nevirapine

The 14-day lead-in period with immediate-release nevirapine (200 mg once daily) must be strictly followed; it has been demonstrated to reduce the frequency of rash. ( 2.5 , 5.2 ) • Must be swallowed whole and must not be chewed, crushed, or divided. ( 2.1 ) • Adult patients must initiate therapy with one 200 mg immediate-release nevirapine tablet once daily for the first 14 days, followed by one 400 mg tablet of nevirapine extended-release once daily. ( 2.2 ) • Adult patients already on a regimen of immediate-release nevirapine twice daily can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period of immediate-release nevirapine. ( 2.2 ) • Pediatric patients (ages 6 to less than 18 years with a BSA of 1.17 m 2 or greater) must initiate therapy with immediate-release nevirapine (as 150 mg/m 2 of nevirapine oral suspension or as nevirapine tablet) at a dose not to exceed 200 mg per day administered once daily for the first 14 days, followed by nevirapine extended-release tablets 400 mg once daily. ( 2.3 ) • Pediatric patients with a BSA of 1.17 m 2 or greater already on a regimen of twice daily nevirapine oral suspension or immediate-release nevirapine tablets can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period of nevirapine oral suspension or immediate-release nevirapine…

Adult patients: The most common adverse reaction is rash. During the lead-in period with immediate-release nevirapine, the incidence of Grade 2 or higher drug-related rash in adults is 3%. After the lead-in period the incidence of Grade 2 or higher drug-related rash in subjects taking nevirapine extended-release tablets is 3%. The incidence of Grade 2 or higher drug-related clinical hepatitis after the lead-in phase was 2%. ( 6.1 ) • Pediatric patients: The incidence of Grade 2 or higher drug-related rash was 1%. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Clinical Trial Experience in Adult Patients 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,…

Nevirapine extended-release tablets are contraindicated: • in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ] . • for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [see Warnings and Precautions (5.1) ] . • Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. ( 4 , 5.1 , 8.7 ) • Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved use. ( 4 , 5.1 )

There is no known antidote for nevirapine overdosage. Cases of immediate-release nevirapine overdose at doses ranging from 800 to 1,800 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 immediate-release nevirapine.

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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 co-administered with nevirapine. The results of drug interactions studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology , Table 4. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 3. The data in Tables 3 and 4 are based on the results of drug interaction studies 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 3. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 3, additional clinical monitoring may be warranted when co-administering 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 co-administered with nevirapine, anticoagulation levels should be monitored frequently. Table 3 Established and Potential Drug Interactions: Use with Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3) , Table 4 for Magnitude of Interaction. Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment HIV Antiviral Agents: Protease Inhibitors (PIs) Atazanavir/Ritonavir The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. Fosamprenavir ↓ Amprenavir ↑ Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir ↓ Amprenavir ↑ Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. Indinavir ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. Lopinavir/Ritonavir ↓ Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra ® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Nelfinavir ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C min The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. Saquinavir/Ritonavir The interaction between nevirapine and saquinavir/ritonavir has not been evaluated. The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established. Etravirine Rilpivirine Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial. Other Agents Analgesics: Methadone ↓ Methadone Methadone levels were 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. Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established. Antibiotics: Clarithromycin ↓ Clarithromycin ↑ 14-OH 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. Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations 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 Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. Anticonvulsants: Carbamazepine, clonazepam, ethosuximide Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants. Antifungals: Fluconazole ↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. Antithrombotics: Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. Calcium Channel Blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established. Cancer Chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established. Ergot Alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established. Opiate Agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established. Oral Contraceptives: Ethinyl Estradiol and Norethindrone ↓ Ethinyl Estradiol ↓ Norethindrone Despite lower ethinyl estradiol and norethindrone exposures when co-administered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When co-administered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablet therapy, the therapeutic effect of the hormonal therapy should be monitored. Co-administration of nevirapine extended-release tablets can alter the concentrations of other drugs, and other drugs may alter the concentration of nevirapine. The potential for drug interactions must be considered prior to and during therapy. ( 5.4 , 7 , 12.3 ) Drug Interactions [see Drug Interactions (7)] Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine extended-release tablets and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects. While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated K i for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A. Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19. Table 4 (see below) contains the results of drug interaction trials performed with immediate-release nevirapine and other drugs likely to be co-administered. The effects of nevirapine on the AUC, C max , and C min of co-administered drugs are summarized. Results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Immediate-Release Nevirapine (All interaction studies were conducted in HIV-1 positive subjects) § = Cmin below detectable level of the assay ↑ = Increase, ↓ = Decrease, ↔ = No Effect Co-administered Drug Dose of Co-administered Drug Dose Regimen of Immediate-release Nevirapine n % Change of Co-administered Drug Pharmacokinetic Parameters (90% CI) Antiretrovirals AUC C max C min Atazanavir/Ritonavir For information regarding clinical recommendations, [see Drug Interactions (7) ] . , Parallel group design; n = 23 for atazanavir/ritonavir + nevirapine, n = 22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. 300/100 mg QD day 4-13, then 400/100 mg QD, day 14-23 200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry. 23 Atazanavir 300/100 mg ↓ 42 (↓ 52 to ↓ 29) Atazanavir 300/100 mg ↓ 28 (↓ 40 to ↓ 14) Atazanavir 300/100 mg ↓ 72 (↓ 80 to ↓ 60) Atazanavir 400/100 mg ↓ 19 (↓ 35 to ↑ 2) Atazanavir 400/100 mg ↑ 2 (↓ 15 to ↑ 24) Atazanavir 400/100 mg ↓ 59 (↓ 73 to ↓ 40) Darunavir/Ritonavir Based on between-trial comparison. 400/100 mg BID 200 mg BID 8 ↑ 24 (↓ 3 to ↑57) ↑ 40 (↑ 14 to ↑ 73) ↑ 2 (↓ 21 to ↑ 32) Didanosine 100-150 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ↔ ↔ § Efavirenz 600 mg QD 200 mg QD x 14 days; 400 mg QD x 14 days 17 ↓ 28 (↓ 34 to ↓ 14) ↓ 12 (↓ 23 to ↑ 1) ↓ 32 (↓ 35 to ↓ 19) Fosamprenavir 1400 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 ↓ 33 (↓ 45 to ↓ 20) ↓ 25 (↓ 37 to ↓ 10) ↓ 35 (↓ 50 to ↓ 15) Fosamprenavir/Ritonavir 700/100 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 ↓ 11 (↓ 23 to ↑ 3) ↔ ↓ 19 (↓ 32 to ↓ 4) Indinavir 800 mg q8H 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↓ 31 (↓ 39 to ↓ 22) ↓ 15 (↓ 24 to ↓ 4) ↓ 44 (↓ 53 to ↓ 33) Lopinavir , Pediatric subjects ranging in age from 6 months to 12 years. 300/75 mg/m 2 (lopinavir/ritonavir) 7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week 12, 15 Parallel group design; n for nevirapine + lopinavir/ritonavir, n for lopinavir/ritonavir alone. ↓ 22 (↓ 44 to ↑ 9) ↓ 14 (↓ 36 to ↑ 16) ↓ 55 (↓ 75 to ↓ 19) Lopinavir 400/100 mg BID (lopinavir/ritonavir) 200 mg QD x 14 days; 200 mg BID > 1 year 22, 19 ↓ 27 (↓ 47 to ↓ 2) ↓ 19 (↓ 38 to ↑ 5) ↓ 51 (↓ 72 to ↓ 26) Maraviroc Based on historical controls. 300 mg SD 200 mg BID 8 ↑ 1 (↓ 35 to ↑ 55) ↑ 54 (↓ 6 to ↑ 151) ↔ Nelfinavir 750 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 23 ↔ ↔ ↓ 32 (↓ 50 to ↑ 5) Nelfinavir-M8 metabolite ↓ 62 (↓ 70 to ↓ 53) ↓ 59 (↓ 68 to ↓ 48) ↓ 66 (↓74 to ↓ 55) Ritonavir 600 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ↔ ↔ ↔ Stavudine 30-40 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 22 ↔ ↔ § Zalcitabine 0.125-0.25 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 6 ↔ ↔ § Zidovudine 100-200 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 11 ↓ 28 (↓ 40 to ↓ 4) ↓ 30 (↓ 51 to ↑ 14) § Other Medications AUC C max C min Clarithromycin 500 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 15 ↓ 31 (↓ 38 to ↓ 24) ↓ 23 (↓ 31 to ↓ 14) ↓ 56 (↓ 70 to ↓ 36) Metabolite 14-OH-clarithromycin ↑ 42 (↑ 16 to ↑ 73) ↑ 47 (↑ 21 to ↑ 80) ↔ Ethinyl Estradiol and Norethindrone 0.035 mg (as Ortho-Novum ® 1/35) 1 mg (as Ortho-Novum ® 1/35) 200 mg QD x 14 days; 200 mg BID x 14 days 10 ↓ 20 (↓ 33 to ↓ 3) ↔ § ↓ 19 (↓ 30 to ↓ 7) ↓ 16 (↓ 27 to ↓ 3) § Depomedroxy- Progesterone Acetate 150 mg every 3 months 200 mg QD x 14 days; 200 mg BID x 14 days 32 ↔ ↔ ↔ Fluconazole 200 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↔ ↔ ↔ Ketoconazole 400 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 21 ↓ 72 (↓ 80 to ↓ 60) ↓ 44 (↓ 58 to ↓ 27) § Methadone Individual Subject Dosing 200 mg QD x 14 days; 200 mg BID ≥ 7 days 9 In a controlled pharmacokinetic trial with 9 subjects receiving chronic methadone to whom steady-state nevirapine therapy was added, the clearance of methadone was increased by 3-fold, resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in 7 of the 9 subjects. Methadone did not have any effect on nevirapine clearance. Rifabutin 150 or 300 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↑ 17 (↓ 2 to ↑ 40) ↑ 28 (↑ 9 to ↑ 51) ↔ Metabolite 25-O-desacetyl-rifabutin ↑ 24 (↓ 16 to ↑ 84) ↑ 29 (↓ 2 to ↑ 68) ↑ 22 (↓ 14 to ↑ 74) Rifampin 600 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 14 ↑ 11 (↓ 4 to ↑ 28) ↔ § Because of the design of the drug interaction trials (addition of 28 days of nevirapine therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by comparison to historical controls. Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and C max by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [see Drug Interactions (7) ]. The effect of other drugs listed in Table 4 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.