Each tablet contains:
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 a , ß, g , or d ) are not inhibited by nevirapine.
Absorption and Bioavailability:
Nevirapine is readily absorbed (>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 mc g/mL (7.5 mc M) 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 mc g/mL (17 ± 7 mc M), (n = 242) were attained at 400 mg/day. Nevirapine tablets and sBPension 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 study in HIV-1-infected patients (n=6), nevirapine steady-state systemic exposure (AUCt ) was not significantly altered by ddI, which is formulated with an alkaline buffering agent. NEVIRAPINEmay be administered with or without food, antacid or ddI.
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 found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mc g/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 studies 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 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a mass balance/excretion study 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 (<5%) of the radioactivity in urine (representing <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 has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The pharmacokinetics of autoinduction are characterized by an approximately 1.5 to 2 fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200 - 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 25-30 hours following multiple dosing with 200 - 400 mg/day.
Nevirapine is indicated for the treatment of HIV infection when antiretroviral therapy is warranted.
DOSAGE AND DIRECTION OF USE:
Nevirapine should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (See Warnings and Precautions). Patients experiencing rash during the 14-day lead-in period of 200 mg/day (or 4 mg/kg/day in paediatric patients) should not have their nevirapine dose increased until the rash has resolved. Nevirapine administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities (excluding GGT), until the liver function test elevations have returned to baseline. Nevirapine may then be restarted at 200 mg per day (or 4 mg/kg/day in paediatric patients). Increasing the daily dose to 200 mg twice daily (4 or 7 mg/kg twice daily, according to age, in paediatric patients) should be done with caution, after extended observation. Nevirapine should be permanently discontinued if moderate or severe liver function test abnormalities recur. Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily (or 4 mg/kg/day in paediatrics) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (4 or 7 mg/kg twice daily, according to age, in paediatric patients). No data are available to recommend a dosage of nevirapine in patients with hepatic dysfunction, renal insufficiency, or undergoing dialysis.
Patients who exhibit potentially life-threatening allergic reactions to any of the components of the formulation.
WARNINGS AND PRECAUTIONS:
Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, blisters, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise and/or significant hepatic abnormalities) must discontinue nevirapine as soon as possible.
Nevirapine therapy must be initiated with a 14-day lead-in period of 200 mg/day (4 mg/kg/day in paediatric patients), which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation should not occur until the rash has resolved.
Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis (transaminase elevations, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), has occurred in patients treated with nevirapine. Some of these cases began in the first few weeks of therapy, and some were accompanied by rash. Nevirapine administration should be interrupted in patients experiencing moderate or severe ALT or AST abnormalities until these return to baseline values. Nevirapine should be permanently discontinued if liver function abnormalities recur upon readministration. Monitoring of ALT and AST is strongly recommended, especially during the first six months of nevirapine treatment.
The duration of clinical benefit from antiretroviral therapy may be limited. Patients receiving nevirapine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
IMPAIRED RENAL AND HEPATIC FUNCTION:
Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. However, the pharmacokinetics of nevirapine have not been evaluated in patients with either hepatic or renal dysfunction. Therefore, nevirapine should be used with caution in these patient populations.
The induction of CYP3A by nevirapine may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolized by CYP3A. Thus, if a patient has been stabilized on a dosage regimen for a drug metabolized by CYP3A, and begins treatment with nevirapine, dose adjustments may be necessary. Rifampin/Rifabutin: There are insufficient data to assess whether dose adjustments are necessary when nevirapine and rifampin or rifabutin are coadministered. Therefore, these drugs should only be used in combination if clearly indicated and with careful monitoring.
Ketoconazole: Nevirapine and ketoconazole should not be administered concomitantly. Coadministration of nevirapine and ketoconazole results in a significant reduction in ketoconazole plasma concentrations. Oral Contraceptives: There are no clinical data on the effects of nevirapine on the pharmacokinetics of oral contraceptives. Nevirapine may decrease plasma concentrations of oral contraceptives (also other hormonal contraceptives); therefore, these drugs should not be administered concomitantly with nevirapine.
Methadone: Based on the known metabolism of methadone, 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. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Category C. There are no adequate and well-controlled studies in pregnant women. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Data indicate that nevirapine is found in breast milk. It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Mothers should discontinue nursing if they are receiving nevirapine.
The most clinically important adverse events associated with nevirapine therapy are rash and increases in liver function
tests. Cases of hypersensitivity reactions have been observed.
The major clinical toxicity of nevirapine is rash, with nevirapine-attributable rash occurring in 16% of patients on combination regimens in Phase II/III controlled studies. Thirty-five percent of patients treated with nevirapine experienced rash compared with 19% of patients treated in control groups of either zidovudine + didanosine or zidovudine alone. Severe or life-threatening rash occurred in 6.6% of nevirapine-treated patients compared with 1.3% of patients treated in the control groups.
Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions; with or without pruritus, located on the trunk, face and extremities. The majority of severe rashes occurred within the first 28 days of treatment. 25% of the patients with severe rashes required hospitalization, and one patient required surgical intervention. Overall, 7% of patients discontinued nevirapine due to rash. With respect to laboratory abnormalities, asymptomatic elevations in GGT levels are more frequent in nevirapine recipients than in controls. Because clinical hepatitis has been reported in nevirapine-treated patients, monitoring of ALT (SGPT) and AST (SGOT) is strongly recommended, especially during the first six months of nevirapine treatment (See Warnings and Precautions). Decreased neutrophils (< 750/mm3), platelets (< 50,000/mm3) and Hb (< 8.0 g/dL), and increased total bilirubin (> 2.5 mg/dL) have also been reported. Grenulocytopenia has been more commonly observed in children. The safety profile of nevirapine in neonates has not
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 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, vomitting and weight decrease. All
events subsided following discontinuation of nevirapine.
The most commonly observed side effects during clinical trials were Headache, malaise and fatigue, nausea, vomiting ,diarrhea,anorexia,fever/chills,neuropathy,insomnia,dizziness,nasal signs and symptoms. Cough,muscloskeletal pain and neutropenia.
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A4 and 2B6. Nevirapine is known to be an inducer of these enzymes. Thus, if a patient has been stabilized on a dosage regimen for a drug metabolized by CYP3A, and begins treatment with nevirapine, dose adjustments may be necessary.
Clinical comments about possible dosage modifications are given below: Established Drug Interactions with nevirapine
Ketoconazole: Nevirapine and ketoconazole should not be administered concomitantly, because decreases in
ketoconazole plasma concentrations may reduce the efficacy of the drug.
Clarithromycin: Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz: Efavirenz concentrations are decreased. Appropriate doses for this combination are not established.
Ethinyl estradiol and Norethindrone: Concentrations of both drugs are decreased. Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Rifabutin: Concentrations of rifabutin and its metabolite were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin: Nevirapine and rifampin should not be administered concomitantly because potentially reduce the efficacy of the drug and also increase the hepatotoxicity risk. Physicians needing treat patients co-infected with tuberculosis should preferentially use alternative drugs (e.g., efavirenz, abacavir).If using a nevirapine-containing regimen, caution should be used in concomitant administration.
Fluconazole: Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapineassociated adverse events.
Indinavir: Concentrations of indinavir are decreased. Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Lopinavir/Ritonavir: A dose increase of lopinavir/ritonavir from 400/100 mg to 533/133 mg twice daily with food is recommended in combination with nevirapine.
Nelfinavir: The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Saquinavir: Apropriate doses for this combination are not established, but an increase in the dosage of saquinavir may
Methadone: Methadone levels may be decreased; increased dosages may be required to prevent symptoms of opiate
withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of
withdrawal and methadone dose should be adjusted accordingly.
Potential drug interactions are listed below:
Examples of drugs in which plasma concentrations may be decreased by Co-administration with nevirapine
Antiarrhythmics: e.g. Amiodarone, disopyramide, and lidocaine
Anticonvulsants: e.g. Carbamazepine, clonazepam, and ethosuximide
Antifungals: e.g. Itraconazole
Calcium channel blockers: Diltiazem, nifedBPine, verapamil
Cancer chemotherapy: Cyclophosphamide
Ergot alkaloids: Ergotamine
Immunosuppressants: Cyclosporin, tacrolimus, sirolimus
Motility agents: Cisapride
Opiate agonists: Fentanyl
Examples of drugs in which plasma concentrations may be increased by co-administration with nevirapine.
Anticoagulants e.g. warfarin. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Store in a cool & dry place, protected from light.
Keep out of reach of children.
1X60’s HDPE Bottles.