICD has been criticized for a long time. It is based on the thin line of difference between something that is a normal variation or just unusual, and something that is pathological.
- According to DSM-III, a patient could have more than one paraphilias but the extent of the multiplicity was not described until later editions.[5]
- Till DSM-IV-TR, the diagnostic category of paraphilia was scrutinized for logic, clarity, and consistency. [6]
- DSM-IV-TR included paraphilias in the chapter ‘Sexual and Gender Identity Disorders’.[3]
- There were proposals to remove paraphilias as a diagnostic category from DSM-5. Some considered the concept of paraphilic disorder as more ideological than scientific. [7][8]
- Despite the ongoing controversies, in DSM-5, the paraphilias have been assigned a separate chapter and are termed Paraphilic disorders. [9]
- According to DSM-5, paraphilia as such does not require psychiatric intervention. Paraphilia causing harm to others or severe distress to oneself, is termed paraphilic disorder and needs treatment. [3]
- It has been found that DSM-5 diagnostic criteria for paraphilias can increase the false-positive rates by diagnosing without assessing the underlying motivation (may not necessarily be paraphilic sexual arousal). As a result, attaining this diagnosis can produce many legal consequences. [10]
- ICD-10 does not comprise a clear-cut definition of paraphilia. It simply refers to paraphilia as a disorder of sexual preference. [11][12]
# Pathophysiology
## Monoamine Hypothesis
- Norepinephrine, serotonin, and dopamine are the monoamines involved in the physiology of sexual behavior.[13]
- Side effects of certain medications like antidepressants and neuroleptics show that the alteration of monoamine levels can adversely affect sexuality.[13]
- Monoamines modulate impulsivity, anxiety, depression, and antisocial behavior. Dysregulation of the neurotransmitters may also produce these conditions in patients with paraphilic disorders. [13]
- The medications that act by increasing the serotonergic function have been found to suppress the paraphilic behavior. This further supports the monoamine hypothesis. [14]
## Role of Testosterone
Sex-steroid genetics influences both antisocial traits, and sexual behavior. The relationship between testosterone and paraphilia is further evident by the positive response seen in these patients with antiandrogen therapy.[15]
# Differential Diagnosis
It is important to differentiate paraphilias from others like[16][3]
- Impulse disorder not otherwise specified (NOS)
- Bipolar affective disorder
- Cyclothymic disorder
- Substance-induced anxiety disorder
- Substance intoxication (like cocaine, or alcohol)
- Dissociative disorder
- Delusional disorder (erotomania)
- Gender identity disorder
- Obsessive-compulsive disorder
- Cognitive disorders like dementia
- Delirium
- Parkinson’s disease
- Other neurological disorders
# Epidemiology and Demographics
- The exact prevalence of Paraphilic Disorders is difficult to estimate.[17]
- Only a few patients seek treatment and most of the data is obtained from the paraphilic cases caught up in the legal system.[18][19]
## Age
- Although discrepancies in studies exist, on average no specific age group has been predisposed to develop Paraphilia.
- Literature has revealed that paraphilias mostly begin in childhood and are manifested later in adolescence. [20]
## Gender
- Paraphilic behavior is seen mostly in men. However, there are studies that show no prominent gender-differences.[12][17][21]
## Race
- Limited studies have been done about racial predilection.
- Most studies present mixed results and it can be concluded that no specific race is predisposed to develop paraphilia.[22]
# Risk Factors
- Noxious child-rearing experiences, non-sexual and sexual both[20]
- Childhood emotional abuse[23]
- Childhood sexual abuse[23]
# Natural History, Complications, and Prognosis
- Patients with paraphilias have high chances of relapse.[1]
- After 15 years, pedophiles attracted to boys are likely to commit the crime again (35%) as compared to those attracted to girls (16%).[19]
- Good prognostic factors are[1]
Early treatment
Individuals with good ego strength and high motivation for treatment
Patients with normal adult sexual experiences
- Early treatment
- Individuals with good ego strength and high motivation for treatment
- Patients with normal adult sexual experiences
- Poor prognostic factors are[1]
Coexisting mental disorders
Early-onset of paraphilic behaviors
Lack of remorse for their behaviors
Substance misuse
Pedophilia with a sexual interest in boys
- Coexisting mental disorders
- Early-onset of paraphilic behaviors
- Lack of remorse for their behaviors
- Substance misuse
- Pedophilia with a sexual interest in boys
- The risk of recurrence depends on[19]
Static risk factors (history of sexual abuse) - The factors that do not change during treatment
Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy
- Static risk factors (history of sexual abuse) - The factors that do not change during treatment
- Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy
# Comorbidities
Various comorbid conditions exist with paraphilias like[12][24][1]
- Major Depressive Disorder
- Anxiety disorders
- Substance abuse
- Erotomania
- Suicidality
- Gender identity disorder
- Autism Spectrum Disorder (ASD)
- Mental Retardation
- Antisocial Personality Disorder
- Personality change due to General Medical Condition
# Diagnosis
## DSM-5 Diagnostic Criteria
- Following conditions have been described in the chapter on Paraphilia
- Exhibitionistic Disorder
- Fetishistic Disorder
- Frotteuristic Disorder
- Paedophilic Disorder
- Sexual Masochism Disorder
- Sexual Sadism Disorder
- Voyeuristic Disorder
- Transvestic Disorder
- Other specified Paraphilic Disorder
- Unspecified Paraphilic Disorder
### Voyeuristic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from observing an unsuspected naked person.
- B. Action has been taken on the urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
- C. The individual is at least 18 years old.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Exhibitionistic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from exposure of one's genitals to an unsuspected person.
- B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify whether:
- Sexually aroused by exposing genitals to the prepubertal children.
- Sexually aroused by exposing genitals to physically mature individuals.
- Sexually aroused by exposing genitals to the prepubertal children as well as physically mature individuals.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Frotteuristic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from touching or rubbing against a non-consenting person, as manifested by fantasies, or behavior.
- B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Sexual Masochism Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from being beaten, bound, humiliated, or made to suffer; is manifested in the form of fantasies, urges, or behaviors.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify if:
With asphyxiophilia: If the individual experiences sexual arousal due to restriction of breathing.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Sexual Sadism Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from the psychological or physical suffering of another person; is manifested in the form of urges, fantasies, or behaviors.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Pedophilic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior involving sexual activity with a child or many children of age 13 or younger.
- B. Significant distress/ interpersonal difficulty is caused by these sexual urges or fantasies, or the individual has acted on these sexual urges.
- C. The individual is at least 16 years old and a minimum of 5 years older than the child.
Specify whether:
- Exclusive type (attracted to children only).
- Non-exclusive type.
Specify if:
- Sexually attracted to males only.
- Sexually attracted to females only.
- Sexually attracted to both.
Specify if:
- Limited to incest.
### Fetishistic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from the use of non-living objects, or a focus on non-genital body part/parts.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior.
- C. The fetish objects are not limited to clothing or objects designed for tactile genital stimulation.
Specify if:
- Body part/parts.
- Non-living object/objects.
- Other.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Transvestic Disorder
- A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from cross-dressing.
- B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior.
Specify if:
- With fetishism.
- With autogynephilia - Sexual arousal by thoughts or images of self as a female.
Specify if:
- In a controlled environment(the individual is living in an institution etc).
- In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment).
### Other Specified Paraphilic Disorder
- Significant distress/ socio-occupational functioning impairment is caused by the symptoms characteristic of a paraphilic disorder but does not completely fulfill the criteria of any of the categories in the Paraphilic Disorders.
### Unspecified Paraphilic Disorder
- Used in the conditions where the clinician chooses not to mention the reason that the criteria are not fulfilled for a specific paraphilic disorder.
# Treatment
- A treatment plan comprising of psychotherapy, and/or pharmacotherapy is usually needed to suppress the paraphiliac fantasies and behaviors.
- The treatment depends on the intensity and frequency of paraphiliac sexual fantasies as well as the risk of sexual violence. [25]
- The very severe conditions may lead to sexual offenses, like rape and it is necessary to manage such patients aggressively with hormonal intervention.[25]
- The treatment regime consists of six levels with escalating degrees of medical intervention, based on the severity of the disorder.[26]
## Pharmacotherapy
- Three main classes of medications used in paraphilias are antidepressants, hormones, and gonadotrophin-releasing hormone (GnRH) analogs.[19]
- Treatment of comorbidities is very important to improve the quality of life.
- Treatment with antiandrogens has the drawback that it may increase psychotic symptoms and depression risk.[3]
### Antidepressants
- Antidepressants are used to treat paraphilias because of their action on involved neurotransmitters. The mechanism of action is supported by the monoamine hypothesis. [19]
- The comorbidities such as obsessive-compulsive spectrum disorders share the dysfunction of similar neurotransmitters. Therefore, antidepressants can treat both the disorders simultaneously.
- Antidepressants commonly used are
Selective Serotonin Reuptake Inhibitors(SSRI) such as Fluoxetine, Paroxetine, and Escitalopram act on serotonergic (5-HT2) receptors and have become the standard of care. Additionally, SSRIs treat the comorbid conditions like depression, OCD, or anxiety disorders.[26]
Tricyclic Antidepressants(TCA) such as Imipramine, Clomipramine, and Desipramine.
- Selective Serotonin Reuptake Inhibitors(SSRI) such as Fluoxetine, Paroxetine, and Escitalopram act on serotonergic (5-HT2) receptors and have become the standard of care. Additionally, SSRIs treat the comorbid conditions like depression, OCD, or anxiety disorders.[26]
- Tricyclic Antidepressants(TCA) such as Imipramine, Clomipramine, and Desipramine.
### Hormones
- Estrogen
- Steroid antiandrogens
Medroxyprogesterone- It is synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamic-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production. [26][27]
Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone.[26]
- Medroxyprogesterone- It is synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamic-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production. [26][27]
- Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone.[26]
### Gonadotrophin Releasing Hormone Analogue (GnRH Analogue)
- They reduce the circulating testosterone, in turn, reducing aggression and hypersexuality.[26] [28]
## Psychotherapy
- In subjects that are not at high risk of victimization, cognitive behavioral therapy(CBT) is the first-line treatment.
- CBT addresses the cognitive distortions, along with empathy training, relapse prevention, sexual impulse control training, and biofeedback. [18]
## Combined Pharmacotherapy and Psychotherapy
- The combination therapy has a better response compared to either therapy used alone.[18]
Very few evidence-based treatment options are available for a complex condition like paraphilia, and further research is warranted to effectively prevent the relapses. | https://www.wikidoc.org/index.php/Paraphilia | |
7857f8845d5e2da44bfc54a7bff717d208320c8b | wikidoc | Paraplegin | Paraplegin
Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16.
# Structure
The SPG7 gene contains 21 exons and encodes for a protein that is approximately 88 kDa in size. Two transcript variants encoding distinct isoforms have been identified for this gene.
The structure of the SPG7 resolved by X-ray crystallography reveals that the protein functions as a hexamer and is structurally most similar to bacterial FtSH proteases. It contains an FtsH-homology protease domain as well as an AAA+ homology ATPase domain. The protein is thought to use ATPase-driven conformational changes to the AAA-domain in order to deliver the substrate peptides to be degraded to its protease core.
# Function
The SPG7 protein is a nuclear-encoded metalloprotease protein that is a member of the AAA protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The SPG7 protein is a transmembrane protein that is located to the inner mitochondrial membrane, and is part of the m-AAA metalloproteinase complex, which constitutes one of the known intra-mitochondrial proteases that function in mitochondrial protein quality control.
# Interactions
SPG7 interacts with AFG like AAA ATPase 2 (AFG3L2) on the mitochondrial inner membrane to form the m-AAA metalloproteinase complex.
# Clinical significance
Mutations associated with this gene cause autosomal recessive spastic paraplegia 7, a neurodegenerative disorder that is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG7 mutations have also been associated with other undiagnosed ataxia.
In model animals, knockdown of spastic paraplegia 7 by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1. It has been shown that an SPG7 variant escapes phosphorylation-regulated processing by AFG3L2 and increases mitochondrial reactive oxygen species generation and is correlated with many clinical phenotypes. Furthermore, SPG7 deficiency is associated with abnormal mitochondrial DNA maintenance, which may lead to secondary mitochondrial DNA lesions and impaired respiratory activities and mitochondrial functions. | Paraplegin
Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16.[1][2][3]
# Structure
The SPG7 gene contains 21 exons and encodes for a protein that is approximately 88 kDa in size. Two transcript variants encoding distinct isoforms have been identified for this gene.
The structure of the SPG7 resolved by X-ray crystallography reveals that the protein functions as a hexamer and is structurally most similar to bacterial FtSH proteases. It contains an FtsH-homology protease domain as well as an AAA+ homology ATPase domain. The protein is thought to use ATPase-driven conformational changes to the AAA-domain in order to deliver the substrate peptides to be degraded to its protease core.[4]
# Function
The SPG7 protein is a nuclear-encoded metalloprotease protein that is a member of the AAA protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The SPG7 protein is a transmembrane protein that is located to the inner mitochondrial membrane, and is part of the m-AAA metalloproteinase complex, which constitutes one of the known intra-mitochondrial proteases that function in mitochondrial protein quality control.
# Interactions
SPG7 interacts with AFG like AAA ATPase 2 (AFG3L2) on the mitochondrial inner membrane to form the m-AAA metalloproteinase complex.
# Clinical significance
Mutations associated with this gene cause autosomal recessive spastic paraplegia 7, a neurodegenerative disorder that is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG7 mutations have also been associated with other undiagnosed ataxia.[5][6][7]
In model animals, knockdown of spastic paraplegia 7 by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1.[8] It has been shown that an SPG7 variant escapes phosphorylation-regulated processing by AFG3L2 and increases mitochondrial reactive oxygen species generation and is correlated with many clinical phenotypes.[9] Furthermore, SPG7 deficiency is associated with abnormal mitochondrial DNA maintenance, which may lead to secondary mitochondrial DNA lesions and impaired respiratory activities and mitochondrial functions.[10] | https://www.wikidoc.org/index.php/Paraplegin | |
35d8751f1399ece220924f2390274e3409ed8bff | wikidoc | Parasitoid | Parasitoid
A parasitoid is an organism that spends a significant portion of its life history attached to or within a single host organism which it ultimately kills (and often consumes) in the process. Thus they are similar to typical parasites except in the certain fate of the host. In a typical parasitic relationship, the parasite and host live side by side without lethal damage to the host. Typically, the parasite takes enough nutrients to thrive without preventing the host from reproducing. In a parasitoid relationship, the host is killed, normally before it can produce offspring. When treated as a form of parasitism, the term necrotroph is sometimes (though rarely) used.
This type of relationship seems to occur only in organisms that have fast reproduction rates (such as insects or (rarely) mites). Parasitoids are also often closely coevolved with their hosts. Most biologists use the term parasitoids to refer only to insects with this type of life history, but some argue the term should be used more embrasively to include parasitic nematodes, seed weevils, and certain bacteria and viruses (e.g. bacteriophages) all of which obligately destroy their host.
# Types of parasitoids
Idiobiont parasitoids are those which prevent any further development of the host after initial parasitization, and this typically involves a host life stage which is immobile (e.g., an egg or pupa), and almost without exception they live outside the host. Koinobiont parasitoids allow the host to continue its development and often do not kill or consume the host until the host is about to either pupate or become an adult; this therefore typically involves living within an active, mobile host. Koinobionts can be further subdivided into endoparasitoids, which develop inside of the prey, and ectoparasitoids, which develop outside the host body, though they are frequently attached or embedded in the host's tissues.
It is not uncommon for a parasitoid to itself serve as the host for another parasitoid's offspring. The latter is commonly termed a hyperparasite but this term is slightly misleading, as both the host and the primary parasitoid are killed. A better term is secondary parasitoid, or hyperparasitoid; most such species known are in the insect order Hymenoptera.
# Insects
About 10% of described insect species are parasitoids, but as many parasitoid groups are poorly known taxonomically the true figure is probably nearer 20%. There are four insect orders that are particularly renowned for this type of life history. By far the majority are in the order Hymenoptera. The largest and best known group comprises the so-called "Parasitica" within the Hymenopteran suborder Apocrita: the largest subgroups of these are the chalcidoid wasps (superfamily Chalcidoidea) and the ichneumon wasps (superfamily Ichneumonoidea), followed by the Proctotrupoidea and Platygastroidea. Outside of the Parasitica there are many other Hymenopteran lineages which include parasitoids, such as most of the Chrysidoidea and Vespoidea, and the rare Symphytan family Orussidae. The flies (order Diptera) include several families of parasitoids, the largest of which is the family Tachinidae, and also smaller families such as Pipunculidae, Conopidae, and others. The other two orders are the "twisted-wing parasites" (order Strepsiptera), which is a small group consisting entirely of parasitoids, and the beetles (order Coleoptera), which includes at least families, Ripiphoridae and Rhipiceridae, that are largely parasitoids, and rove beetles (family Staphylinidae) of the genus Aleochara. Occasional members of other orders can be parasitoids; one of the more remarkable is the moth family Epipyropidae, which are ectoparasitoids of planthoppers.
See also: Parasitic wasp
# In fact and fiction
The term parasitoid was coined in 1913 by the German writer O. M. Reuter (and adopted in English by his reviewer, W. M. Wheeler) to describe the strategy in which during its development, the parasite lives in or on the body of a single host individual, eventually killing that host, the adult parasitoids being free-living.
Many "parasites" portrayed in fiction are actually parasitoids; these include;
- The Xenomorphs from the Alien films.
- The X Parasites and Metroids from the Metroid series.
- Several of the symbionts from the Spider-Man comics.
- The Flood from the Halo video game series.
- The Headcrabs from the game Half Life.
- The "shit-weasels" from Stephen King's novel, Dreamcatcher.
- The Magog from the television series Gene Roddenberry's Andromeda.
- The Black Oil alien virus from The X-Files. | Parasitoid
A parasitoid is an organism that spends a significant portion of its life history attached to or within a single host organism which it ultimately kills (and often consumes) in the process. Thus they are similar to typical parasites except in the certain fate of the host. In a typical parasitic relationship, the parasite and host live side by side without lethal damage to the host. Typically, the parasite takes enough nutrients to thrive without preventing the host from reproducing. In a parasitoid relationship, the host is killed, normally before it can produce offspring. When treated as a form of parasitism, the term necrotroph is sometimes (though rarely) used.
This type of relationship seems to occur only in organisms that have fast reproduction rates (such as insects or (rarely) mites). Parasitoids are also often closely coevolved with their hosts. Most biologists use the term parasitoids to refer only to insects with this type of life history, but some argue the term should be used more embrasively to include parasitic nematodes, seed weevils, and certain bacteria and viruses (e.g. bacteriophages) all of which obligately destroy their host.
# Types of parasitoids
Idiobiont parasitoids are those which prevent any further development of the host after initial parasitization, and this typically involves a host life stage which is immobile (e.g., an egg or pupa), and almost without exception they live outside the host. Koinobiont parasitoids allow the host to continue its development and often do not kill or consume the host until the host is about to either pupate or become an adult; this therefore typically involves living within an active, mobile host. Koinobionts can be further subdivided into endoparasitoids, which develop inside of the prey, and ectoparasitoids, which develop outside the host body, though they are frequently attached or embedded in the host's tissues.
It is not uncommon for a parasitoid to itself serve as the host for another parasitoid's offspring. The latter is commonly termed a hyperparasite but this term is slightly misleading, as both the host and the primary parasitoid are killed. A better term is secondary parasitoid, or hyperparasitoid; most such species known are in the insect order Hymenoptera.
# Insects
About 10% of described insect species are parasitoids,[1] but as many parasitoid groups are poorly known taxonomically the true figure is probably nearer 20%[citation needed]. There are four insect orders that are particularly renowned for this type of life history. By far the majority are in the order Hymenoptera. The largest and best known group comprises the so-called "Parasitica" within the Hymenopteran suborder Apocrita: the largest subgroups of these are the chalcidoid wasps (superfamily Chalcidoidea) and the ichneumon wasps (superfamily Ichneumonoidea), followed by the Proctotrupoidea and Platygastroidea. Outside of the Parasitica there are many other Hymenopteran lineages which include parasitoids, such as most of the Chrysidoidea and Vespoidea, and the rare Symphytan family Orussidae. The flies (order Diptera) include several families of parasitoids, the largest of which is the family Tachinidae, and also smaller families such as Pipunculidae, Conopidae, and others. The other two orders are the "twisted-wing parasites" (order Strepsiptera), which is a small group consisting entirely of parasitoids, and the beetles (order Coleoptera), which includes at least families, Ripiphoridae and Rhipiceridae, that are largely parasitoids, and rove beetles (family Staphylinidae) of the genus Aleochara. Occasional members of other orders can be parasitoids; one of the more remarkable is the moth family Epipyropidae, which are ectoparasitoids of planthoppers.
See also: Parasitic wasp
# In fact and fiction
The term parasitoid was coined in 1913 by the German writer O. M. Reuter (and adopted in English by his reviewer, W. M. Wheeler) to describe the strategy in which during its development, the parasite lives in or on the body of a single host individual, eventually killing that host, the adult parasitoids being free-living.
Many "parasites" portrayed in fiction are actually parasitoids; these include;
- The Xenomorphs from the Alien films.
- The X Parasites and Metroids from the Metroid series.
- Several of the symbionts from the Spider-Man comics.
- The Flood from the Halo video game series.
- The Headcrabs from the game Half Life.
- The "shit-weasels" from Stephen King's novel, Dreamcatcher.
- The Magog from the television series Gene Roddenberry's Andromeda.
- The Black Oil alien virus from The X-Files. | https://www.wikidoc.org/index.php/Parasitoid | |
aa307f69010ee55c8feef691c64b0fc18f239e6a | wikidoc | Parasomnia | Parasomnia
# Overview
A parasomnia is any sleep disorder such as sleepwalking, sleepeating, sleep sex, teeth grinding, night terrors, rhythmic movement disorder, REM behaviour disorder, restless legs syndrome, and somniloquy, characterized by partial arousals during sleep or during transitions between wakefulness and sleep. Parasomnias are often associated with stress and depression, and biological factors may also be involved. Many parasomnias are more common in children than in adults.
Unlike dyssomnias, parasomnias do not involve abnormalities of the mechanisms generating sleep-wake states, nor of the timing of sleep and wakefulness. Rather, parasomnias represent the activation of physiological systems at inappropriate times during the sleep-wake cycle. In particular, these disorders involve activation of the autonomic nervous system, motor system, or cognitive processes during sleep or sleep-wake transitions.
Parasomnias occur during deep sleep (stages III and IV). On an electroencephalogram (EEG), this corresponds to slow wave sleep.
Many parasomnias, such as sleepwalking, have serious risks. For example, a person with REM behavior disorder, while trying to swing a tennis racket in a dream, can potentially injure their bedmate. People with night terrors can prevent others from sleeping well, as well as waking themselves up. For these reasons, parasomniacs sometimes need medical treatment. | Parasomnia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A parasomnia is any sleep disorder such as sleepwalking, sleepeating, sleep sex, teeth grinding, night terrors, rhythmic movement disorder, REM behaviour disorder, restless legs syndrome, and somniloquy, characterized by partial arousals during sleep or during transitions between wakefulness and sleep. Parasomnias are often associated with stress and depression, and biological factors may also be involved. Many parasomnias are more common in children than in adults.
Unlike dyssomnias, parasomnias do not involve abnormalities of the mechanisms generating sleep-wake states, nor of the timing of sleep and wakefulness. Rather, parasomnias represent the activation of physiological systems at inappropriate times during the sleep-wake cycle. In particular, these disorders involve activation of the autonomic nervous system, motor system, or cognitive processes during sleep or sleep-wake transitions.
Parasomnias occur during deep sleep (stages III and IV). On an electroencephalogram (EEG), this corresponds to slow wave sleep.
Many parasomnias, such as sleepwalking, have serious risks. For example, a person with REM behavior disorder, while trying to swing a tennis racket in a dream, can potentially injure their bedmate. People with night terrors can prevent others from sleeping well, as well as waking themselves up. For these reasons, parasomniacs sometimes need medical treatment. | https://www.wikidoc.org/index.php/Parasomnia | |
773a8630b5547e2a9126bf3aa966a531a2fc823e | wikidoc | Pareidolia | Pareidolia
# Overview
The term pareidolia (Template:PronEng), referenced in 1994 by Steven Goldstein, describes a psychological phenomenon involving a vague and random stimulus (often an image or sound) being perceived as significant. Common examples include images of animals or faces in clouds, the man in the moon, and hidden messages on records played in reverse. The word comes from the Greek para- — beside, with or alongside — and eidolon — image (the diminutive of eidos — image, form, shape). Pareidolia is a type of apophenia.
# Examples
## Religious
There have been many instances of perceptions of religious imagery and themes, especially the faces of religious figures, in ordinary phenomena. Many involve images of Jesus, the Virgin Mary, or the word Allah.
In 1978, a New Mexican woman found that the burn marks on a tortilla she had made appeared similar to Jesus Christ's face. Thousands of people came to see the framed tortilla.
The recent publicity surrounding sightings of religious figures and other surprising images in ordinary objects, combined with the growing popularity of online auctions, has spawned a market for such items on eBay. One famous instance was a grilled-cheese sandwich with the Virgin Mary's face.
In September, 2007, the so-called "monkey tree phenomenon" caused a minor social mania in Singapore. A callus on a tree there resembles a monkey, and believers have flocked to the tree to pay homage to the Monkey God.
## Rorschach test
The Rorschach inkblot test uses pareidolia to attempt to gain insight into a person's mental state. The Rorschach is a projective test, because it intentionally calls out one's internal thoughts or feelings to be projected onto the cards. Projection in this instance is a form of "directed pareidolia" because the cards are not actually designed to resemble anything.
## Audio
In 1971, Konstantin Raudive wrote Breakthrough, detailing what he believed was the discovery of electronic voice phenomenon (EVP). EVP has been described as auditory pareidolia.
The allegations of backmasking in popular music have also been described as pareidolia.
# Explanations
## Carl Sagan
Carl Sagan hypothesized that as a survival technique, human beings are "hard-wired" from birth to identify the human face. This allows people to use only minimal details to recognize faces from a distance and in poor visibility, but can also lead them to interpret random images or patterns of light and shade as being faces.
## Clarence Irving Lewis
In his 1929 book Mind and the World Order, epistemologist and logician Clarence Irving Lewis, a founder of the philosophical school of conceptual pragmatism, used the question of how to determine whether a perception is a mirage as a touchstone for his philosophical approach to knowledge. Lewis argued that one has no way of knowing whether or not perceptions are "true" in any absolute sense; all one can do is determine whether one's purpose is thwarted by regarding it as true and acting on that basis. According to this approach, two people with two different purposes will often have different views on whether or not to regard a perception as true.
# Gallery
- This alarm clock appears to have a sad face.
This alarm clock appears to have a sad face.
- A satellite photo of a Mars mesa, with shadows creating the famous Face on Mars
A satellite photo of a Mars mesa, with shadows creating the famous Face on Mars
- A tree in the shape of a person bowing
A tree in the shape of a person bowing
- False wood
False wood | Pareidolia
# Overview
The term pareidolia (Template:PronEng), referenced in 1994 by Steven Goldstein,[1] describes a psychological phenomenon involving a vague and random stimulus (often an image or sound) being perceived as significant. Common examples include images of animals or faces in clouds, the man in the moon, and hidden messages on records played in reverse. The word comes from the Greek para- — beside, with or alongside — and eidolon — image (the diminutive of eidos — image, form, shape). Pareidolia is a type of apophenia.
# Examples
## Religious
There have been many instances of perceptions of religious imagery and themes, especially the faces of religious figures, in ordinary phenomena. Many involve images of Jesus, the Virgin Mary, or the word Allah.
In 1978, a New Mexican woman found that the burn marks on a tortilla she had made appeared similar to Jesus Christ's face. Thousands of people came to see the framed tortilla.[2]
The recent publicity surrounding sightings of religious figures and other surprising images in ordinary objects, combined with the growing popularity of online auctions, has spawned a market for such items on eBay. One famous instance was a grilled-cheese sandwich with the Virgin Mary's face.[3]
In September, 2007, the so-called "monkey tree phenomenon" caused a minor social mania in Singapore. A callus on a tree there resembles a monkey, and believers have flocked to the tree to pay homage to the Monkey God.[4]
## Rorschach test
The Rorschach inkblot test uses pareidolia to attempt to gain insight into a person's mental state. The Rorschach is a projective test, because it intentionally calls out one's internal thoughts or feelings to be projected onto the cards. Projection in this instance is a form of "directed pareidolia" because the cards are not actually designed to resemble anything. [2]
## Audio
In 1971, Konstantin Raudive wrote Breakthrough, detailing what he believed was the discovery of electronic voice phenomenon (EVP). EVP has been described as auditory pareidolia.[2]
The allegations of backmasking in popular music have also been described as pareidolia.[2]
# Explanations
## Carl Sagan
Carl Sagan hypothesized that as a survival technique, human beings are "hard-wired" from birth to identify the human face. This allows people to use only minimal details to recognize faces from a distance and in poor visibility, but can also lead them to interpret random images or patterns of light and shade as being faces.[5]
## Clarence Irving Lewis
In his 1929 book Mind and the World Order, epistemologist and logician Clarence Irving Lewis, a founder of the philosophical school of conceptual pragmatism, used the question of how to determine whether a perception is a mirage as a touchstone for his philosophical approach to knowledge. Lewis argued that one has no way of knowing whether or not perceptions are "true" in any absolute sense; all one can do is determine whether one's purpose is thwarted by regarding it as true and acting on that basis. According to this approach, two people with two different purposes will often have different views on whether or not to regard a perception as true. [6]
# Gallery
- This alarm clock appears to have a sad face.
This alarm clock appears to have a sad face.
- A satellite photo of a Mars mesa, with shadows creating the famous Face on Mars
A satellite photo of a Mars mesa, with shadows creating the famous Face on Mars
- A tree in the shape of a person bowing
A tree in the shape of a person bowing
- False wood
False wood | https://www.wikidoc.org/index.php/Pareidolia | |
276ba7a98a7a396344942454b12f54c63679349a | wikidoc | Parenchyma | Parenchyma
# Overview
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.
The term is New Latin, from Greek parenkhuma, visceral flesh, from parenkhein, to pour in beside : para-, beside + en-, in + khein, to pour.
# In animals
The parenchyma are the functional parts of an organ in the body. This is in contrast to the stroma, which refers to the supporting tissue of organs.
Examples include:
# In plants
Parenchyma cells are thin-walled cells of the ground tissue that make up the bulk of most nonwoody structures, although sometimes their cell walls can be lignified. Parenchyma cells in between the epidermis and pericycle in a root or shoot constitute the cortex, and are used for storage of food. Parenchyma cells within the center of the root or shoot constitute the pith. Parenchyma cells in the ovary constitutes the nucellus and are brick-like in formation. Parenchyma cells in the leaf constitute the mesophyll; they are responsible for photosynthesis and they allow for the interchange of gases. | Parenchyma
# Overview
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.
The term is New Latin, from Greek parenkhuma, visceral flesh, from parenkhein, to pour in beside : para-, beside + en-, in + khein, to pour.[1]
# In animals
The parenchyma are the functional parts of an organ in the body.[2] This is in contrast to the stroma, which refers to the supporting tissue of organs.
Examples include:
# In plants
Parenchyma cells are thin-walled cells of the ground tissue that make up the bulk of most nonwoody structures, although sometimes their cell walls can be lignified. Parenchyma cells in between the epidermis and pericycle in a root or shoot constitute the cortex, and are used for storage of food. Parenchyma cells within the center of the root or shoot constitute the pith. Parenchyma cells in the ovary constitutes the nucellus and are brick-like in formation. Parenchyma cells in the leaf constitute the mesophyll; they are responsible for photosynthesis and they allow for the interchange of gases[3]. | https://www.wikidoc.org/index.php/Parenchyma | |
6b3b04681512bda487d3f60b6cb1715919e15550 | wikidoc | Paul David | Paul David
Paul David, CC, GOQ, MD (December 25, 1919 – April 5, 1999) was a Canadian cardiologist, founder of the Montreal Heart Institute, and Senator.
Born in Montreal, Quebec, the son of Louis-Athanase David and Antonia Nantel, he received his Bachelor's degree from the University of Paris in 1939 and his MD from the Université de Montréal in 1944. He specializsed in cardiology in Boston at the Massachusetts General Hospital in 1946 and in Paris at the Hôpital Lareboisière in 1947. Upon his return to Montreal, he worked at the Notre-Dame Hospital. He founded the Montreal Heart Institute in 1954. It was under his direction that the first heart transplant ever performed in Canada was carried out at the Institute, in 1968.
In 1985, he was appointed to the Canadian Senate on the recommendation of Prime Minister Brian Mulroney. He sat as a Progressive Conservative senator representing the Senatorial division of Bedford, Quebec. He retired on his 75th birthday in 1994. His father, Louis-Athanase David and grandfather, Laurent-Olivier David had also been Senators.
In 1968, he was made an Officer of the Order of Canada and was promoted to Companion in 1981. In 1988, he was named a Grand Officer of the National Order of Quebec.
He married Yvette Lemire and had six children: Françoise, Pierre, Charles-Philippe, Thérèse, Anne-Marie and Hélène. | Paul David
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Paul David, CC, GOQ, MD (December 25, 1919 – April 5, 1999) was a Canadian cardiologist, founder of the Montreal Heart Institute, and Senator.
Born in Montreal, Quebec, the son of Louis-Athanase David and Antonia Nantel, he received his Bachelor's degree from the University of Paris in 1939 and his MD from the Université de Montréal in 1944. He specializsed in cardiology in Boston at the Massachusetts General Hospital in 1946 and in Paris at the Hôpital Lareboisière in 1947. Upon his return to Montreal, he worked at the Notre-Dame Hospital. He founded the Montreal Heart Institute in 1954. It was under his direction that the first heart transplant ever performed in Canada was carried out at the Institute, in 1968.
In 1985, he was appointed to the Canadian Senate on the recommendation of Prime Minister Brian Mulroney. He sat as a Progressive Conservative senator representing the Senatorial division of Bedford, Quebec. He retired on his 75th birthday in 1994. His father, Louis-Athanase David and grandfather, Laurent-Olivier David had also been Senators.
In 1968, he was made an Officer of the Order of Canada and was promoted to Companion in 1981. In 1988, he was named a Grand Officer of the National Order of Quebec.
He married Yvette Lemire and had six children: Françoise, Pierre, Charles-Philippe, Thérèse, Anne-Marie and Hélène. | https://www.wikidoc.org/index.php/Paul_David | |
54a2b4b3d642e052aff072e99a131d69a3f44351 | wikidoc | Paul N. Yu | Paul N. Yu
Paul N. Yu, M.D. (b. 1915) was an American cardiologist, physician-scientist and educator of Chinese descent, and a product of Chinese, British and American medical education. Over a career spanning several decades he trained numerous individuals in clinical cardiology who went on to leadership positions in academia throughout this country. Dr. Yu performed pioneering research in cardiac physiology, making seminal observations about the pulmonary circulation in health and disease, and the relationship to ventricular function, and key observations about the care of patients with coronary artery disease. He cared for prominent individuals such as the Taiwanese president Chiang Kai Shek and his family. He served in numerous leadership roles during his career, including a term as President of the American Heart Association (1972-3).
Subsequently he was awarded the American Heart Association's prestigious James Bryan Herrick Award for distinguished service to clinical cardiology during the course of his career.
The Paul N. Yu Professorship of Cardiology at the University of Rochester was first awarded to Bradford C. Berk, MD, PhD, who is the current Chair of Medicine, and served as Chief of the Cardiology Unit, and Director of the Center for Cardiovascular Research until 2002. Since then current Chief of Cardiology and Director of the Center for Cellular and Molecular Cardiology Mark B. Taubman, M.D. has held the Paul N. Yu Professorship of Cardiology. The Paul N. Yu Heart Center contains clinical inpatient and outpatient facilities for the treatment of Cardiovascular disease at Strong Memorial Hospital, with Nuclear Cardiology, Echocardiography, Electrophysiology, Interventional Cardiology Laboratories as well as Cardiac Rehabilitation facilities.
# Selected bibiliography
- "Progress in cardiology," ed. by Paul N. Yu. Philadelphia, Lea & Febiger, Volumes 1 - 16, 1972 - 1988 (Yearly).
- "Pulmonary blood volume in health and disease," by Paul N. Yu. Philadelphia, Lea & Febiger, 1969. | Paul N. Yu
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Paul N. Yu, M.D. (b. 1915) was an American cardiologist, physician-scientist and educator of Chinese descent, and a product of Chinese, British and American medical education. Over a career spanning several decades he trained numerous individuals in clinical cardiology who went on to leadership positions in academia throughout this country. Dr. Yu performed pioneering research in cardiac physiology, making seminal observations about the pulmonary circulation in health and disease, and the relationship to ventricular function, and key observations about the care of patients with coronary artery disease. He cared for prominent individuals such as the Taiwanese president Chiang Kai Shek and his family. He served in numerous leadership roles during his career, including a term as President of the American Heart Association (1972-3).
Subsequently he was awarded the American Heart Association's prestigious James Bryan Herrick Award for distinguished service to clinical cardiology during the course of his career.
The Paul N. Yu Professorship of Cardiology at the University of Rochester was first awarded to Bradford C. Berk, MD, PhD, who is the current Chair of Medicine, and served as Chief of the Cardiology Unit, and Director of the Center for Cardiovascular Research until 2002. Since then current Chief of Cardiology and Director of the Center for Cellular and Molecular Cardiology Mark B. Taubman, M.D. has held the Paul N. Yu Professorship of Cardiology. The Paul N. Yu Heart Center contains clinical inpatient and outpatient facilities for the treatment of Cardiovascular disease at Strong Memorial Hospital, with Nuclear Cardiology, Echocardiography, Electrophysiology, Interventional Cardiology Laboratories as well as Cardiac Rehabilitation facilities.
# Selected bibiliography
- "Progress in cardiology," ed. by Paul N. Yu. Philadelphia, Lea & Febiger, Volumes 1 - 16, 1972 - 1988 (Yearly).
- "Pulmonary blood volume in health and disease," by Paul N. Yu. Philadelphia, Lea & Febiger, 1969. | https://www.wikidoc.org/index.php/Paul_N._Yu | |
6e1a6dc92f28340ecd7e788c8ccb8e740635a314 | wikidoc | Pefloxacin | Pefloxacin
# Overview
Pefloxacin is a quinolone drug used to treat bacterial infections. It is an analog of norfloxacin, belonging to the 3rd generation of quinolones. Pefloxacin has not been approved for use in the United States.
# History
Pefloxacin was developed in 1979 and approved in France for human use in 1985.
# Licensed uses
- Uncomplicated gonococcal urethritis in males.
- Bacterial infections in the gastrointestinal system.
- Genitourinary tract infections.
- Gonorrhoeae. however this indication is no longer effective due to bacterial resistance.
Pefloxacin has been increasingly used as a veterinary medicine to treat microbial infections.
# Mode of action
Pefloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, which is an enzyme necessary to separate, replicated DNA, thereby inhibiting cell division.
# Adverse effects
Tendinitis and rupture, usually of the Achilles tendon, are a class-effects of the fluoroquinolones, most frequently reported with pefloxacin. The estimated risk of tendon damage during pefloxacin therapy has been estimated by the French authorities in 2000 to be 1 case per 23,130 treatment days as compared to ciprofloxacin where it has been estimated to be 1 case per 779,600. | Pefloxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pefloxacin is a quinolone drug used to treat bacterial infections. It is an analog of norfloxacin, belonging to the 3rd generation of quinolones. Pefloxacin has not been approved for use in the United States.
# History
Pefloxacin was developed in 1979 and approved in France for human use in 1985.[1]
# Licensed uses
- Uncomplicated gonococcal urethritis in males.[2]
- Bacterial infections in the gastrointestinal system.[2]
- Genitourinary tract infections.[2]
- Gonorrhoeae. however this indication is no longer effective due to bacterial resistance.[3]
Pefloxacin has been increasingly used as a veterinary medicine to treat microbial infections.[4]
# Mode of action
Pefloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,[5] which is an enzyme necessary to separate, replicated DNA, thereby inhibiting cell division.
# Adverse effects
Tendinitis and rupture, usually of the Achilles tendon, are a class-effects of the fluoroquinolones, most frequently reported with pefloxacin.[6] The estimated risk of tendon damage during pefloxacin therapy has been estimated by the French authorities in 2000 to be 1 case per 23,130 treatment days as compared to ciprofloxacin where it has been estimated to be 1 case per 779,600.[7] | https://www.wikidoc.org/index.php/Pefloxacin | |
9d1759432a67f6ca3c9e5f24ca4df4197a9dc4d9 | wikidoc | Pegademase | Pegademase
# 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
Pegademase is a Enzyme that is FDA approved for the treatment of adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease. Common adverse reactions include Injection site pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ADAGEN® (pegademase bovine) Injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for – or who have failed – bone marrow transplantation. ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis. ADAGEN® (pegademase bovine) Injection is not intended as a replacement for HLA identical bone marrow transplant therapy. ADAGEN® (pegademase bovine) Injection is also not intended to replace continued close medical supervision and the initiation of appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gammaglobulin) as indicated for intercurrent illnesses.
### Dosage
- Before prescribing ADAGEN® (pegademase bovine) Injection the physician should be thoroughly familiar with the details of this prescribing information. For further information concerning the essential monitoring of ADAGEN® (pegademase bovine) Injection therapy, the prescribing physician should contact Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878. Telephone 1-866-792-5172.
- ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permits.
- ADAGEN® (pegademase bovine) Injection should not be diluted nor mixed with any other drug prior to administration.
- ADAGEN® (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of ADAGEN® (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice the upper limit of 35 μmol/hr/mL have occurred on occasion in several patients, and have been maintained for several weeks in one patient who received twice weekly injections (20 U/kg per dose) of ADAGEN® (pegademase bovine) Injection. No adverse effects have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 μmol/hr/mL produces any additional clinical benefits.
- Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. ADAGEN® (pegademase bovine) Injection is not recommended for intravenous administration.
- The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell dATP content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before maintenance injection) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 μmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with ADAGEN® (pegademase bovine) Injection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegademase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegademase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- ADAGEN® (pegademase bovine) Injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for – or who have failed – bone marrow transplantation. ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis. ADAGEN® (pegademase bovine) Injection is not intended as a replacement for HLA identical bone marrow transplant therapy. ADAGEN® (pegademase bovine) Injection is also not intended to replace continued close medical supervision and the initiation of appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gammaglobulin) as indicated for intercurrent illnesses.
### Dosage
- Before prescribing ADAGEN® (pegademase bovine) Injection the physician should be thoroughly familiar with the details of this prescribing information. For further information concerning the essential monitoring of ADAGEN® (pegademase bovine) Injection therapy, the prescribing physician should contact Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878. Telephone 1-866-792-5172.
- ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permits.
- ADAGEN® (pegademase bovine) Injection should not be diluted nor mixed with any other drug prior to administration.
- ADAGEN® (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of ADAGEN® (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice the upper limit of 35 μmol/hr/mL have occurred on occasion in several patients, and have been maintained for several weeks in one patient who received twice weekly injections (20 U/kg per dose) of ADAGEN® (pegademase bovine) Injection. No adverse effects have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 μmol/hr/mL produces any additional clinical benefits.
- Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. ADAGEN® (pegademase bovine) Injection is not recommended for intravenous administration.
- The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell dATP content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before maintenance injection) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 μmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with ADAGEN® (pegademase bovine) Injection.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegademase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegademase in pediatric patients.
# Contraindications
- There is no evidence to support the safety and efficacy of ADAGEN® (pegademase bovine) Injection as preparatory or support therapy for bone marrow transplantation. Since ADAGEN® (pegademase bovine) Injection is administered by intramuscular injection, it should be used with caution in patients with thrombocytopenia and should not be used if thrombocytopenia is severe.
# Warnings
### Precautions
- Any laboratory or clinical indication of a decrease in potency of ADAGEN® (pegademase bovine) Injection should be reported immediately by telephone to Sigma-Tau Pharmaceuticals, Inc. Telephone 1-866-792-5172.
- There have been no reports of hypersensitivity reactions in patients who have been treated with ADAGEN® (pegademase bovine) Injection.
- One of 12 patients showed an enhanced rate of clearance of plasma ADA activity after 5 months of therapy at 15 U/kg/week. Enhanced clearance was correlated with the appearance of an antibody that directly inhibited both unmodified ADA and ADAGEN® (pegademase bovine) Injection. Subsequently, the patient was treated with twice weekly intramuscular injections at an increased dose of 20 U/kg, or a total weekly dose of 40 U/kg. No adverse effects were observed at the higher dose and effective levels of plasma ADA were restored. After 4 months, the patient returned to a weekly dosage schedule of 20 U/kg and effective plasma levels have been maintained.
- Appropriate care to protect immune deficient patients should be maintained until improvement in immune function has been documented. The degree of immune function improvement may vary from patient to patient and, therefore, each patient will require appropriate care consistent with immunologic status.
- The treatment of SCID associated with ADA deficiency with ADAGEN® (pegademase bovine) Injection should be monitored by measuring plasma ADA activity and red blood cell dATP levels.
- Plasma ADA activity and red cell dATP should be determined prior to treatment. Once treatment with ADAGEN® (pegademase bovine) Injection has been initiated, a desirable range of plasma ADA activity (trough level before maintenance injection) should be 15–35 μmol/hr/mL. This minimum trough level will ensure that plasma ADA activity from injection to injection is maintained above the level of total erythrocyte ADA activity in the blood of normal individuals.
- Plasma ADA activity (pre-injection) should be determined every 1-2 weeks during the first 8-12 weeks of treatment in order to establish an effective dose of ADAGEN® (pegademase bovine) Injection. After 2 months of maintenance treatment with ADAGEN® (pegademase bovine) Injection, red cell dATP levels should decrease to a range of ≤ 0.005 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. Once the level of dATP has fallen adequately, it should be measured 2-4 times a year during the remainder of the first year and 2-3 times a year thereafter, assuming no interruption in therapy.
- Between 3 and 9 months, plasma ADA should be determined twice a month, then monthly until after 18-24 months of treatment with ADAGEN® (pegademase bovine) Injection.
- Patients who have successfully been maintained on therapy for two years should continue to have plasma ADA measured every 2-4 months and red cell dATP measured twice yearly. More frequent monitoring would be necessary if therapy were interrupted or if an enhanced rate of clearance of plasma ADA activity develops.
- Once effective ADA plasma levels have been established, should a patient’s plasma ADA activity level fall below 10 μmol/hr/mL (which cannot be attributed to improper dosing, sample handling or antibody development) then the patients receiving this lot of ADAGEN® (pegademase bovine) Injection should be requested to have a blood sample for plasma ADA determination taken prior to their next injection of ADAGEN® (pegademase bovine) Injection.
- Immune function, including the ability to produce antibodies, generally improves after 2-6 months of therapy, and matures over a longer period. Compared with the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving ADAGEN® (pegademase bovine) Injection. However, the lag between the correction of the metabolic abnormalities and improved immune function with a trend toward diminished frequency of infections and complications of infection is variable, and has ranged from a few weeks to approximately 6 months. Improvement in the general clinical status of the patient may be gradual (as evidenced by improvement in various clinical parameters) but should be apparent by the end of the first year of therapy. Antibody to ADAGEN® (pegademase bovine) Injection may develop in patients and may result in more rapid clearance of ADAGEN® (pegademase bovine) Injection. Antibody to ADAGEN® (pegademase bovine) Injection should be suspected if a persistent fall in pre-injection levels of plasma ADA to < 10 μmol/hr/mL occurs. If other causes for a decline in plasma ADA levels can be ruled out , then a specific assay for antibody to ADA and ADAGEN® (pegademase bovine) Injection (ELISA, enzyme inhibition) should be performed.
- In patients undergoing treatment with ADAGEN® (pegademase bovine) Injection, a decline in immune function, with increased risk of opportunistic infections and complications of infection, will result from failure to maintain adequate levels of plasma ADA activity . If a persistent decline in plasma ADA activity occurs, immune function and clinical status should be monitored closely and precautions should be taken to minimize the risk of infection. If antibody to ADA or ADAGEN® (pegademase bovine) Injection is found to be the cause of a persistent fall in plasma ADA activity, then adjustment in the dosage of ADAGEN® (pegademase bovine) Injection and other measures may be taken to induce tolerance and restore adequate ADA activity.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with ADAGEN® (pegademase bovine) Injection has been limited. The following adverse reactions were reported: headache in one patient and pain at the injection site in two patients. The following adverse reactions have been identified during post-approval use of ADAGEN® (pegademase bovine) Injection. Because these reactions are reported voluntarily from a very small population, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Hematologic events: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia.
- Dermatological events: injection site erythema, urticaria.
- Lymphomas
- To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc. at 1-888-393-4584 or by email at [email protected] or contact the FDA at 1-800-FDA-1088 or WWW.FDA.GOV/SAFETY/MEDWATCH.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pegademase in the drug label.
# Drug Interactions
- There are no known drug interactions with ADAGEN® (pegademase bovine) Injection. However, Vidarabine is a substrate for ADA and 2′-deoxycoformycin is a potent inhibitor of ADA. Thus, the activities of these drugs and ADAGEN® (pegademase bovine) Injection could be substantially altered if they are used in combination with one another.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with ADAGEN® (pegademase bovine) Injection. It is also not known whether ADAGEN® (pegademase bovine) Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ADAGEN® (pegademase bovine) Injection should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegademase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegademase during labor and delivery.
### Nursing Mothers
- It is not known whether ADAGEN® (pegademase bovine) Injection is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ADAGEN® (pegademase bovine) Injection is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Pegademase with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Pegademase with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pegademase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegademase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegademase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegademase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegademase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegademase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
### Monitoring
- The treatment of SCID associated with ADA deficiency with ADAGEN® (pegademase bovine) Injection should be monitored by measuring plasma ADA activity and red blood cell dATP levels.
# IV Compatibility
There is limited information regarding IV Compatibility of Pegademase in the drug label.
# Overdosage
- There is no documented experience with ADAGEN® (pegademase bovine) Injection overdosage. An intraperitoneal dose of 50,000 U/kg of ADAGEN® (pegademase bovine) Injection in mice resulted in weight loss up to 9%.
# Pharmacology
## Mechanism of Action
- ADAGEN® (pegademase bovine) Injection provides specific replacement of the deficient enzyme.
- In the absence of the enzyme ADA, the purine substrates adenosine, 2′-deoxyadenosine and their metabolites are toxic to lymphocytes. The direct action of ADAGEN® (pegademase bovine) Injection is the correction of these metabolic abnormalities. Improvement in immune function and diminished frequency of opportunistic infections compared with the natural history of combined immunodeficiency due to ADA deficiency only occurs after metabolic abnormalities are corrected. There is a lag between the correction of the metabolic abnormalities and improved immune function. This period of time is variable, and has been reported to be from a few weeks to as long as 6 months. In contrast to the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving ADAGEN® (pegademase bovine) Injection.
## Structure
- ADAGEN® (pegademase bovine) Injection is a modified enzyme used for enzyme replacement therapy for the treatment of severe combined immunodeficiency disease (SCID) associated with a deficiency of adenosine deaminase.
- ADAGEN® (pegademase bovine) Injection is supplied in an isotonic, pyrogen free, sterile solution, pH 7.2-7.4, for intramuscular injection only. The solution is clear and colorless. It is supplied in 1.5 mL single-dose vials.
- The chemical name for ADAGEN® (pegademase bovine) Injection is (monomethoxypolyethylene glycol succinimidyl) 11-17-adenosine deaminase. It is a conjugate of numerous strands of monomethoxypolyethylene glycol (PEG), molecular weight 5,000, covalently attached to the enzyme adenosine deaminase (ADA). ADA (adenosine deaminase EC 3.5.4.4) used in the manufacture of ADAGEN® (pegademase bovine) Injection is derived from bovine intestine.
- The structural formula of ADAGEN® (pegademase bovine) Injection is:
- Each milliliter of ADAGEN® (pegademase bovine) Injection contains:
- One unit of activity is defined as the amount of ADA that converts 1μM of adenosine to inosine per minute at 25°C and pH 7.3.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pegademase in the drug label.
## Pharmacokinetics
- The pharmacokinetics and biochemical effects of ADAGEN® (pegademase bovine) Injection have been studied in six children ranging in age from 6 weeks to 12 years with SCID associated with ADA deficiency.
- After the intramuscular injection of ADAGEN® (pegademase bovine) Injection, peak plasma levels of ADA activity were reached 2 to 3 days following administration. The plasma elimination half-life of ADA following the administration of ADAGEN® (pegademase bovine) Injection was variable, even for the same child. The range was 3 to > 6 days. Following weekly injections of ADAGEN® (pegademase bovine) Injection at 15 U/kg, the average trough level of ADA activity in plasma was between 20 and 25 μmol/hr/mL.
- The changes in red blood cell deoxyadenosine nucleotide (dATP) and S-adenosylhomocysteine hydrolase (SAHase) have been evaluated. In patients with ADA deficiency, inadequate elimination of 2′-deoxyadenosine caused a marked elevation in dATP and a decrease in SAHase level in red blood cells. Prior to treatment with ADAGEN® (pegademase bovine) Injection, the levels of dATP in the red blood cells ranged from 0.056 to 0.899 μmol/mL of erythrocytes. After 2 months of maintenance treatment with ADAGEN® (pegademase bovine) Injection, the levels decreased to 0.007 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. In the same period of time, the levels of SAHase increased from the pretreatment range of 0.09 to 0.22 nmol/hr/mg protein to a range of 2.37 to 5.16 nmol/hr/mg protein. The normal value for SAHase is 4.18 ± 1.9 nmol/hr/mg protein.
- The optimal dosage and schedule of administration of ADAGEN® (pegademase bovine) Injection should be established for each patient, based on monitoring of plasma ADA activity levels (trough levels before maintenance injection), biochemical markers of ADA deficiency (primarily red cell dATP content), and parameters of immune function. Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 µmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample.
- In vitro immunologic data (lymphocyte response to mitogens and lymphocyte surface antigens) were obtained, but their clinical significance is unknown. Prior to treatment with ADAGEN® (pegademase bovine) Injection, immune status was significantly below normal, as indicated by < 10% of normal mitogen responses and circulating mononuclear cells bearing T-cell surface antigens. These parameters improved, though not always to normal, within 2 to 6 months of therapy.
- Severe Combined Immunodeficiency Disease Associated with ADA Deficiency
- Severe combined immunodeficiency disease (SCID) associated with a deficiency of ADA is a rare, inherited, and often fatal disease. In the absence of the ADA enzyme, the purine substrates adenosine and 2′-deoxyadenosine accumulate, causing metabolic abnormalities that are directly toxic to lymphocytes.
- The immune deficiency can be cured by bone marrow transplantation. When a suitable bone marrow donor is unavailable or when bone marrow transplantation fails, non-selective replacement of the ADA enzyme has been provided by periodic irradiated red blood cell transfusions. However, transmission of viral infections and iron overload are serious risks associated with irradiated red blood cell transfusions, and relatively few ADA deficient patients have benefitted from chronic transfusion therapy.
- ADAGEN® (pegademase bovine) Injection provides specific and direct replacement of the deficient enzyme, but will not benefit patients with immunodeficiency due to other causes.
- In patients with ADA deficiency, rigorous adherence to a schedule of ADAGEN® (pegademase bovine) Injection administration can eliminate the toxic metabolites of ADA deficiency and result in improved immune function. It is imperative that treatment with ADAGEN® (pegademase bovine) Injection be carefully monitored by measurement of the level of ADA activity in plasma. Monitoring of the level of deoxyadenosine triphosphate (dATP) in erythrocytes is also helpful in determining that the dose of ADAGEN® (pegademase bovine) Injection is adequate.
## Nonclinical Toxicology
- Long-term carcinogenic studies in animals have not been performed with ADAGEN® (pegademase bovine) Injection nor have studies been performed on impairment of fertility.
- ADAGEN® (pegademase bovine) Injection did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Pegademase in the drug label.
# How Supplied
- ADAGEN® (pegademase bovine) Injection is a clear, colorless, preservative free solution for intramuscular injection. ADAGEN® is supplied as a sterile solution in single-use vials containing 375 units per 1.5 mL solution, in boxes of 4 vials (NDC-57665-001-01).
- Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.
## Storage
Refrigerate. Store between +2°C and +8°C (36°F and 46°F). DO NOT FREEZE. ADAGEN® (pegademase bovine) Injection should not be stored at room temperature. This product should not be used if there are any indications that it may have been frozen.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - CARTON LABEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pegademase in the drug label.
# Precautions with Alcohol
- Alcohol-Pegademase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Adagen®
# Look-Alike Drug Names
There is limited information regarding the look alike drug name.
# Drug Shortage Status
# Price | Pegademase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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
Pegademase is a Enzyme that is FDA approved for the treatment of adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease. Common adverse reactions include Injection site pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- ADAGEN® (pegademase bovine) Injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for – or who have failed – bone marrow transplantation. ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis. ADAGEN® (pegademase bovine) Injection is not intended as a replacement for HLA identical bone marrow transplant therapy. ADAGEN® (pegademase bovine) Injection is also not intended to replace continued close medical supervision and the initiation of appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gammaglobulin) as indicated for intercurrent illnesses.
### Dosage
- Before prescribing ADAGEN® (pegademase bovine) Injection the physician should be thoroughly familiar with the details of this prescribing information. For further information concerning the essential monitoring of ADAGEN® (pegademase bovine) Injection therapy, the prescribing physician should contact Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878. Telephone 1-866-792-5172.
- ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permits.
- ADAGEN® (pegademase bovine) Injection should not be diluted nor mixed with any other drug prior to administration.
- ADAGEN® (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of ADAGEN® (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice the upper limit of 35 μmol/hr/mL have occurred on occasion in several patients, and have been maintained for several weeks in one patient who received twice weekly injections (20 U/kg per dose) of ADAGEN® (pegademase bovine) Injection. No adverse effects have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 μmol/hr/mL produces any additional clinical benefits.
- Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. ADAGEN® (pegademase bovine) Injection is not recommended for intravenous administration.
- The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell dATP content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before maintenance injection) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 μmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with ADAGEN® (pegademase bovine) Injection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegademase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegademase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- ADAGEN® (pegademase bovine) Injection is indicated for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for – or who have failed – bone marrow transplantation. ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis. ADAGEN® (pegademase bovine) Injection is not intended as a replacement for HLA identical bone marrow transplant therapy. ADAGEN® (pegademase bovine) Injection is also not intended to replace continued close medical supervision and the initiation of appropriate diagnostic tests and therapy (e.g., antibiotics, nutrition, oxygen, gammaglobulin) as indicated for intercurrent illnesses.
### Dosage
- Before prescribing ADAGEN® (pegademase bovine) Injection the physician should be thoroughly familiar with the details of this prescribing information. For further information concerning the essential monitoring of ADAGEN® (pegademase bovine) Injection therapy, the prescribing physician should contact Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878. Telephone 1-866-792-5172.
- ADAGEN® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permits.
- ADAGEN® (pegademase bovine) Injection should not be diluted nor mixed with any other drug prior to administration.
- ADAGEN® (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of ADAGEN® (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice the upper limit of 35 μmol/hr/mL have occurred on occasion in several patients, and have been maintained for several weeks in one patient who received twice weekly injections (20 U/kg per dose) of ADAGEN® (pegademase bovine) Injection. No adverse effects have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 μmol/hr/mL produces any additional clinical benefits.
- Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. ADAGEN® (pegademase bovine) Injection is not recommended for intravenous administration.
- The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell dATP content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before maintenance injection) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 μmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with ADAGEN® (pegademase bovine) Injection.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pegademase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegademase in pediatric patients.
# Contraindications
- There is no evidence to support the safety and efficacy of ADAGEN® (pegademase bovine) Injection as preparatory or support therapy for bone marrow transplantation. Since ADAGEN® (pegademase bovine) Injection is administered by intramuscular injection, it should be used with caution in patients with thrombocytopenia and should not be used if thrombocytopenia is severe.
# Warnings
### Precautions
- Any laboratory or clinical indication of a decrease in potency of ADAGEN® (pegademase bovine) Injection should be reported immediately by telephone to Sigma-Tau Pharmaceuticals, Inc. Telephone 1-866-792-5172.
- There have been no reports of hypersensitivity reactions in patients who have been treated with ADAGEN® (pegademase bovine) Injection.
- One of 12 patients showed an enhanced rate of clearance of plasma ADA activity after 5 months of therapy at 15 U/kg/week. Enhanced clearance was correlated with the appearance of an antibody that directly inhibited both unmodified ADA and ADAGEN® (pegademase bovine) Injection. Subsequently, the patient was treated with twice weekly intramuscular injections at an increased dose of 20 U/kg, or a total weekly dose of 40 U/kg. No adverse effects were observed at the higher dose and effective levels of plasma ADA were restored. After 4 months, the patient returned to a weekly dosage schedule of 20 U/kg and effective plasma levels have been maintained.
- Appropriate care to protect immune deficient patients should be maintained until improvement in immune function has been documented. The degree of immune function improvement may vary from patient to patient and, therefore, each patient will require appropriate care consistent with immunologic status.
- The treatment of SCID associated with ADA deficiency with ADAGEN® (pegademase bovine) Injection should be monitored by measuring plasma ADA activity and red blood cell dATP levels.
- Plasma ADA activity and red cell dATP should be determined prior to treatment. Once treatment with ADAGEN® (pegademase bovine) Injection has been initiated, a desirable range of plasma ADA activity (trough level before maintenance injection) should be 15–35 μmol/hr/mL. This minimum trough level will ensure that plasma ADA activity from injection to injection is maintained above the level of total erythrocyte ADA activity in the blood of normal individuals.
- Plasma ADA activity (pre-injection) should be determined every 1-2 weeks during the first 8-12 weeks of treatment in order to establish an effective dose of ADAGEN® (pegademase bovine) Injection. After 2 months of maintenance treatment with ADAGEN® (pegademase bovine) Injection, red cell dATP levels should decrease to a range of ≤ 0.005 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. Once the level of dATP has fallen adequately, it should be measured 2-4 times a year during the remainder of the first year and 2-3 times a year thereafter, assuming no interruption in therapy.
- Between 3 and 9 months, plasma ADA should be determined twice a month, then monthly until after 18-24 months of treatment with ADAGEN® (pegademase bovine) Injection.
- Patients who have successfully been maintained on therapy for two years should continue to have plasma ADA measured every 2-4 months and red cell dATP measured twice yearly. More frequent monitoring would be necessary if therapy were interrupted or if an enhanced rate of clearance of plasma ADA activity develops.
- Once effective ADA plasma levels have been established, should a patient’s plasma ADA activity level fall below 10 μmol/hr/mL (which cannot be attributed to improper dosing, sample handling or antibody development) then the patients receiving this lot of ADAGEN® (pegademase bovine) Injection should be requested to have a blood sample for plasma ADA determination taken prior to their next injection of ADAGEN® (pegademase bovine) Injection.
- Immune function, including the ability to produce antibodies, generally improves after 2-6 months of therapy, and matures over a longer period. Compared with the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving ADAGEN® (pegademase bovine) Injection. However, the lag between the correction of the metabolic abnormalities and improved immune function with a trend toward diminished frequency of infections and complications of infection is variable, and has ranged from a few weeks to approximately 6 months. Improvement in the general clinical status of the patient may be gradual (as evidenced by improvement in various clinical parameters) but should be apparent by the end of the first year of therapy. Antibody to ADAGEN® (pegademase bovine) Injection may develop in patients and may result in more rapid clearance of ADAGEN® (pegademase bovine) Injection. Antibody to ADAGEN® (pegademase bovine) Injection should be suspected if a persistent fall in pre-injection levels of plasma ADA to < 10 μmol/hr/mL occurs. If other causes for a decline in plasma ADA levels can be ruled out [such as improper storage of ADAGEN® (pegademase bovine) Injection vials (freezing or prolonged storage at temperatures above 8°C), or improper handling of plasma samples (e.g., repeated freezing and thawing during transport to laboratory)], then a specific assay for antibody to ADA and ADAGEN® (pegademase bovine) Injection (ELISA, enzyme inhibition) should be performed.
- In patients undergoing treatment with ADAGEN® (pegademase bovine) Injection, a decline in immune function, with increased risk of opportunistic infections and complications of infection, will result from failure to maintain adequate levels of plasma ADA activity [whether due to the development of antibody to ADAGEN® (pegademase bovine) Injection, to improper calculation of ADAGEN® (pegademase bovine) Injection dosage, to interruption of treatment or to improper storage of ADAGEN® (pegademase bovine) Injection with subsequent loss of activity]. If a persistent decline in plasma ADA activity occurs, immune function and clinical status should be monitored closely and precautions should be taken to minimize the risk of infection. If antibody to ADA or ADAGEN® (pegademase bovine) Injection is found to be the cause of a persistent fall in plasma ADA activity, then adjustment in the dosage of ADAGEN® (pegademase bovine) Injection and other measures may be taken to induce tolerance and restore adequate ADA activity.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with ADAGEN® (pegademase bovine) Injection has been limited. The following adverse reactions were reported: headache in one patient and pain at the injection site in two patients. The following adverse reactions have been identified during post-approval use of ADAGEN® (pegademase bovine) Injection. Because these reactions are reported voluntarily from a very small population, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Hematologic events: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia.
- Dermatological events: injection site erythema, urticaria.
- Lymphomas
- To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc. at 1-888-393-4584 or by email at [email protected] or contact the FDA at 1-800-FDA-1088 or WWW.FDA.GOV/SAFETY/MEDWATCH.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pegademase in the drug label.
# Drug Interactions
- There are no known drug interactions with ADAGEN® (pegademase bovine) Injection. However, Vidarabine is a substrate for ADA and 2′-deoxycoformycin is a potent inhibitor of ADA. Thus, the activities of these drugs and ADAGEN® (pegademase bovine) Injection could be substantially altered if they are used in combination with one another.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with ADAGEN® (pegademase bovine) Injection. It is also not known whether ADAGEN® (pegademase bovine) Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ADAGEN® (pegademase bovine) Injection should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegademase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegademase during labor and delivery.
### Nursing Mothers
- It is not known whether ADAGEN® (pegademase bovine) Injection is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ADAGEN® (pegademase bovine) Injection is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Pegademase with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Pegademase with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pegademase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegademase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegademase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegademase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegademase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegademase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
### Monitoring
- The treatment of SCID associated with ADA deficiency with ADAGEN® (pegademase bovine) Injection should be monitored by measuring plasma ADA activity and red blood cell dATP levels.
# IV Compatibility
There is limited information regarding IV Compatibility of Pegademase in the drug label.
# Overdosage
- There is no documented experience with ADAGEN® (pegademase bovine) Injection overdosage. An intraperitoneal dose of 50,000 U/kg of ADAGEN® (pegademase bovine) Injection in mice resulted in weight loss up to 9%.
# Pharmacology
## Mechanism of Action
- ADAGEN® (pegademase bovine) Injection provides specific replacement of the deficient enzyme.
- In the absence of the enzyme ADA, the purine substrates adenosine, 2′-deoxyadenosine and their metabolites are toxic to lymphocytes. The direct action of ADAGEN® (pegademase bovine) Injection is the correction of these metabolic abnormalities. Improvement in immune function and diminished frequency of opportunistic infections compared with the natural history of combined immunodeficiency due to ADA deficiency only occurs after metabolic abnormalities are corrected. There is a lag between the correction of the metabolic abnormalities and improved immune function. This period of time is variable, and has been reported to be from a few weeks to as long as 6 months. In contrast to the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving ADAGEN® (pegademase bovine) Injection.
## Structure
- ADAGEN® (pegademase bovine) Injection is a modified enzyme used for enzyme replacement therapy for the treatment of severe combined immunodeficiency disease (SCID) associated with a deficiency of adenosine deaminase.
- ADAGEN® (pegademase bovine) Injection is supplied in an isotonic, pyrogen free, sterile solution, pH 7.2-7.4, for intramuscular injection only. The solution is clear and colorless. It is supplied in 1.5 mL single-dose vials.
- The chemical name for ADAGEN® (pegademase bovine) Injection is (monomethoxypolyethylene glycol succinimidyl) 11-17-adenosine deaminase. It is a conjugate of numerous strands of monomethoxypolyethylene glycol (PEG), molecular weight 5,000, covalently attached to the enzyme adenosine deaminase (ADA). ADA (adenosine deaminase EC 3.5.4.4) used in the manufacture of ADAGEN® (pegademase bovine) Injection is derived from bovine intestine.
- The structural formula of ADAGEN® (pegademase bovine) Injection is:
- Each milliliter of ADAGEN® (pegademase bovine) Injection contains:
- One unit of activity is defined as the amount of ADA that converts 1μM of adenosine to inosine per minute at 25°C and pH 7.3.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pegademase in the drug label.
## Pharmacokinetics
- The pharmacokinetics and biochemical effects of ADAGEN® (pegademase bovine) Injection have been studied in six children ranging in age from 6 weeks to 12 years with SCID associated with ADA deficiency.
- After the intramuscular injection of ADAGEN® (pegademase bovine) Injection, peak plasma levels of ADA activity were reached 2 to 3 days following administration. The plasma elimination half-life of ADA following the administration of ADAGEN® (pegademase bovine) Injection was variable, even for the same child. The range was 3 to > 6 days. Following weekly injections of ADAGEN® (pegademase bovine) Injection at 15 U/kg, the average trough level of ADA activity in plasma was between 20 and 25 μmol/hr/mL.
- The changes in red blood cell deoxyadenosine nucleotide (dATP) and S-adenosylhomocysteine hydrolase (SAHase) have been evaluated. In patients with ADA deficiency, inadequate elimination of 2′-deoxyadenosine caused a marked elevation in dATP and a decrease in SAHase level in red blood cells. Prior to treatment with ADAGEN® (pegademase bovine) Injection, the levels of dATP in the red blood cells ranged from 0.056 to 0.899 μmol/mL of erythrocytes. After 2 months of maintenance treatment with ADAGEN® (pegademase bovine) Injection, the levels decreased to 0.007 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. In the same period of time, the levels of SAHase increased from the pretreatment range of 0.09 to 0.22 nmol/hr/mg protein to a range of 2.37 to 5.16 nmol/hr/mg protein. The normal value for SAHase is 4.18 ± 1.9 nmol/hr/mg protein.
- The optimal dosage and schedule of administration of ADAGEN® (pegademase bovine) Injection should be established for each patient, based on monitoring of plasma ADA activity levels (trough levels before maintenance injection), biochemical markers of ADA deficiency (primarily red cell dATP content), and parameters of immune function. Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 µmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample.
- In vitro immunologic data (lymphocyte response to mitogens and lymphocyte surface antigens) were obtained, but their clinical significance is unknown. Prior to treatment with ADAGEN® (pegademase bovine) Injection, immune status was significantly below normal, as indicated by < 10% of normal mitogen responses and circulating mononuclear cells bearing T-cell surface antigens. These parameters improved, though not always to normal, within 2 to 6 months of therapy.
- Severe Combined Immunodeficiency Disease Associated with ADA Deficiency
- Severe combined immunodeficiency disease (SCID) associated with a deficiency of ADA is a rare, inherited, and often fatal disease. In the absence of the ADA enzyme, the purine substrates adenosine and 2′-deoxyadenosine accumulate, causing metabolic abnormalities that are directly toxic to lymphocytes.
- The immune deficiency can be cured by bone marrow transplantation. When a suitable bone marrow donor is unavailable or when bone marrow transplantation fails, non-selective replacement of the ADA enzyme has been provided by periodic irradiated red blood cell transfusions. However, transmission of viral infections and iron overload are serious risks associated with irradiated red blood cell transfusions, and relatively few ADA deficient patients have benefitted from chronic transfusion therapy.
- ADAGEN® (pegademase bovine) Injection provides specific and direct replacement of the deficient enzyme, but will not benefit patients with immunodeficiency due to other causes.
- In patients with ADA deficiency, rigorous adherence to a schedule of ADAGEN® (pegademase bovine) Injection administration can eliminate the toxic metabolites of ADA deficiency and result in improved immune function. It is imperative that treatment with ADAGEN® (pegademase bovine) Injection be carefully monitored by measurement of the level of ADA activity in plasma. Monitoring of the level of deoxyadenosine triphosphate (dATP) in erythrocytes is also helpful in determining that the dose of ADAGEN® (pegademase bovine) Injection is adequate.
## Nonclinical Toxicology
- Long-term carcinogenic studies in animals have not been performed with ADAGEN® (pegademase bovine) Injection nor have studies been performed on impairment of fertility.
- ADAGEN® (pegademase bovine) Injection did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Pegademase in the drug label.
# How Supplied
- ADAGEN® (pegademase bovine) Injection is a clear, colorless, preservative free solution for intramuscular injection. ADAGEN® is supplied as a sterile solution in single-use vials containing 375 units per 1.5 mL solution, in boxes of 4 vials (NDC-57665-001-01).
- Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused drug for later administration.
## Storage
Refrigerate. Store between +2°C and +8°C (36°F and 46°F). DO NOT FREEZE. ADAGEN® (pegademase bovine) Injection should not be stored at room temperature. This product should not be used if there are any indications that it may have been frozen.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - CARTON LABEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pegademase in the drug label.
# Precautions with Alcohol
- Alcohol-Pegademase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Adagen®[1]
# Look-Alike Drug Names
There is limited information regarding the look alike drug name.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pegademase | |
e138784262df7fa6f44030b810b344fb12ee8ff6 | wikidoc | Pegvaliase | Pegvaliase
# Disclaimer
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# Black Box Warning
# Overview
Pegvaliase is a phenylalanine-metabolizing enzyme that is FDA approved for the reduction of blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Pegvaliase is indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.
- Treatment with pegvaliase should be managed by a healthcare provider experienced in the management of PKU.
- Obtain baseline blood phenylalanine concentration before initiating treatment.
- The recommended initial induction dosage for pegvaliase is 2.5 mg subcutaneously once weekly for 4 weeks. Administer the initial dose under the supervision of a healthcare provider.
- Titrate the pegvaliase dosage in a step-wise manner, based on tolerability, over at least 5 weeks, to achieve a dosage of 20 mg subcutaneously once daily according to Table 1.
- Therapeutic response may not be achieved until the patient is titrated to an effective maintenance dosage of pegvaliase. Use the lowest effective and tolerated dosage of pegvaliase.
- Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment. Maintain the pegvaliase dosage at 20 mg subcutaneously once daily for at least 24 weeks. Consider increasing the pegvaliase dosage to a maximum of 40 mg subcutaneously once daily in patients who have been maintained continuously on 20 mg once daily for at least 24 weeks and who have not achieved either a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L.
- Discontinue pegvaliase in patients who have not achieved a response (at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L) after 16 weeks of continuous treatment with the maximum dosage of 40 mg once daily.
- During titration and maintenance of pegvaliase treatment, patients may experience blood phenylalanine concentrations below 30 micromol/L. For blood phenylalanine concentrations below 30 micromol/L, the dosage of pegvaliase may be reduced and/or dietary protein and phenylalanine intake may be modified to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L.
- If the decision is made to readminister pegvaliase after an anaphylaxis episode, administer the first dose following the anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent dose titration should be based on patient tolerability and therapeutic response.
- If a dose is missed, instruct patients to take their next dose as scheduled and to not take two doses of pegvaliase to make up for the missed dose.
- For hypersensitivity reactions, consider premedication with an H1‑receptor antagonist, H2‑receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability.
- Pegvaliase is a clear to slightly opalescent, colorless to pale yellow solution available as follows:
- Injection: 2.5 mg/0.5 mL single-dose prefilled syringe
- Injection: 10 mg/0.5 mL single-dose prefilled syringe
- Injection: 20 mg/mL single-dose prefilled syringe
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding pegvaliase Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding pegvaliase 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 Pegvaliase FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding pegvaliase Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding pegvaliase Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- In clinical trials of pegvaliase with induction/titration/maintenance dosing, 26 out of 285 (9%) patients experienced a total of 37 anaphylaxis episodes. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases (0.15 episodes/person‑years; 5% of patients with at least one episode) and decreased in the maintenance phase (0.04 episodes/person‑years; 6% of patients with at least one episode). Signs and symptoms of anaphylaxis reported in clinical trials of pegvaliase included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). In clinical trials of pegvaliase, anaphylaxis generally occurred within 1 hour after injection (84%; 28/37 episodes); however, delayed episodes also occurred up to 48 hours after pegvaliase administration. Most episodes of anaphylaxis occurred within the first year of dosing (78%, 29/37 episodes), but cases also occurred after one year of dosing and up to 834 days (2.3 years) into treatment. Management of anaphylaxis in pegvaliase clinical trials included: administration of auto-injectable epinephrine (54%; 20/37 episodes), corticosteroids (54%; 20/37 episodes), antihistamines (51%; 19/37 episodes), and/or oxygen (5%; 2/37 episodes). Eighteen out of the 26 (69%) patients who experienced anaphylaxis were rechallenged with pegvaliase and 5 out of the 18 patients who were rechallenged (28%) had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae.
- Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during pegvaliase treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after pegvaliase administration, should be able to administer auto‑injectable epinephrine, and to call for emergency medical support upon its use.
- Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto‑injectable epinephrine to all patients receiving pegvaliase and instruct patients to carry auto‑injectable epinephrine with them at all times during pegvaliase treatment. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto‑injectable epinephrine, and to seek immediate medical care upon its use. Consider the risks associated with auto-injectable epinephrine use when prescribing pegvaliase. Refer to the auto‑injectable epinephrine prescribing information for complete information.
- Consider the risks and benefits of readministering pegvaliase following an episode of anaphylaxis. If the decision is made to readminister pegvaliase, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent pegvaliase dose titration should be based on patient tolerability and therapeutic response.
- Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability.
- Pegvaliase is available only through a restricted program under a REMS
- Pegvaliase is available only through a restricted program under a REMS called the pegvaliase REMS, because of the risk of anaphylaxis.
- Notable requirements of the pegvaliase REMS include the following:
- Prescribers must be certified with the program by enrolling in the program and completing training.
- Prescribers must prescribe auto‑injectable epinephrine with pegvaliase.
- Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive pegvaliase.
- Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with pegvaliase.
- Patients must have auto‑injectable epinephrine available at all times while taking pegvaliase.
- Further information, including a list of qualified pharmacies, is available at WWW.PALYNZIQREMS.COM or by telephone 1‑855‑758‑REMS (1‑855‑758‑7367).
- Hypersensitivity reactions, other than anaphylaxis, have been reported in 196 out of 285 (69%) patients treated with pegvaliase. The exposure adjusted rate of other hypersensitivity reactions was highest during the induction and titration phases (4.5 episodes/person-year; 50% of patients with at least one adverse reaction) and decreased in the maintenance phase (1.5 episodes/person-year; 57% of patients with at least one adverse reaction).
- Consider premedication with an H1‑receptor antagonist, H2‑receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability. Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgement of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.
# 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 a total treatment exposure of 580 patient-years in 285 patients who received pegvaliase in an induction/titration/maintenance regimen in clinical trials. Of the 285 patients, 229 patients were exposed to pegvaliase for 24 weeks, 209 patients were exposed for 1 year, 137 patients were exposed for 2 years, and 85 patients were exposed for 3 years or longer. The patient population was evenly distributed between male and female patients, the mean age was 29 years (range: 16 to 56 years), and 98% of patients were White.
- The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
- Of the 285 patients exposed to pegvaliase in an induction/titration/maintenance regimen in clinical trials, 31 (11%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients) and angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients).
- The most common adverse reactions leading to dosage reduction were arthralgia (14% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients).
- The most common adverse reactions leading to temporary drug interruption were arthralgia (13% of patients), hypersensitivity reactions (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients).
- Table 2 lists adverse reactions reported in at least 15% of patients treated with pegvaliase in an induction/titration/maintenance dosage regimen in clinical trials, and illustrates the adverse reaction rates over time by treatment phase. Table 3 lists laboratory abnormalities reported in at least 10% of patients treated with pegvaliase in an induction/titration/maintenance dosage regimen in clinical trials.
- For these analyses, the induction/titration phase was defined as the time prior to reaching a stable dose (completing an 8‑week phase at the same dose level). Once a stable dosage was reached, patients were considered to be in the maintenance phase thereafter. Safety data for patients who reached the maintenance phase are included within either the induction/titration or maintenance phases depending on the onset date of the adverse reaction. Safety data for patients who did not reach the maintenance phase are included within the induction/titration phase. The maintenance phase includes data for patients who were previously on pegvaliase and transitioned to placebo during the randomized withdrawal period of Study 302.
- Rates of adverse reactions (adjusted for duration of exposure) generally decreased over time and for some stayed relatively stable. In the maintenance phase, the rate of adverse reactions (adjusted for duration of exposure) in patients who reached the maintenance phase was comparable across dosages evaluated. The types and rate of adverse reactions reported during the maintenance phase in patients who received 20 mg once daily and 40 mg once daily were similar.
- Rates of laboratory abnormalities (adjusted for duration of exposure) stayed relatively stable over time, except for complement C4 below lower limit of normal (LLN) and hs-CRP above 0.287 mg/dL over a 6 month period (both decreased over time) and hypophenylalaninemia (blood phenylalanine concentration below 30 micromol/L) on a single measurement (increased over time). The types and rates of laboratory abnormalities (adjusted for duration of exposure) reported during the maintenance phase in patients receiving 20 mg once daily and 40 mg once daily were similar with the exception of hs‑CRP above 0.287 mg/dL over a 6 month period (exposure‑adjusted event rates 0.04 and 0.08 in patients on 20 mg once daily and 40 mg once daily, respectively).
Arthralgia
- In clinical trials, 235 out of 285 (83%) patients experienced episodes consistent with arthralgia (includes back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia episodes were more frequent during the induction/titration phase (7.6 episodes/patient-year) and decreased over time (1.5 episodes/patient-year in the maintenance phase). Thirty-nine out of 285 (14%) patients had one episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of pegvaliase and occurred at any time during treatment. The mean duration of arthralgia was 14 days (median: 3 days, range: 1 to 580 days), and 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia (severe pain limiting self-care activities of daily living) was reported by 14 (5%) patients. In addition to arthralgia, other joint-related signs and symptoms reported were: joint swelling (22 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (19 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), pegvaliase dosage reduction (4% of episodes), pegvaliase interruption (4% of episodes), or pegvaliase withdrawal (0.6% of episodes). 97% of arthralgia episodes were reported as resolved at the time of last observation (up to 59 months of follow‑up).
Injection Site Reactions
- Injection site reactions were reported as early as after the first dose of pegvaliase and occurred at any time during treatment. Injection site reactions were more frequent during the induction/titration phase (21.9 episodes/patient-years) and decreased over time (4 episodes/patient‑years in the maintenance phase). The mean duration of injection site reaction was 8 days (median: 2 days, range: 1 to 970 days), and 7% of injection site reactions had a duration of at least 14 days. 99% of injection site reactions were reported as resolved at the time of last observation (up to 59 months of follow‑up).
- Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred after 464 days of pegvaliase treatment and lasted 16 days), xanthogranuloma (occurred after 378 days of pegvaliase treatment and lasted 638 days) was treated with a topical antihistamine, corticosteroid, and pegvaliase treatment was discontinued, and necrobiosis lipoidica diabeticorum (occurred after 281 days of pegvaliase treatment and lasted 281 days). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All three injection site reactions resolved.
- One patient reported soft tissue infection (occurred after 196 days of pegvaliase treatment and lasted 8 days) associated with mesenteric panniculitis treated with antibiotics, which resulted in treatment discontinuation.
Generalized Skin Reactions (not limited to the injection site) Lasting at Least 14 Days
- In clinical trials, 125 out of 285 (44%) patients treated with pegvaliase experienced generalized skin reactions (not limited to the injection site) lasting at least 14 days. Mean duration of these reactions was 58 days (median: 34 days; range: 14 to 638 days). Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient‑years), and decreased over time (0.3 episodes/patient-years in the maintenance phase).
- The mean time from first dose of pegvaliase to onset of skin reactions was 319 days (median: 169 days; range: 2 to 1237 days). 5% of these reactions persisted at least 180 days, and 85% of these reactions were reported as resolved at the time of last observation (up to 59 months of follow‑up).
Angioedema
- In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and face edema) occurring independent of anaphylaxis. Angioedema (included under Hypersensitivity in Table 2) was more frequent during the induction/titration phase (0.15 episodes/patient-year) and decreased over time (0.06 episodes/patient-year in the maintenance phase). Three patients discontinued treatment. All episodes resolved. Angioedema can present as a symptom of anaphylaxis.
Serum Sickness
- In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness episodes were more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year during the maintenance phase). All serum sickness reactions resolved without sequelae (duration of serum sickness ranged from 1 to 8 days). Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence, and managed serum sickness with drug interruption, dosage reduction and/or concomitant medication. Two patients discontinued treatment.
- As with all therapeutic proteins, there is potential for immunogenicity. 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 the incidence of antibodies to pegvaliase in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- All patients treated with pegvaliase developed a sustained total anti-drug antibody (TAb) response with a majority of patients (91%; N = 235/258) developing that response by Week 4 of treatment. Mean TAb titers peaked 2 weeks after pegvaliase initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in all patients with a majority of patients (98%; N = 265/270) becoming positive for anti-PAL IgM by 2 months after treatment initiation. Anti‑PAL IgG antibodies were detected in almost all patients (N = 226/227) by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in the majority of patients (98%; N = 277/284 for IgM; and 278/284 for IgG) with mean titers for both peaking at 1 to 3 months after treatment initiation. Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in the majority of patients (88%; N = 249/284) over time. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 1 year after treatment initiation).
- Twenty-five of 26 patients who had anaphylaxis were tested for anti‑pegvaliase‑pqpz IgE antibodies, which recognize the PEGylated protein product. Of the 25 patients tested for anti‑pegvaliase‑pqpz IgE antibodies, 24 patients tested negative. The one patient who tested positive for anti‑pegvaliase‑pqpz IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti‑pegvaliase‑pqpz IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis). Sixty‑eight of 285 patients in clinical trials were tested for both anti‑PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti‑pegvaliase‑pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 68 patients, 5 (7%) tested positive at least once for anti‑PAL IgE antibodies but negative for anti‑pegvaliase‑pqpz IgE antibodies.
- The highest frequency of hypersensitivity reactions (consistent with a Type III immune complex-mediated hypersensitivity mechanism) occurred within the first 6 months of pegvaliase treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. IgG and IgM CIC concentrations were above the upper limit of normal in 63% (N = 164/259) and 41% of patients (N = 106/259), respectively, at 12 weeks of pegvaliase treatment. The incidence of CIC positivity decreased over time. 61% of patients (N = 110/180) had complement C3 concentrations less than lower limit of normal (LLN) at 6 months after treatment initiation and 38% of patients (N = 94/248) had complement C4 concentrations less than LLN at 3 months after treatment initiation. The incidence of low complement C3 and C4 concentrations decreased over time, but approximately 39% (N = 19/49) and 12% (N = 6/49) of patients had low C3 and C4 concentrations, respectively, at 36 months after treatment initiation.
- Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase‑pqpz concentrations and with higher blood phenylalanine concentrations. Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some but not all antibody analytes. Patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than patients with lower mean change in IgG CIC concentrations. Mean antibody titers for anti‑PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.
## Postmarketing Experience
There is limited information regarding Pegvaliase Postmarketing Experience in the drug label.
# Drug Interactions
- Effect of Pegvaliase on Other PEGylated Products
- In a single dose study of pegvaliase in adult patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced hypersensitivity reactions. One of the two patients experienced a hypersensitivity reaction on day 15 after a single pegvaliase dosage of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single pegvaliase dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti‑PEG IgG antibody titers at or around the time of the hypersensitivity reactions.
- In pegvaliase clinical trials, the majority of patients developed anti‑PEG IgM and IgG antibodies after treatment with pegvaliase. The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with pegvaliase and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Based on findings in studies of pregnant animals without PKU treated with pegvaliase-pqpz, pegvaliase may cause fetal harm when administered to a pregnant woman. Limited available data with pegvaliase-pqpz use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. There are risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy including increased risk for miscarriage, major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ; therefore, phenylalanine concentrations should be closely monitored in women with PKU during pregnancy. Advise pregnant women of the potential risks to the fetus.
- A reproduction study in pregnant rabbits treated with pegvaliase‑pqpz demonstrated a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes. Embryo-fetal toxicity (increased resorptions and reduced fetal weight) was also observed. These effects occurred at 7.5 times the maximum recommended daily dose and were associated with strong signs of maternal toxicity, including marked reductions in weight gain and food consumption, and death. A reproduction study in pregnant rats treated with pegvaliase-pqpz demonstrated an increase in skeletal variations, with no malformations observed. The effects in rats occurred at 4.2 times the maximum recommended daily dose. In a pre-/post-natal development study in rats, pegvaliase‑pqpz produced reduced survival of offspring during lactation, decreases in pup weight and litter size, and delayed sexual maturation of offspring when administered daily at 19.4 times the maximum recommended daily dose. The effects on rat embryo‑fetal and post-natal development were associated with maternal toxicity.
- All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. 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. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU.
- There is a pregnancy surveillance program for pegvaliase. If pegvaliase is administered during pregnancy, or if a patient becomes pregnant while receiving pegvaliase or within one month following the last dose of pegvaliase, healthcare providers should report pegvaliase exposure by calling 1-866-906-6100.
Disease-Associated Maternal and/or Embryo-Fetal Risk
- Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception.
Dose Adjustments During Pregnancy and the Postpartum Period
- Phenylalanine concentrations below 30 micromol/L in pregnant women with PKU treated with pegvaliase may be associated with adverse fetal outcomes. Monitor blood phenylalanine concentrations during pregnancy and adjust the dosage of pegvaliase or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L.
Human Data
- Uncontrolled Maternal PKU: Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled phenylalanine concentrations above 600 micromol/L are associated with an increased risk for miscarriage, major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ.
- Limited data from case reports of pegvaliase use in pregnant women are insufficient to determine a drug‑associated risk of adverse developmental outcomes.
Animal Data
- All developmental toxicity studies were conducted in animals (rats and rabbits) without PKU, in which treatment with pegvaliase-pqpz produced a dose-dependent reduction in maternal blood phenylalanine concentrations. At doses that produced maternal toxicity and/or effects on embryo-fetal development, the maternal plasma phenylalanine concentrations were markedly reduced compared to the control group. The contribution of maternal phenylalanine depletion to the incidence of embryo‑fetal developmental effects was not evaluated.
&Subcutaneous administration of 5 mg/kg/day pegvaliase-pqpz (7.5 times the maximum recommended daily dose based on bodyweight ) in pregnant rabbits during the period of organogenesis produced embryo-lethality (increased resorptions), marked reduction in fetal weight, and fetal malformations. The malformations included multiple external abnormalities of the head, body and limbs, multiple soft tissue malformations (reduced size or absence of kidneys, diaphragmatic hernia, corneal opacity, discoloration or reduced size of eyes, and reduced size of lungs) and multiple skeletal malformations of the craniofacial bones, vertebrae, sternebrae, ribs, pelvis, limbs, and digits. An increase in variations and delayed ossification was also observed in all skeletal regions. The adverse developmental effects were associated with maternal toxicity, as indicated by marked impairment of weight gain and food consumption. Deaths associated with weight loss and abortion occurred in 8% of the pregnant rabbits treated with 5 mg/kg/day pegvaliase-pqpz.
- Subcutaneous administration of 2 mg/kg/day pegvaliase‑pqpz (3 times the maximum recommended daily dose based on bodyweight ) in pregnant rabbits had no adverse effects on embryo-fetal development. Systemic exposure to pegvaliase‑pqpz was detected in fetuses from rabbits treated with 2 or 5 mg/kg/day.
- Pegvaliase-pqpz increased fetal alterations when administered daily in pregnant rats at doses of 8 mg/kg subcutaneously and higher (4.2 times the human steady-state area under the curve at the maximum recommended daily dose) during a 28‑day premating period, mating, and through the period of organogenesis. The fetal alterations were limited to skeletal variations such as cervical ribs, bifid centra of lumbar and thoracic vertebrae, and incomplete ossification of squamosal bones, frontal bones, lumbar vertebra arch, and ribs. Daily administration of 20 mg/kg subcutaneously (19.4 times the human steady-state AUC at the recommended maximum daily dose) to pregnant rats produced reductions in litter sizes and fetal weights, which was associated with maternal toxicity (decreased body weight, ovarian weight, and food consumption). The decrease in litter sizes at 20 mg/kg subcutaneously was secondary to reductions in corpora lutea and implantations. Systemic exposure to pegvaliase-pqpz was detected in fetuses from rats treated with 20 mg/kg of pegvaliase-pqpz (19.4 times the human steady-state AUC at the recommended maximum daily dose). Subcutaneous administration of 2 mg/kg/day pegvaliase-pqpz (less than the human steady state AUC at the maximum recommended daily dose) in pregnant rats had no adverse effects on embryo‑fetal development.
- Pegvaliase-pqpz decreased pup weight, litter size, and survival of offspring during lactation, and delayed sexual maturation of offspring when administered daily in rats at 20 mg/kg subcutaneously (19.4 times the human steady‑state AUC at the recommended maximum daily dose), with dosing starting before mating and continuing through lactation. The effects in offspring were associated with maternal toxicity. No effects in offspring were observed at 8 mg/kg/day subcutaneously (4.2 times the human steady-state AUC at the recommended maximum daily dose). This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of pegvaliase‑pqpz were noted in tests of learning and memory.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegvaliase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegvaliase during labor and delivery.
### Nursing Mothers
- There are no data on the presence of pegvaliase-pqpz in human milk, the effects on the breastfed infant, or the effects on milk production. A pre-/post-natal study in rats showed that pegvaliase-pqpz is present in rat milk and that administration of pegvaliase-pqpz during lactation decreased pup weight and survival. However, systemic absorption of pegvaliase-pqpz was not detected in the rat pups. Pegvaliase may cause low phenylalanine concentrations in human milk. The developmental and health benefits of breastfeeding should be considered along with the clinical need for pegvaliase treatment and any potential adverse effect on the breastfed infant from pegvaliase or from the underlying condition.
- Monitor blood phenylalanine concentrations in breastfeeding women treated with pegvaliase.
### Pediatric Use
- The safety and effectiveness of pegvaliase in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of pegvaliase did not include patients aged 65 years and older.
### Gender
There is no FDA guidance on the use of Pegvaliase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegvaliase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegvaliase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegvaliase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegvaliase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegvaliase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Each prefilled syringe of pegvaliase is intended for use as a single subcutaneous injection.
- Inspect pegvaliase visually for particulate matter and discoloration prior to administration. Pegvaliase is a clear to slightly opalescent, colorless to pale yellow solution. *Discard if discolored, cloudy, or if particulate matter is present.
- Prior to first dose of pegvaliase, prescribe auto-injectable epinephrine, and instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use.
- Perform initial administration(s) and/or readministration after an anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self‑administration.
- Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during pegvaliase treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after each pegvaliase administration, should be able to administer auto-injectable epinephrine, and to call for emergency medical support upon its use.
- The recommended injection sites for pegvaliase are: the front middle of thighs and the abdomen at least 2 inches (five centimeters) away from the navel. If a caregiver is giving the injection, the top of buttocks and the back of the upper arms are also appropriate injection sites.
- Do not inject pegvaliase into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed. Check the injection site for redness, swelling, or tenderness.
- Rotate sites for subcutaneous injections of pegvaliase. If more than one injection is needed for a single dose of pegvaliase, the injection sites should be at least 2 inches away from each other. The second injection site can be on the same part of the body or a different part of the body.
### Monitoring
- Reduction in blood phenylalanine concentrations is indicative of efficacy.
- Improvement in inattention and mood may indicate efficacy.
- Blood phenylalanine concentration: Prior to initiation, every 4 weeks until a maintenance dose is reached, and then periodically throughout treatment.
- Signs and symptoms of anaphylaxis: Monitor for at least 60 minutes after initial dose or upon reinitiation of therapy after a previous episode of anaphylaxis.
- Dietary protein and phenylalanine intake: Throughout therapy.
- After initiating treatment with pegvaliase, obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established. After a maintenance dosage is established, periodic blood phenylalanine monitoring is recommended to assess blood phenylalanine control.
- Monitor patients’ dietary protein and phenylalanine intake throughout treatment with pegvaliase and counsel them on how to adjust their dietary intake, as needed, based on blood phenylalanine concentrations.
# IV Compatibility
There is limited information regarding the compatibility of Pegvaliase and IV administrations.
# Overdosage
There is limited information regarding Pegvaliase overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans‑cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.
## Structure
(Description with picture)
## Pharmacodynamics
- Pegvaliase treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline. The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase‑pqpz plasma concentrations.
## Pharmacokinetics
- The pharmacokinetics of pegvaliase‑pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase‑pqpz. In the first eight weeks of induction and titration treatment, plasma pegvaliase‑pqpz concentrations were low to not measurable. At steady state during maintenance treatment with pegvaliase 20 mg and 40 mg subcutaneously once daily, the mean ± SD (range) plasma trough pegvaliase‑pqpz concentrations were: 11.2 ± 9.0 (0.21 to 29.6) mg/L and 10.4 ± 12.7 (0.18 to 43.1) mg/L, respectively. The following pharmacokinetic parameters were observed in adult patients with PKU treated with pegvaliase at maintenance dosages of 20 mg once daily and 40 mg once daily.
- The median Tmax was approximately 8 hours. The mean ± SD (range) peak concentration (Cmax) at steady state was: 14.0 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively.
- The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively.
- The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 L/h (0.034 to 8.88), respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively.
- The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.
- The route of elimination of pegvaliase‑pqpz has not been studied in humans.
## Nonclinical Toxicology
- Carcinogenicity and genotoxicity studies have not been performed with pegvaliase‑pqpz. Based on its mechanism of action, pegvaliase‑pqpz is not expected to be tumorigenic.
- Pegvaliase-pqpz produced impaired fertility in female rats at 20 mg/kg/day subcutaneously (19.4 times the human steady‑state AUC at the maximum recommended daily dose), as indicated by decreases in corpora lutea, implantations, and litter size. These effects were associated with toxicity (decreased body weight, ovarian weight, and food consumption). No effects on mating or fertility were observed in female rats with 8 mg/kg/day subcutaneously (4.2 times the human steady‑state AUC at the maximum recommended daily dose) or in male rats with 20 mg/kg/day subcutaneously.
- In rats without PKU treated with pegvaliase-pqpz, dose-dependent vacuolation in multiple organs and tissues was observed in the 4‑ and 26‑week repeat dose toxicity studies at doses of 8 mg/kg subcutaneously or greater administered twice weekly (less than the human steady state AUC at the maximum recommended daily dose). Vacuolation occurred in renal tubule cells and in histiocytic cells of the liver, spleen, testes, adrenal cortex, mesenteric lymph node, and mandibular lymph node. Vacuolation in histiocytes of the affected organs and tissues persisted after cessation of treatment. The vacuolation observed in these studies was not associated with organ‑related toxicities as determined by clinical chemistry/urinalysis and histopathological examination. The clinical significance of these findings and functional consequences are unknown.
- In the 39‑week repeat dose toxicity study in monkeys, pegvaliase-pqpz 3 mg/kg subcutaneously twice weekly (3 times the human steady state AUC at the maximum recommended daily dose) produced systemic arteritis involving small arteries and arterioles in a wide range of organs and tissues (kidney, urinary bladder, pancreas, gallbladder, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, lung, heart, sciatic nerve, lacrimal gland, mandibular lymph node, epididymis, seminal vesicle, ovary, uterus, cervix, and vagina) and in subcutaneous injection sites. Arteritis was likely due to the immune-mediated response (e.g., immune complex deposition in blood vessels) associated with chronic administration of a foreign protein to the animals. The incidence and severity of systemic arteritis was dose-dependent. The vascular inflammation observed in this study was not associated with organ related toxicities as determined by clinical pathology parameters (hematology, clinical chemistry, and urinalysis) and histopathological examination.
- Studies of longer duration in rats and monkeys treated with pegvaliase‑pqpz have not been conducted.
# Clinical Studies
- Study 165‑301 (referred to as Study 301, NCT01819727) was an open-label randomized, multi-center study of adults with PKU to assess safety and tolerability of self-administered pegvaliase in an induction/titration/maintenance regimen with a target maintenance dose of 20 mg subcutaneously once daily or 40 mg subcutaneously once daily. At pegvaliase treatment initiation, 253 patients demonstrated inadequate blood phenylalanine control (blood phenylalanine concentration greater than 600 micromol/L) on existing management, and 8 patients had blood phenylalanine concentrations less than or equal to 600 micromol/L. Existing management options included prior or current restriction of dietary phenylalanine and protein intake, and/or prior treatment with sapropterin dihydrochloride. Patients previously treated with sapropterin dihydrochloride were required to discontinue use at least 14 days prior to the first dose.
- The 261 enrolled patients were aged 16 to 55 years (mean: 29 years) and had a baseline mean (range) blood phenylalanine of 1,233 (285, 2330) micromol/L. One hundred forty nine out of 261 (57%) patients were taking medical food at baseline and 41 out of 261 patients (16%) were on a protein-restricted diet at baseline (defined as receiving greater than 75% of total protein intake from medical food). Patients were randomized (1:1) to one of two target maintenance dosage arms: 20 mg once daily or 40 mg once daily. Patients were titrated to reach their randomized target dosage of 20 mg once daily or 40 mg once daily. The duration of titration varied among patients and was based on patient tolerability. Of the 261 enrolled patients, 195 (75%) patients reached their randomized maintenance dosage (103 in the 20 mg once daily arm, 92 in the 40 mg once daily arm). Among the patients who reached their randomized maintenance dosage, patients in the 20 mg once daily randomized arm reached their maintenance dosage at a median time of 10 weeks (range: 9 to 29 weeks) and patients in the 40 mg once daily arm reached their maintenance dosage at a median time of 11 weeks (range: 10 to 33 weeks).
- Of the 261 patients who enrolled in Study 301, 54 (21%) patients discontinued treatment during Study 301, 4 patients completed Study 301 and did not continue to Study 165‑302 (referred to as Study 302, NCT01889862), 152 patients continued to the eligibility period of Study 302, and 51 patients continued directly from Study 301 into the long‑term treatment period of Study 302.
- A total of 164 adult patients with PKU who were previously-treated with pegvaliase (152 patients from Study 301 and 12 patients from other pegvaliase trials) enrolled in Study 302 and continued treatment with pegvaliase in Study 302 for up to 13 weeks to assess eligibility for randomized withdrawal period.
Randomized Withdrawal Period
- Following this period of up to 13 weeks of additional pegvaliase treatment in Study 302, eligibility for entry into the efficacy assessment period (randomized withdrawal period) was determined by whether a patient achieved at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline (when in previous studies). Eighty‑six out of 164 patients (52%) met this response target and continued into the randomized withdrawal period. In the double-blind, placebo-controlled, randomized withdrawal period, patients were randomized in a 2:1 ratio to either continue their maintenance pegvaliase dosage or to receive matching placebo for a total of 8 weeks. The treatment difference in least squares (LS) mean change in blood phenylalanine concentration from the Study 302 randomized withdrawal baseline to randomized withdrawal Week 8 for each randomized study arm is shown in Table 5. Mean blood phenylalanine concentrations at pre-treatment baseline (Study 301 or other pegvaliase trials) are also shown in Table 5. At Study 302 randomized withdrawal Week 8, pegvaliase‑treated patients (20 mg once daily or 40 mg once daily) maintained their blood phenylalanine concentrations as compared to their randomized withdrawal baseline, whereas patients randomized to matching placebo (20 mg once daily or 40 mg once daily) returned to their pretreatment baseline blood phenylalanine concentrations (Figure 1).
- Of 118 patients from Study 301 with a pre‑treatment baseline blood phenylalanine concentration greater than 600 micromol/L who were randomized to and received at least one dose of 20 mg once daily pegvaliase, 108 patients, 98 patients, and 51 patients were treated for at least 24 weeks, 48 weeks, and 96 weeks, respectively.
- Of the 118 patients, 53 patients reached their first response (at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L) by 4 weeks of treatment with 20 mg once daily and 28 patients reached their first response between Weeks 4 and 24 with 20 mg once daily. Of the 118 patients, 25 patients escalated their dosage from 20 mg once daily to 40 mg once daily before reaching a first response; of those 25 patients, 8 patients reached their first response by 4 weeks of treatment with 40 mg once daily and 6 patients reached their first response between Weeks 4 and 16 with 40 mg once daily.
# How Supplied
- Pegvaliase (pegvaliase-pqpz) injection is supplied as a preservative-free, sterile, clear to slightly opalescent, colorless to pale yellow solution. All dosage strengths of pegvaliase are provided in a 1 mL glass syringe with a 26 gauge, 0.5 inch needle.
- Each carton contains 1 or 10 trays with single-dose prefilled syringe(s), Prescribing Information, Medication Guide, and Instructions for Use. The following packaging configurations are available.
## Storage
- Store in refrigerator at 36°F to 46°F (2°C to 8°C) in its original carton to protect from light.
- Do not freeze or shake.
- For patients: If needed, store pegvaliase in the original carton at room temperature between 68°F to 77°F (20°C to 25°C) for up to 30 days. Record the date removed from refrigeration on the carton. Once stored at room temperature, do not return the product to the refrigerator.
- The shelf-life expires after storage at room temperature for 30 days, or after the expiration date on the product carton, whichever is earlier.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Advise patients that pegvaliase may cause hypersensitivity reactions, including anaphylaxis that can occur at any time. Instruct patients to recognize the signs and symptoms of anaphylaxis.
- Instruct patients to carry auto-injectable epinephrine with them at all times during pegvaliase treatment. Instruct the patient and observer (if applicable) on the appropriate use of auto‑injectable epinephrine for anaphylaxis.
- Instruct patients who experience anaphylaxis to seek immediate medical care, discontinue therapy, and resume treatment only at the instruction of a healthcare provider.
- Pegvaliase is available only through a restricted program called the pegvaliase REMS. Inform the patient of the following notable requirements:
- Patients must be enrolled in the pegvaliase REMS.
- Patients must be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with pegvaliase.
- Patients must fill a prescription for auto-injectable epinephrine and carry it with them at all times.
- Patients will be given a pegvaliase Patient Wallet Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the :*patient and observer (if applicable) to immediately seek medical care. Advise the patient to show the pegvaliase Wallet Card to other treating healthcare providers.
- pegvaliase is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.
- Advise patients to monitor their dietary protein and phenylalanine intake throughout treatment with pegvaliase, and adjust intake as directed by their healthcare provider based on blood phenylalanine concentrations.
- Provide appropriate instruction for methods of self-injection, including careful review of the pegvaliase Medication Guide and Instructions for Use. Instruct patients in the use of aseptic technique when administering pegvaliase.
- Inform patients that a healthcare provider will show them or their caregiver how to prepare to inject pegvaliase before self-administering.
- Advise patients not to inject into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed.
- Advise patients to rotate areas of injection with each dose. Advise patients to check the injection site for redness, swelling, and tenderness, and to contact their healthcare provider if they have a skin reaction and it does not clear up, or worsens.
- Advise patients to follow sharps disposal recommendations patients on safe disposal procedures.
- Advise patients that the shelf‑life expires after storage at room temperature for 30 days or after the expiration date on the product carton, whichever is earlier.
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.
- Advise women who are exposed to pegvaliase during pregnancy or who become pregnant within one month following the last dose of pegvaliase that there is a pregnancy surveillance program that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to BioMarin (1‑866‑906‑6100).
# Precautions with Alcohol
Alcohol-Pegvaliase interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Palynziq
# Look-Alike Drug Names
There is limited information regarding Pegvaliase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Pegvaliase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
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# Black Box Warning
# Overview
Pegvaliase is a phenylalanine-metabolizing enzyme that is FDA approved for the reduction of blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Pegvaliase is indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.
- Treatment with pegvaliase should be managed by a healthcare provider experienced in the management of PKU.
- Obtain baseline blood phenylalanine concentration before initiating treatment.
- The recommended initial induction dosage for pegvaliase is 2.5 mg subcutaneously once weekly for 4 weeks. Administer the initial dose under the supervision of a healthcare provider.
- Titrate the pegvaliase dosage in a step-wise manner, based on tolerability, over at least 5 weeks, to achieve a dosage of 20 mg subcutaneously once daily according to Table 1.
- Therapeutic response may not be achieved until the patient is titrated to an effective maintenance dosage of pegvaliase. Use the lowest effective and tolerated dosage of pegvaliase.
- Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment. Maintain the pegvaliase dosage at 20 mg subcutaneously once daily for at least 24 weeks. Consider increasing the pegvaliase dosage to a maximum of 40 mg subcutaneously once daily in patients who have been maintained continuously on 20 mg once daily for at least 24 weeks and who have not achieved either a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L.
- Discontinue pegvaliase in patients who have not achieved a response (at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L) after 16 weeks of continuous treatment with the maximum dosage of 40 mg once daily.
- During titration and maintenance of pegvaliase treatment, patients may experience blood phenylalanine concentrations below 30 micromol/L. For blood phenylalanine concentrations below 30 micromol/L, the dosage of pegvaliase may be reduced and/or dietary protein and phenylalanine intake may be modified to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L.
- If the decision is made to readminister pegvaliase after an anaphylaxis episode, administer the first dose following the anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent dose titration should be based on patient tolerability and therapeutic response.
- If a dose is missed, instruct patients to take their next dose as scheduled and to not take two doses of pegvaliase to make up for the missed dose.
- For hypersensitivity reactions, consider premedication with an H1‑receptor antagonist, H2‑receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability.
- Pegvaliase is a clear to slightly opalescent, colorless to pale yellow solution available as follows:
- Injection: 2.5 mg/0.5 mL single-dose prefilled syringe
- Injection: 10 mg/0.5 mL single-dose prefilled syringe
- Injection: 20 mg/mL single-dose prefilled syringe
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding pegvaliase Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding pegvaliase 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 Pegvaliase FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding pegvaliase Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding pegvaliase Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- In clinical trials of pegvaliase with induction/titration/maintenance dosing, 26 out of 285 (9%) patients experienced a total of 37 anaphylaxis episodes. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases (0.15 episodes/person‑years; 5% of patients with at least one episode) and decreased in the maintenance phase (0.04 episodes/person‑years; 6% of patients with at least one episode). Signs and symptoms of anaphylaxis reported in clinical trials of pegvaliase included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). In clinical trials of pegvaliase, anaphylaxis generally occurred within 1 hour after injection (84%; 28/37 episodes); however, delayed episodes also occurred up to 48 hours after pegvaliase administration. Most episodes of anaphylaxis occurred within the first year of dosing (78%, 29/37 episodes), but cases also occurred after one year of dosing and up to 834 days (2.3 years) into treatment. Management of anaphylaxis in pegvaliase clinical trials included: administration of auto-injectable epinephrine (54%; 20/37 episodes), corticosteroids (54%; 20/37 episodes), antihistamines (51%; 19/37 episodes), and/or oxygen (5%; 2/37 episodes). Eighteen out of the 26 (69%) patients who experienced anaphylaxis were rechallenged with pegvaliase and 5 out of the 18 patients who were rechallenged (28%) had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae.
- Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during pegvaliase treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after pegvaliase administration, should be able to administer auto‑injectable epinephrine, and to call for emergency medical support upon its use.
- Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto‑injectable epinephrine to all patients receiving pegvaliase and instruct patients to carry auto‑injectable epinephrine with them at all times during pegvaliase treatment. Prior to the first dose, instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto‑injectable epinephrine, and to seek immediate medical care upon its use. Consider the risks associated with auto-injectable epinephrine use when prescribing pegvaliase. Refer to the auto‑injectable epinephrine prescribing information for complete information.
- Consider the risks and benefits of readministering pegvaliase following an episode of anaphylaxis. If the decision is made to readminister pegvaliase, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent pegvaliase dose titration should be based on patient tolerability and therapeutic response.
- Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability.
- Pegvaliase is available only through a restricted program under a REMS
- Pegvaliase is available only through a restricted program under a REMS called the pegvaliase REMS, because of the risk of anaphylaxis.
- Notable requirements of the pegvaliase REMS include the following:
- Prescribers must be certified with the program by enrolling in the program and completing training.
- Prescribers must prescribe auto‑injectable epinephrine with pegvaliase.
- Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive pegvaliase.
- Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with pegvaliase.
- Patients must have auto‑injectable epinephrine available at all times while taking pegvaliase.
- Further information, including a list of qualified pharmacies, is available at WWW.PALYNZIQREMS.COM or by telephone 1‑855‑758‑REMS (1‑855‑758‑7367).
- Hypersensitivity reactions, other than anaphylaxis, have been reported in 196 out of 285 (69%) patients treated with pegvaliase. The exposure adjusted rate of other hypersensitivity reactions was highest during the induction and titration phases (4.5 episodes/person-year; 50% of patients with at least one adverse reaction) and decreased in the maintenance phase (1.5 episodes/person-year; 57% of patients with at least one adverse reaction).
- Consider premedication with an H1‑receptor antagonist, H2‑receptor antagonist, and/or antipyretic prior to pegvaliase administration based upon individual patient tolerability. Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgement of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.
# 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 a total treatment exposure of 580 patient-years in 285 patients who received pegvaliase in an induction/titration/maintenance regimen in clinical trials. Of the 285 patients, 229 patients were exposed to pegvaliase for 24 weeks, 209 patients were exposed for 1 year, 137 patients were exposed for 2 years, and 85 patients were exposed for 3 years or longer. The patient population was evenly distributed between male and female patients, the mean age was 29 years (range: 16 to 56 years), and 98% of patients were White.
- The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus, nausea, abdominal pain, oropharyngeal pain, vomiting, cough, diarrhea, and fatigue.
- Of the 285 patients exposed to pegvaliase in an induction/titration/maintenance regimen in clinical trials, 31 (11%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients) and angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients).
- The most common adverse reactions leading to dosage reduction were arthralgia (14% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients).
- The most common adverse reactions leading to temporary drug interruption were arthralgia (13% of patients), hypersensitivity reactions (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients).
- Table 2 lists adverse reactions reported in at least 15% of patients treated with pegvaliase in an induction/titration/maintenance dosage regimen in clinical trials, and illustrates the adverse reaction rates over time by treatment phase. Table 3 lists laboratory abnormalities reported in at least 10% of patients treated with pegvaliase in an induction/titration/maintenance dosage regimen in clinical trials.
- For these analyses, the induction/titration phase was defined as the time prior to reaching a stable dose (completing an 8‑week phase at the same dose level). Once a stable dosage was reached, patients were considered to be in the maintenance phase thereafter. Safety data for patients who reached the maintenance phase are included within either the induction/titration or maintenance phases depending on the onset date of the adverse reaction. Safety data for patients who did not reach the maintenance phase are included within the induction/titration phase. The maintenance phase includes data for patients who were previously on pegvaliase and transitioned to placebo during the randomized withdrawal period of Study 302.
- Rates of adverse reactions (adjusted for duration of exposure) generally decreased over time and for some stayed relatively stable. In the maintenance phase, the rate of adverse reactions (adjusted for duration of exposure) in patients who reached the maintenance phase was comparable across dosages evaluated. The types and rate of adverse reactions reported during the maintenance phase in patients who received 20 mg once daily and 40 mg once daily were similar.
- Rates of laboratory abnormalities (adjusted for duration of exposure) stayed relatively stable over time, except for complement C4 below lower limit of normal (LLN) and hs-CRP above 0.287 mg/dL over a 6 month period (both decreased over time) and hypophenylalaninemia (blood phenylalanine concentration below 30 micromol/L) on a single measurement (increased over time). The types and rates of laboratory abnormalities (adjusted for duration of exposure) reported during the maintenance phase in patients receiving 20 mg once daily and 40 mg once daily were similar with the exception of hs‑CRP above 0.287 mg/dL over a 6 month period (exposure‑adjusted event rates 0.04 and 0.08 in patients on 20 mg once daily and 40 mg once daily, respectively).
Arthralgia
- In clinical trials, 235 out of 285 (83%) patients experienced episodes consistent with arthralgia (includes back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia episodes were more frequent during the induction/titration phase (7.6 episodes/patient-year) and decreased over time (1.5 episodes/patient-year in the maintenance phase). Thirty-nine out of 285 (14%) patients had one episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of pegvaliase and occurred at any time during treatment. The mean duration of arthralgia was 14 days (median: 3 days, range: 1 to 580 days), and 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia (severe pain limiting self-care activities of daily living) was reported by 14 (5%) patients. In addition to arthralgia, other joint-related signs and symptoms reported were: joint swelling (22 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (19 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), pegvaliase dosage reduction (4% of episodes), pegvaliase interruption (4% of episodes), or pegvaliase withdrawal (0.6% of episodes). 97% of arthralgia episodes were reported as resolved at the time of last observation (up to 59 months of follow‑up).
Injection Site Reactions
- Injection site reactions were reported as early as after the first dose of pegvaliase and occurred at any time during treatment. Injection site reactions were more frequent during the induction/titration phase (21.9 episodes/patient-years) and decreased over time (4 episodes/patient‑years in the maintenance phase). The mean duration of injection site reaction was 8 days (median: 2 days, range: 1 to 970 days), and 7% of injection site reactions had a duration of at least 14 days. 99% of injection site reactions were reported as resolved at the time of last observation (up to 59 months of follow‑up).
- Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred after 464 days of pegvaliase treatment and lasted 16 days), xanthogranuloma (occurred after 378 days of pegvaliase treatment and lasted 638 days) was treated with a topical antihistamine, corticosteroid, and pegvaliase treatment was discontinued, and necrobiosis lipoidica diabeticorum (occurred after 281 days of pegvaliase treatment and lasted 281 days). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All three injection site reactions resolved.
- One patient reported soft tissue infection (occurred after 196 days of pegvaliase treatment and lasted 8 days) associated with mesenteric panniculitis treated with antibiotics, which resulted in treatment discontinuation.
Generalized Skin Reactions (not limited to the injection site) Lasting at Least 14 Days
- In clinical trials, 125 out of 285 (44%) patients treated with pegvaliase experienced generalized skin reactions (not limited to the injection site) lasting at least 14 days. Mean duration of these reactions was 58 days (median: 34 days; range: 14 to 638 days). Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient‑years), and decreased over time (0.3 episodes/patient-years in the maintenance phase).
- The mean time from first dose of pegvaliase to onset of skin reactions was 319 days (median: 169 days; range: 2 to 1237 days). 5% of these reactions persisted at least 180 days, and 85% of these reactions were reported as resolved at the time of last observation (up to 59 months of follow‑up).
Angioedema
- In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and face edema) occurring independent of anaphylaxis. Angioedema (included under Hypersensitivity in Table 2) was more frequent during the induction/titration phase (0.15 episodes/patient-year) and decreased over time (0.06 episodes/patient-year in the maintenance phase). Three patients discontinued treatment. All episodes resolved. Angioedema can present as a symptom of anaphylaxis.
Serum Sickness
- In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness episodes were more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year during the maintenance phase). All serum sickness reactions resolved without sequelae (duration of serum sickness ranged from 1 to 8 days). Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence, and managed serum sickness with drug interruption, dosage reduction and/or concomitant medication. Two patients discontinued treatment.
- As with all therapeutic proteins, there is potential for immunogenicity. 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 the incidence of antibodies to pegvaliase in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- All patients treated with pegvaliase developed a sustained total anti-drug antibody (TAb) response with a majority of patients (91%; N = 235/258) developing that response by Week 4 of treatment. Mean TAb titers peaked 2 weeks after pegvaliase initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in all patients with a majority of patients (98%; N = 265/270) becoming positive for anti-PAL IgM by 2 months after treatment initiation. Anti‑PAL IgG antibodies were detected in almost all patients (N = 226/227) by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 1 year after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in the majority of patients (98%; N = 277/284 for IgM; and 278/284 for IgG) with mean titers for both peaking at 1 to 3 months after treatment initiation. Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in the majority of patients (88%; N = 249/284) over time. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 1 year after treatment initiation).
- Twenty-five of 26 patients who had anaphylaxis were tested for anti‑pegvaliase‑pqpz IgE antibodies, which recognize the PEGylated protein product. Of the 25 patients tested for anti‑pegvaliase‑pqpz IgE antibodies, 24 patients tested negative. The one patient who tested positive for anti‑pegvaliase‑pqpz IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti‑pegvaliase‑pqpz IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis). Sixty‑eight of 285 patients in clinical trials were tested for both anti‑PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti‑pegvaliase‑pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 68 patients, 5 (7%) tested positive at least once for anti‑PAL IgE antibodies but negative for anti‑pegvaliase‑pqpz IgE antibodies.
- The highest frequency of hypersensitivity reactions (consistent with a Type III immune complex-mediated hypersensitivity mechanism) occurred within the first 6 months of pegvaliase treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. IgG and IgM CIC concentrations were above the upper limit of normal in 63% (N = 164/259) and 41% of patients (N = 106/259), respectively, at 12 weeks of pegvaliase treatment. The incidence of CIC positivity decreased over time. 61% of patients (N = 110/180) had complement C3 concentrations less than lower limit of normal (LLN) at 6 months after treatment initiation and 38% of patients (N = 94/248) had complement C4 concentrations less than LLN at 3 months after treatment initiation. The incidence of low complement C3 and C4 concentrations decreased over time, but approximately 39% (N = 19/49) and 12% (N = 6/49) of patients had low C3 and C4 concentrations, respectively, at 36 months after treatment initiation.
- Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase‑pqpz concentrations and with higher blood phenylalanine concentrations. Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some but not all antibody analytes. Patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than patients with lower mean change in IgG CIC concentrations. Mean antibody titers for anti‑PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.
## Postmarketing Experience
There is limited information regarding Pegvaliase Postmarketing Experience in the drug label.
# Drug Interactions
- Effect of Pegvaliase on Other PEGylated Products
- In a single dose study of pegvaliase in adult patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced hypersensitivity reactions. One of the two patients experienced a hypersensitivity reaction on day 15 after a single pegvaliase dosage of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single pegvaliase dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti‑PEG IgG antibody titers at or around the time of the hypersensitivity reactions.
- In pegvaliase clinical trials, the majority of patients developed anti‑PEG IgM and IgG antibodies after treatment with pegvaliase. The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with pegvaliase and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Based on findings in studies of pregnant animals without PKU treated with pegvaliase-pqpz, pegvaliase may cause fetal harm when administered to a pregnant woman. Limited available data with pegvaliase-pqpz use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. There are risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy including increased risk for miscarriage, major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ; therefore, phenylalanine concentrations should be closely monitored in women with PKU during pregnancy. Advise pregnant women of the potential risks to the fetus.
- A reproduction study in pregnant rabbits treated with pegvaliase‑pqpz demonstrated a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes. Embryo-fetal toxicity (increased resorptions and reduced fetal weight) was also observed. These effects occurred at 7.5 times the maximum recommended daily dose and were associated with strong signs of maternal toxicity, including marked reductions in weight gain and food consumption, and death. A reproduction study in pregnant rats treated with pegvaliase-pqpz demonstrated an increase in skeletal variations, with no malformations observed. The effects in rats occurred at 4.2 times the maximum recommended daily dose. In a pre-/post-natal development study in rats, pegvaliase‑pqpz produced reduced survival of offspring during lactation, decreases in pup weight and litter size, and delayed sexual maturation of offspring when administered daily at 19.4 times the maximum recommended daily dose. The effects on rat embryo‑fetal and post-natal development were associated with maternal toxicity.
- All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. 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. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU.
- There is a pregnancy surveillance program for pegvaliase. If pegvaliase is administered during pregnancy, or if a patient becomes pregnant while receiving pegvaliase or within one month following the last dose of pegvaliase, healthcare providers should report pegvaliase exposure by calling 1-866-906-6100.
Disease-Associated Maternal and/or Embryo-Fetal Risk
- Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception.
Dose Adjustments During Pregnancy and the Postpartum Period
- Phenylalanine concentrations below 30 micromol/L in pregnant women with PKU treated with pegvaliase may be associated with adverse fetal outcomes. Monitor blood phenylalanine concentrations during pregnancy and adjust the dosage of pegvaliase or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L.
Human Data
- Uncontrolled Maternal PKU: Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled phenylalanine concentrations above 600 micromol/L are associated with an increased risk for miscarriage, major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ.
- Limited data from case reports of pegvaliase use in pregnant women are insufficient to determine a drug‑associated risk of adverse developmental outcomes.
Animal Data
- All developmental toxicity studies were conducted in animals (rats and rabbits) without PKU, in which treatment with pegvaliase-pqpz produced a dose-dependent reduction in maternal blood phenylalanine concentrations. At doses that produced maternal toxicity and/or effects on embryo-fetal development, the maternal plasma phenylalanine concentrations were markedly reduced compared to the control group. The contribution of maternal phenylalanine depletion to the incidence of embryo‑fetal developmental effects was not evaluated.
&Subcutaneous administration of 5 mg/kg/day pegvaliase-pqpz (7.5 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits during the period of organogenesis produced embryo-lethality (increased resorptions), marked reduction in fetal weight, and fetal malformations. The malformations included multiple external abnormalities of the head, body and limbs, multiple soft tissue malformations (reduced size or absence of kidneys, diaphragmatic hernia, corneal opacity, discoloration or reduced size of eyes, and reduced size of lungs) and multiple skeletal malformations of the craniofacial bones, vertebrae, sternebrae, ribs, pelvis, limbs, and digits. An increase in variations and delayed ossification was also observed in all skeletal regions. The adverse developmental effects were associated with maternal toxicity, as indicated by marked impairment of weight gain and food consumption. Deaths associated with weight loss and abortion occurred in 8% of the pregnant rabbits treated with 5 mg/kg/day pegvaliase-pqpz.
- Subcutaneous administration of 2 mg/kg/day pegvaliase‑pqpz (3 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits had no adverse effects on embryo-fetal development. Systemic exposure to pegvaliase‑pqpz was detected in fetuses from rabbits treated with 2 or 5 mg/kg/day.
- Pegvaliase-pqpz increased fetal alterations when administered daily in pregnant rats at doses of 8 mg/kg subcutaneously and higher (4.2 times the human steady-state area under the curve [AUC] at the maximum recommended daily dose) during a 28‑day premating period, mating, and through the period of organogenesis. The fetal alterations were limited to skeletal variations such as cervical ribs, bifid centra of lumbar and thoracic vertebrae, and incomplete ossification of squamosal bones, frontal bones, lumbar vertebra arch, and ribs. Daily administration of 20 mg/kg subcutaneously (19.4 times the human steady-state AUC at the recommended maximum daily dose) to pregnant rats produced reductions in litter sizes and fetal weights, which was associated with maternal toxicity (decreased body weight, ovarian weight, and food consumption). The decrease in litter sizes at 20 mg/kg subcutaneously was secondary to reductions in corpora lutea and implantations. Systemic exposure to pegvaliase-pqpz was detected in fetuses from rats treated with 20 mg/kg of pegvaliase-pqpz (19.4 times the human steady-state AUC at the recommended maximum daily dose). Subcutaneous administration of 2 mg/kg/day pegvaliase-pqpz (less than the human steady state AUC at the maximum recommended daily dose) in pregnant rats had no adverse effects on embryo‑fetal development.
- Pegvaliase-pqpz decreased pup weight, litter size, and survival of offspring during lactation, and delayed sexual maturation of offspring when administered daily in rats at 20 mg/kg subcutaneously (19.4 times the human steady‑state AUC at the recommended maximum daily dose), with dosing starting before mating and continuing through lactation. The effects in offspring were associated with maternal toxicity. No effects in offspring were observed at 8 mg/kg/day subcutaneously (4.2 times the human steady-state AUC at the recommended maximum daily dose). This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of pegvaliase‑pqpz were noted in tests of learning and memory.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegvaliase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pegvaliase during labor and delivery.
### Nursing Mothers
- There are no data on the presence of pegvaliase-pqpz in human milk, the effects on the breastfed infant, or the effects on milk production. A pre-/post-natal study in rats showed that pegvaliase-pqpz is present in rat milk and that administration of pegvaliase-pqpz during lactation decreased pup weight and survival. However, systemic absorption of pegvaliase-pqpz was not detected in the rat pups. Pegvaliase may cause low phenylalanine concentrations in human milk. The developmental and health benefits of breastfeeding should be considered along with the clinical need for pegvaliase treatment and any potential adverse effect on the breastfed infant from pegvaliase or from the underlying condition.
- Monitor blood phenylalanine concentrations in breastfeeding women treated with pegvaliase.
### Pediatric Use
- The safety and effectiveness of pegvaliase in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of pegvaliase did not include patients aged 65 years and older.
### Gender
There is no FDA guidance on the use of Pegvaliase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pegvaliase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pegvaliase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pegvaliase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pegvaliase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pegvaliase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Each prefilled syringe of pegvaliase is intended for use as a single subcutaneous injection.
- Inspect pegvaliase visually for particulate matter and discoloration prior to administration. Pegvaliase is a clear to slightly opalescent, colorless to pale yellow solution. *Discard if discolored, cloudy, or if particulate matter is present.
- Prior to first dose of pegvaliase, prescribe auto-injectable epinephrine, and instruct the patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use.
- Perform initial administration(s) and/or readministration after an anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self‑administration.
- Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during pegvaliase treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after each pegvaliase administration, should be able to administer auto-injectable epinephrine, and to call for emergency medical support upon its use.
- The recommended injection sites for pegvaliase are: the front middle of thighs and the abdomen at least 2 inches (five centimeters) away from the navel. If a caregiver is giving the injection, the top of buttocks and the back of the upper arms are also appropriate injection sites.
- Do not inject pegvaliase into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed. Check the injection site for redness, swelling, or tenderness.
- Rotate sites for subcutaneous injections of pegvaliase. If more than one injection is needed for a single dose of pegvaliase, the injection sites should be at least 2 inches away from each other. The second injection site can be on the same part of the body or a different part of the body.
### Monitoring
- Reduction in blood phenylalanine concentrations is indicative of efficacy.
- Improvement in inattention and mood may indicate efficacy.
- Blood phenylalanine concentration: Prior to initiation, every 4 weeks until a maintenance dose is reached, and then periodically throughout treatment.
- Signs and symptoms of anaphylaxis: Monitor for at least 60 minutes after initial dose or upon reinitiation of therapy after a previous episode of anaphylaxis.
- Dietary protein and phenylalanine intake: Throughout therapy.
- After initiating treatment with pegvaliase, obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established. After a maintenance dosage is established, periodic blood phenylalanine monitoring is recommended to assess blood phenylalanine control.
- Monitor patients’ dietary protein and phenylalanine intake throughout treatment with pegvaliase and counsel them on how to adjust their dietary intake, as needed, based on blood phenylalanine concentrations.
# IV Compatibility
There is limited information regarding the compatibility of Pegvaliase and IV administrations.
# Overdosage
There is limited information regarding Pegvaliase overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans‑cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.
## Structure
(Description with picture)
## Pharmacodynamics
- Pegvaliase treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline. The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase‑pqpz plasma concentrations.
## Pharmacokinetics
- The pharmacokinetics of pegvaliase‑pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase‑pqpz. In the first eight weeks of induction and titration treatment, plasma pegvaliase‑pqpz concentrations were low to not measurable. At steady state during maintenance treatment with pegvaliase 20 mg and 40 mg subcutaneously once daily, the mean ± SD (range) plasma trough pegvaliase‑pqpz concentrations were: 11.2 ± 9.0 (0.21 to 29.6) mg/L and 10.4 ± 12.7 (0.18 to 43.1) mg/L, respectively. The following pharmacokinetic parameters were observed in adult patients with PKU treated with pegvaliase at maintenance dosages of 20 mg once daily and 40 mg once daily.
- The median Tmax was approximately 8 hours. The mean ± SD (range) peak concentration (Cmax) at steady state was: 14.0 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively.
- The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively.
- The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 L/h (0.034 to 8.88), respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively.
- The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.
- The route of elimination of pegvaliase‑pqpz has not been studied in humans.
## Nonclinical Toxicology
- Carcinogenicity and genotoxicity studies have not been performed with pegvaliase‑pqpz. Based on its mechanism of action, pegvaliase‑pqpz is not expected to be tumorigenic.
- Pegvaliase-pqpz produced impaired fertility in female rats at 20 mg/kg/day subcutaneously (19.4 times the human steady‑state AUC at the maximum recommended daily dose), as indicated by decreases in corpora lutea, implantations, and litter size. These effects were associated with toxicity (decreased body weight, ovarian weight, and food consumption). No effects on mating or fertility were observed in female rats with 8 mg/kg/day subcutaneously (4.2 times the human steady‑state AUC at the maximum recommended daily dose) or in male rats with 20 mg/kg/day subcutaneously.
- In rats without PKU treated with pegvaliase-pqpz, dose-dependent vacuolation in multiple organs and tissues was observed in the 4‑ and 26‑week repeat dose toxicity studies at doses of 8 mg/kg subcutaneously or greater administered twice weekly (less than the human steady state AUC at the maximum recommended daily dose). Vacuolation occurred in renal tubule cells and in histiocytic cells of the liver, spleen, testes, adrenal cortex, mesenteric lymph node, and mandibular lymph node. Vacuolation in histiocytes of the affected organs and tissues persisted after cessation of treatment. The vacuolation observed in these studies was not associated with organ‑related toxicities as determined by clinical chemistry/urinalysis and histopathological examination. The clinical significance of these findings and functional consequences are unknown.
- In the 39‑week repeat dose toxicity study in monkeys, pegvaliase-pqpz 3 mg/kg subcutaneously twice weekly (3 times the human steady state AUC at the maximum recommended daily dose) produced systemic arteritis involving small arteries and arterioles in a wide range of organs and tissues (kidney, urinary bladder, pancreas, gallbladder, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, lung, heart, sciatic nerve, lacrimal gland, mandibular lymph node, epididymis, seminal vesicle, ovary, uterus, cervix, and vagina) and in subcutaneous injection sites. Arteritis was likely due to the immune-mediated response (e.g., immune complex deposition in blood vessels) associated with chronic administration of a foreign protein to the animals. The incidence and severity of systemic arteritis was dose-dependent. The vascular inflammation observed in this study was not associated with organ related toxicities as determined by clinical pathology parameters (hematology, clinical chemistry, and urinalysis) and histopathological examination.
- Studies of longer duration in rats and monkeys treated with pegvaliase‑pqpz have not been conducted.
# Clinical Studies
- Study 165‑301 (referred to as Study 301, NCT01819727) was an open-label randomized, multi-center study of adults with PKU to assess safety and tolerability of self-administered pegvaliase in an induction/titration/maintenance regimen with a target maintenance dose of 20 mg subcutaneously once daily or 40 mg subcutaneously once daily. At pegvaliase treatment initiation, 253 patients demonstrated inadequate blood phenylalanine control (blood phenylalanine concentration greater than 600 micromol/L) on existing management, and 8 patients had blood phenylalanine concentrations less than or equal to 600 micromol/L. Existing management options included prior or current restriction of dietary phenylalanine and protein intake, and/or prior treatment with sapropterin dihydrochloride. Patients previously treated with sapropterin dihydrochloride were required to discontinue use at least 14 days prior to the first dose.
- The 261 enrolled patients were aged 16 to 55 years (mean: 29 years) and had a baseline mean (range) blood phenylalanine of 1,233 (285, 2330) micromol/L. One hundred forty nine out of 261 (57%) patients were taking medical food at baseline and 41 out of 261 patients (16%) were on a protein-restricted diet at baseline (defined as receiving greater than 75% of total protein intake from medical food). Patients were randomized (1:1) to one of two target maintenance dosage arms: 20 mg once daily or 40 mg once daily. Patients were titrated to reach their randomized target dosage of 20 mg once daily or 40 mg once daily. The duration of titration varied among patients and was based on patient tolerability. Of the 261 enrolled patients, 195 (75%) patients reached their randomized maintenance dosage (103 in the 20 mg once daily arm, 92 in the 40 mg once daily arm). Among the patients who reached their randomized maintenance dosage, patients in the 20 mg once daily randomized arm reached their maintenance dosage at a median time of 10 weeks (range: 9 to 29 weeks) and patients in the 40 mg once daily arm reached their maintenance dosage at a median time of 11 weeks (range: 10 to 33 weeks).
- Of the 261 patients who enrolled in Study 301, 54 (21%) patients discontinued treatment during Study 301, 4 patients completed Study 301 and did not continue to Study 165‑302 (referred to as Study 302, NCT01889862), 152 patients continued to the eligibility period of Study 302, and 51 patients continued directly from Study 301 into the long‑term treatment period of Study 302.
- A total of 164 adult patients with PKU who were previously-treated with pegvaliase (152 patients from Study 301 and 12 patients from other pegvaliase trials) enrolled in Study 302 and continued treatment with pegvaliase in Study 302 for up to 13 weeks to assess eligibility for randomized withdrawal period.
Randomized Withdrawal Period
- Following this period of up to 13 weeks of additional pegvaliase treatment in Study 302, eligibility for entry into the efficacy assessment period (randomized withdrawal period) was determined by whether a patient achieved at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline (when in previous studies). Eighty‑six out of 164 patients (52%) met this response target and continued into the randomized withdrawal period. In the double-blind, placebo-controlled, randomized withdrawal period, patients were randomized in a 2:1 ratio to either continue their maintenance pegvaliase dosage or to receive matching placebo for a total of 8 weeks. The treatment difference in least squares (LS) mean change in blood phenylalanine concentration from the Study 302 randomized withdrawal baseline to randomized withdrawal Week 8 for each randomized study arm is shown in Table 5. Mean blood phenylalanine concentrations at pre-treatment baseline (Study 301 or other pegvaliase trials) are also shown in Table 5. At Study 302 randomized withdrawal Week 8, pegvaliase‑treated patients (20 mg once daily or 40 mg once daily) maintained their blood phenylalanine concentrations as compared to their randomized withdrawal baseline, whereas patients randomized to matching placebo (20 mg once daily or 40 mg once daily) returned to their pretreatment baseline blood phenylalanine concentrations (Figure 1).
- Of 118 patients from Study 301 with a pre‑treatment baseline blood phenylalanine concentration greater than 600 micromol/L who were randomized to and received at least one dose of 20 mg once daily pegvaliase, 108 patients, 98 patients, and 51 patients were treated for at least 24 weeks, 48 weeks, and 96 weeks, respectively.
- Of the 118 patients, 53 patients reached their first response (at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline or a blood phenylalanine concentration less than or equal to 600 micromol/L) by 4 weeks of treatment with 20 mg once daily and 28 patients reached their first response between Weeks 4 and 24 with 20 mg once daily. Of the 118 patients, 25 patients escalated their dosage from 20 mg once daily to 40 mg once daily before reaching a first response; of those 25 patients, 8 patients reached their first response by 4 weeks of treatment with 40 mg once daily and 6 patients reached their first response between Weeks 4 and 16 with 40 mg once daily.
# How Supplied
- Pegvaliase (pegvaliase-pqpz) injection is supplied as a preservative-free, sterile, clear to slightly opalescent, colorless to pale yellow solution. All dosage strengths of pegvaliase are provided in a 1 mL glass syringe with a 26 gauge, 0.5 inch needle.
- Each carton contains 1 or 10 trays with single-dose prefilled syringe(s), Prescribing Information, Medication Guide, and Instructions for Use. The following packaging configurations are available.
## Storage
- Store in refrigerator at 36°F to 46°F (2°C to 8°C) in its original carton to protect from light.
- Do not freeze or shake.
- For patients: If needed, store pegvaliase in the original carton at room temperature between 68°F to 77°F (20°C to 25°C) for up to 30 days. Record the date removed from refrigeration on the carton. Once stored at room temperature, do not return the product to the refrigerator.
- The shelf-life expires after storage at room temperature for 30 days, or after the expiration date on the product carton, whichever is earlier.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Advise patients that pegvaliase may cause hypersensitivity reactions, including anaphylaxis that can occur at any time. Instruct patients to recognize the signs and symptoms of anaphylaxis.
- Instruct patients to carry auto-injectable epinephrine with them at all times during pegvaliase treatment. Instruct the patient and observer (if applicable) on the appropriate use of auto‑injectable epinephrine for anaphylaxis.
- Instruct patients who experience anaphylaxis to seek immediate medical care, discontinue therapy, and resume treatment only at the instruction of a healthcare provider.
- Pegvaliase is available only through a restricted program called the pegvaliase REMS. Inform the patient of the following notable requirements:
- Patients must be enrolled in the pegvaliase REMS.
- Patients must be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with pegvaliase.
- Patients must fill a prescription for auto-injectable epinephrine and carry it with them at all times.
- Patients will be given a pegvaliase Patient Wallet Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the :*patient and observer (if applicable) to immediately seek medical care. Advise the patient to show the pegvaliase Wallet Card to other treating healthcare providers.
- pegvaliase is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.
- Advise patients to monitor their dietary protein and phenylalanine intake throughout treatment with pegvaliase, and adjust intake as directed by their healthcare provider based on blood phenylalanine concentrations.
- Provide appropriate instruction for methods of self-injection, including careful review of the pegvaliase Medication Guide and Instructions for Use. Instruct patients in the use of aseptic technique when administering pegvaliase.
- Inform patients that a healthcare provider will show them or their caregiver how to prepare to inject pegvaliase before self-administering.
- Advise patients not to inject into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed.
- Advise patients to rotate areas of injection with each dose. Advise patients to check the injection site for redness, swelling, and tenderness, and to contact their healthcare provider if they have a skin reaction and it does not clear up, or worsens.
- Advise patients to follow sharps disposal recommendations patients on safe disposal procedures.
- Advise patients that the shelf‑life expires after storage at room temperature for 30 days or after the expiration date on the product carton, whichever is earlier.
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.
- Advise women who are exposed to pegvaliase during pregnancy or who become pregnant within one month following the last dose of pegvaliase that there is a pregnancy surveillance program that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to BioMarin (1‑866‑906‑6100).
# Precautions with Alcohol
Alcohol-Pegvaliase interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Palynziq
# Look-Alike Drug Names
There is limited information regarding Pegvaliase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Pegvaliase | |
30b5d2e074869f815f60f1d2bf9add76a0684653 | wikidoc | Peking Man | Peking Man
Peking Man (now sometimes called Beijing Man), also called Sinanthropus pekinensis (currently Homo erectus pekinensis), is an example of Homo erectus. The remains were first discovered in 1923-27 during excavations at Zhoukoudian (Choukoutien) near Beijing (Peking), China. The finds have been dated from roughly 250,000-400,000 years ago in the Pleistocene.
# Original fossils
First studies began at Zhoukoudian in 1923 with an investigation of a number of caves in the limestone there. Otto Zdansky was working for geologist Johan Gunnar Andersson who described this event in Children of the Yellow Earth. According to Andersson, a local man led him, American paleontologist Walter Granger and Zdansky to what is today known as the Dragon Bone Hill, a place full of fossilized bones. The party immediately began an excavation. After Andersson and Granger left the site three days later, Zdansky found fossil teeth that resembled human molars. He did not, however, disclose his finds to Andersson and Granger. In 1926, he took them to the Peking Union Medical College, in Peking, where Canadian anatomist Davidson Black analyzed them. He later published his finds in the journal Nature.
The first specimens of Homo erectus had been found in Java in 1891 by Eugene Dubois, with the Java Man initially being named Pithecanthropus erectus but later transferred to the genus Homo.
The Rockefeller Foundation agreed to fund the work at Zhoukoudian. By 1929, Chinese archaeologists Yang Zhongjian and Pei Wenzhong, and later Jia Lanpo, had taken over the excavation. Over the next seven years, they uncovered fossils of more than 40 specimens including 6 nearly complete skullcaps. Pierre Teilhard de Chardin and Franz Weidenreich were also involved.
Excavation ended in July 1937 when the Japanese occupied Beijing. Fossils of the Peking Man were placed in the safe at the Cenozoic Laboratory of the Peking Union Medical College. Eventually, in November 1941, secretary Hu Chengzi packed up the fossils so they could be sent to USA for safekeeping until the end of the war. They vanished en route to the port city of Qinghuangdao. They were probably in possession of a group of US marines who the Japanese captured when the war began between Japan and USA.
Various parties have tried to locate the fossils but, so far, without result. In 1972, a US financier Christopher Janus promised a $5,000 (U.S.) reward for the missing skulls; one woman contacted him, asking for $500,000 (U.S.) but she later vanished. In July 2005, the Chinese government founded a committee to find the bones to coincide with the 60th anniversary of the end of World War II.
There are also various theories of what might have happened, including a theory that the bones had sunk with a Japanese ship Awa Maru in 1945.
# Subsequent Research
Excavations at Zhoukoudian resumed after the war, and parts of another skull were found in 1966. To date a number of other partial fossil remains have been found. The Peking Man Site at Zhoukoudian was listed by UNESCO as a World Heritage Site in 1987.
# Paleontological conclusions
Because all the pre-war findings at Zhoukoudian were lost during transit to the USA, subsequent researchers have had to rely on casts and existing writings from the original discoverers.
Contiguous findings of animal remains and evidence of fire and tool usage, as well as the manufacturing of tools, were used to support H. erectus being the first "faber" or tool-worker. The analysis of the remains of "Peking Man" led to the claim that the Zhoukoudian and Java fossils were examples of the same broad stage of human evolution. This is also the official view of the Chinese Communist Party.
This interpretation was challenged in 1985 by Lewis Binford, who claimed that the Peking Man was a scavenger, not a hunter. The 1998 team of Steve Weiner of the Weizmann Institute of Science concluded that they had not found evidence that the Peking Man had used fire.
# Relation to modern Chinese people
Some Chinese paleoanthropologists have asserted in the past that the modern Chinese are descendants of the Peking Man. However, modern genetic research does not support this hypothesis. A recent study undertaken by Chinese geneticist Jin Li showed that there was no inter-breeding between modern human immigrants to East Asia and Homo erectus, contradicting the Peking Man-hypothesis and affirming that the Chinese descended from Africans in accordance with the Recent single-origin hypothesis.
However, some paleontologists see continuity in skeletal remains.
# Popular culture
- The disappearance of Peking Man's remains, and speculation of where they ended up, is the plot of January 7, 1975 episode Season 7, Episode 160 of Hawaii Five-O, "Bones of Contention".
- Canadian science-fiction writer Robert J. Sawyer won an Aurora Award for his 1996 short story "Peking Man," which connects the lost bones to the Dracula legend; the story first appeared in the anthology Dark Destiny III: Children of Dracula edited by Edward E. Kramer, and is reprinted in Sawyer's collection Iterations.
- The discovery of Peking Man is referred to in the book The Bonesetter's Daughter by Amy Tan.
- Peking Man is part of the central plot in the mystery Sleeping Bones by Katherine V. Forrest.
- A Peking Man fossil is among those which can be found in the Nintendo DS video game Animal Crossing: Wild World.
- Peking Man is part of the central plot of Philip K. Dick's The Crack In Space.
- Peking Man's bones is the subject of an episode of the Japanese Anime "Lupin the 3rd" titled: Jumping the Bones
- Peking Man is part of the plot of Clive Cussler's Flood Tide
- Peking Man is the main part of the central plot of Carolyn G. Hart's mystery novel Skulduggery, set in San Francisco's Chinatown in the early 1980s. ISBN 0-7862-2672-2
- The mystery of the missing Peking Man fossils is central to the 1999 novel Lost in Translation, by Nicole Mones.
- Sega and Vivarium's "Seaman 2 Peking Genjin no Ikusei Kit" (Peking Man Growth Kit) for the PlayStation 2 will let players interact with a 20 centimeter tall Peking Man clone. | Peking Man
Peking Man (now sometimes called Beijing Man), also called Sinanthropus pekinensis (currently Homo erectus pekinensis), is an example of Homo erectus. The remains were first discovered in 1923-27 during excavations at Zhoukoudian (Choukoutien) near Beijing (Peking), China. The finds have been dated from roughly 250,000-400,000 years ago in the Pleistocene.
# Original fossils
First studies began at Zhoukoudian in 1923 with an investigation of a number of caves in the limestone there. Otto Zdansky was working for geologist Johan Gunnar Andersson who described this event in Children of the Yellow Earth. According to Andersson, a local man led him, American paleontologist Walter Granger and Zdansky to what is today known as the Dragon Bone Hill, a place full of fossilized bones. The party immediately began an excavation. After Andersson and Granger left the site three days later, Zdansky found fossil teeth that resembled human molars. He did not, however, disclose his finds to Andersson and Granger. In 1926, he took them to the Peking Union Medical College, in Peking, where Canadian anatomist Davidson Black analyzed them. He later published his finds in the journal Nature.
The first specimens of Homo erectus had been found in Java in 1891 by Eugene Dubois, with the Java Man initially being named Pithecanthropus erectus but later transferred to the genus Homo.
The Rockefeller Foundation agreed to fund the work at Zhoukoudian. By 1929, Chinese archaeologists Yang Zhongjian and Pei Wenzhong, and later Jia Lanpo, had taken over the excavation. Over the next seven years, they uncovered fossils of more than 40 specimens including 6 nearly complete skullcaps. Pierre Teilhard de Chardin and Franz Weidenreich were also involved.
Excavation ended in July 1937 when the Japanese occupied Beijing. Fossils of the Peking Man were placed in the safe at the Cenozoic Laboratory of the Peking Union Medical College. Eventually, in November 1941, secretary Hu Chengzi packed up the fossils so they could be sent to USA for safekeeping until the end of the war. They vanished en route to the port city of Qinghuangdao. They were probably in possession of a group of US marines who the Japanese captured when the war began between Japan and USA.
Various parties have tried to locate the fossils but, so far, without result. In 1972, a US financier Christopher Janus promised a $5,000 (U.S.) reward for the missing skulls; one woman contacted him, asking for $500,000 (U.S.) but she later vanished. In July 2005, the Chinese government founded a committee to find the bones to coincide with the 60th anniversary of the end of World War II.
There are also various theories of what might have happened, including a theory that the bones had sunk with a Japanese ship Awa Maru in 1945.[citation needed]
# Subsequent Research
Excavations at Zhoukoudian resumed after the war, and parts of another skull were found in 1966. To date a number of other partial fossil remains have been found. The Peking Man Site at Zhoukoudian was listed by UNESCO as a World Heritage Site in 1987.[1]
# Paleontological conclusions
Because all the pre-war findings at Zhoukoudian were lost during transit to the USA, subsequent researchers have had to rely on casts and existing writings from the original discoverers.
Contiguous findings of animal remains and evidence of fire and tool usage, as well as the manufacturing of tools, were used to support H. erectus being the first "faber" or tool-worker. The analysis of the remains of "Peking Man" led to the claim that the Zhoukoudian and Java fossils were examples of the same broad stage of human evolution. This is also the official view of the Chinese Communist Party.
This interpretation was challenged in 1985 by Lewis Binford, who claimed that the Peking Man was a scavenger, not a hunter. The 1998 team of Steve Weiner of the Weizmann Institute of Science concluded that they had not found evidence that the Peking Man had used fire.
# Relation to modern Chinese people
Some Chinese paleoanthropologists have asserted in the past that the modern Chinese are descendants of the Peking Man. However, modern genetic research does not support this hypothesis. A recent study undertaken by Chinese geneticist Jin Li showed that there was no inter-breeding between modern human immigrants to East Asia and Homo erectus, contradicting the Peking Man-hypothesis and affirming that the Chinese descended from Africans in accordance with the Recent single-origin hypothesis. [2] [3][4]
However, some paleontologists see continuity in skeletal remains.
[5]
# Popular culture
- The disappearance of Peking Man's remains, and speculation of where they ended up, is the plot of January 7, 1975 episode Season 7, Episode 160 of Hawaii Five-O, "Bones of Contention". [1]
- Canadian science-fiction writer Robert J. Sawyer won an Aurora Award for his 1996 short story "Peking Man," which connects the lost bones to the Dracula legend; the story first appeared in the anthology Dark Destiny III: Children of Dracula edited by Edward E. Kramer, and is reprinted in Sawyer's collection Iterations.
- The discovery of Peking Man is referred to in the book The Bonesetter's Daughter by Amy Tan.
- Peking Man is part of the central plot in the mystery Sleeping Bones by Katherine V. Forrest.
- A Peking Man fossil is among those which can be found in the Nintendo DS video game Animal Crossing: Wild World.
- Peking Man is part of the central plot of Philip K. Dick's The Crack In Space.
- Peking Man's bones is the subject of an episode of the Japanese Anime "Lupin the 3rd" titled: Jumping the Bones
- Peking Man is part of the plot of Clive Cussler's Flood Tide
- Peking Man is the main part of the central plot of Carolyn G. Hart's mystery novel Skulduggery, set in San Francisco's Chinatown in the early 1980s. ISBN 0-7862-2672-2
- The mystery of the missing Peking Man fossils is central to the 1999 novel Lost in Translation, by Nicole Mones.
- Sega and Vivarium's "Seaman 2 Peking Genjin no Ikusei Kit" (Peking Man Growth Kit) for the PlayStation 2 will let players interact with a 20 centimeter tall Peking Man clone. | https://www.wikidoc.org/index.php/Peking_Man |
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