NEVIRAPINE

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds. The chemical name of nevirapine is 11-Cyclopropyl-5,11-dihydro-4-methyl-6 H -dipyrido[3,2- b :2’,3’- e ][1, 4]diazepin-6-one. Nevirapine, USP (anhydrous) is a white to off-white, odorless to nearly odorless crystalline powder with the molecular weight of 266.30 and the molecular formula C 15 H 14 N 4 O. Nevirapine has the following structural formula: Nevirapine extended-release tablets, USP are for oral administration. Each tablet contains 400 mg of nevirapine and the inactive ingredients hypromellose, lactose monohydrate and sodium stearyl fumarate. Nevirapine Structural Formula

Nevirapine extended-release tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m 2 or greater [see Clinical Studies (14.1 , 14.2) ] . Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine extended-release tablets are not recommended to be initiated, unless the benefit outweighs the risk, in: • adult females with CD4 + cell counts greater than 250 cells/mm 3 or • adult males with CD4 + cell counts greater than 400 cells/mm 3 [see Warnings and Precautions (5.1) ] . Nevirapine extended-release tablets are an NNRTI indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 6 years of age or older with a BSA of 1.17 m 2 or greater. ( 1 ) Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine extended-release tablets are not recommended to be initiated, unless the benefit outweighs the risk, in: • adult females with CD4 + cell counts greater than 250 cells/mm 3 • adult males with CD4 + cell counts greater than 400 cells/mm 3 ( 1 , 5.1 )

• 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 tablets. ( 2.3 ) • If any patient experiences rash during the 14-day lead-in period with immediate-release nevirapine do not initiate nevirapine extended-release tablets until the rash has resolved. Do not continue the immediate-release nevirapine lead-in dosing regimen beyond 28 days. ( 2.5 ) • If dosing is interrupted for greater than 7 days, restart 14-day lead-in dosing. ( 2.5 ) 2.1 General Dosing Considerations • Nevirapine extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. • Pediatric patients should be assessed for their ability to swallow the extended-release tablets before prescribing nevirapine extended-release tablets. • Nevirapine extended-release tablets can be taken with or without food. 2.2 Recommended Dosage in Adult Patients Patients not currently taking immediate-release nevirapine Patients must initiate therapy with one 200-mg tablet of immediate-release nevirapine daily for the first 14 days in combination with other antiretroviral agents. The 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed (the lead-in period has been observed to decrease the incidence of rash), followed by one 400-mg tablet of nevirapine extended-release once daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.2) ] . If rash persists beyond the 14-day lead-in period with immediate-release nevirapine, do not begin dosing with nevirapine extended-release tablets. The lead-in dosing with 200 mg once daily immediate-release nevirapine should not be continued beyond 28 days, at which point an alternative regimen should be sought . Switching patients from immediate-release nevirapine to nevirapine extended-release tablets Patients already on a regimen of immediate-release nevirapine twice daily in combination with other antiretroviral agents can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period. Patients already on a regimen of immediate-release nevirapine twice daily who switch to nevirapine extended-release tablet therapy should continue with their ongoing clinical and laboratory monitoring . 2.3 Recommended Dosage in Pediatric Patients Nevirapine extended-release tablets in pediatric patients are dosed based on body surface area (BSA) calculated using the Mosteller formula. All pediatric patients must initiate therapy with immediate-release nevirapine (as 150 mg/m 2 of nevirapine oral suspension or as nevirapine tablets), at a dose not to exceed 200 mg per day, administered once daily for the first 14 days. This lead-in period should be used because it has been demonstrated to reduce the frequency of rash. This lead-in period is not required if the patient is already on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents. The recommended oral dosage of nevirapine extended-release tablets for pediatric patients with a BSA of 1.17 m 2 or greater is 400 mg following the lead-in period with immediate-release nevirapine. The total daily dose should not exceed 400 mg for any patient . Mosteller Formula 2.4 Monitoring of Patients Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine. 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 prior to beginning the 14-day lead-in period with immediate-release nevirapine, prior to initiation of nevirapine extended-release tablets, and at two weeks after initiation of nevirapine extended-release tablet therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine extended-release tablet treatment [see Warnings and Precautions (5) ] . In some cases, hepatic injury has progressed despite discontinuation of treatment . Patients already on a regimen of immediate-release nevirapine twice daily who switch to nevirapine extended-release tablets once daily should continue with their ongoing clinical and laboratory monitoring . 2.5 Dosage Adjustment Patients with Rash Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2) ] . Do not initiate therapy with nevirapine extended-release tablets if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of immediate-release nevirapine until the rash has resolved [see Warnings and Precautions (5.2) ] . The total duration of the once daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen should be sought . Patients with Hepatic Events If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine. Do not restart nevirapine after recovery [see Warnings and Precautions (5.1) ] . Patients with Dose Interruption For patients who interrupt nevirapine extended-release tablet dosing for more than 7 days, restart the recommended lead-in dosing with immediate-release nevirapine, using one 200-mg tablet daily for the first 14 days . Patients with Renal Impairment Patients with CrCl greater than or equal to 20 mL per min and not requiring dialysis do not require an adjustment in dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. An additional 200 mg dose of immediate-release nevirapine following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [see Clinical Pharmacology (12.3) ] . Nevirapine extended-release tablets have not been studied in patients with renal dysfunction .

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 )

• 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, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions (5.1 , 5.2) ]. The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2) ]. 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. The safety database in nevirapine extended-release tablet clinical trials contains data from 800 subjects treated with nevirapine extended-release tablets and 654 subjects treated with immediate-release nevirapine. Trial 1100.1486 (VERxVE) In Trial 1100.1486 (VERxVE), treatment-naïve subjects received a lead-in dose of immediate-release nevirapine 200 mg once daily for 14 days (n = 1,068) and then were randomized to receive either immediate-release nevirapine 200 mg twice daily (n = 506) or nevirapine extended-release tablets 400 mg once daily (n = 505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4 + counts less than 250 cells/mm 3 for women and less than 400 cells/mm 3 for men [see Indications and Usage (1) ]. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subject’s completion of the 96-week endpoint in the trial (mean observation period 98 weeks). After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release nevirapine group and 6% in the nevirapine extended-release tablets group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 8% in both the immediate-release nevirapine group and nevirapine extended-release tablets group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE. Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release nevirapine, and in 1% of subjects in either treatment group during the randomized phase. In addition, six cases of Stevens-Johnson syndrome were reported; all but one occurred within the first 30 days of nevirapine treatment. No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release nevirapine (200 mg once daily), except for rash which occurred in 4% of subjects. Adverse reactions of at least moderate intensity (Grades 2 or above) occurring in 2% or more of treatment-naïve subjects receiving either immediate-release nevirapine or nevirapine extended-release tablets after randomization in Trial 1100.1486 are shown in Table 1. Table 1 Selected Clinical Adverse Drug Reactions Excludes laboratory abnormalities reported as ADRs of at least Moderate Intensity (Grade 2 or above) Occurring in 2% or more of Adult Subjects - Week 96 Analysis of Trial 1100.1486 Mean observation period 98 weeks. Adverse Drug Reaction Immediate-Release Nevirapine N = 506 (%) Nevirapine Extended-Release Tablets N = 505 (%) Rash Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS). 4 5 Diarrhea 4 4 Headache 4 4 Clinical Hepatitis Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, jaundice. 4 2 Abdominal Pain 2 3 Arthralgia 2 2 Pyrexia 2 1 Nausea 2 1 Fatigue 2 2 Laboratory Abnormalities Liver enzyme test abnormalities (AST, ALT) were observed in subjects receiving nevirapine extended-release tablets. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue therapy with nevirapine in the absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 2. Table 2 Grade 2 to Grade 4 Laboratory Abnormalities that Represent a Worsening from Baseline Observed in at least 5% of Subjects in Either Treatment Group - Trial 1100.1486 Laboratory Parameter (unit) Limit Immediate-Release Nevirapine (%) (N = 506) Nevirapine Extended-Release Tablets (%) (N = 505) Chemistry SGPT/ALT (U/L) Grade 2 2.6-5.0 x ULN 13 10 Grade 3 5.1-10.0 x ULN 3 4 Grade 4 > 10.0 x ULN 4 2 SGOT/AST (U/L) Grade 2 2.6-5.0 x ULN 9 7 Grade 3 5.1-10.0 x ULN 2 3 Grade 4 > 10.0 x ULN 2 2 Amylase (U/L) Grade 2 1.6-2.0 x ULN 4 5 Grade 3 2.1-5.0 x ULN 4 2 Grade 4 > 5.0 x ULN 0 < 1 Phosphate (mg/dL) Grade 2 2.0-2.4 x ULN 38 33 Grade 3 1.0-1.9 x ULN 6 7 Grade 4 < 1.0 x ULN < 1 0 Hematology Neutrophils Grade 2 750-999/mm 3 7 4 Grade 3 500-749/mm 3 2 2 Grade 4 < 500/mm 3 1 1 Lipids LDL (mg/dL) Grade 2 160-190 mg/dL 15 15 Grade 3 > 190 mg/dL 5 5 Cholesterol (mg/dL) Grade 2 240-300 mg/dL 18 19 Grade 3 > 300 mg/dL 4 3 Trial 1100.1526 (TRANxITION) In Trial 1100.1526 (TRANxITION) subjects on immediate-release nevirapine 200 mg twice daily for at least 18 weeks were randomized to either receive nevirapine extended-release tablets 400 mg once daily (n = 295) or remain on their immediate-release nevirapine treatment (n = 148). Adverse reactions observed for nevirapine extended-release tablet subjects (48-week analysis) were similar to those observed in trial 1100.1486, as displayed in Table 1. Clinical Trial Experience in Pediatric Patients Adverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, non-randomized, cross-over trial to evaluate the safety and steady-state pharmacokinetic parameters of nevirapine extended-release tablets in HIV-1-infected pediatric subjects 3 to less than 18 years of age. Safety was further examined in an optional extension phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were treated with nevirapine extended-release tablets once daily in combination with other antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse reactions related to nevirapine extended-release tablets in pediatric subjects were similar to those observed in adults. In pediatric subjects the incidence of Grade 2 or higher drug-related rash was 1%. There were no adverse reactions of Grade 2 or above which were considered to be related to treatment by the investigator that occurred in more than 1% of subjects [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release 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 [see Drug Interactions (7) ] , redistribution/accumulation of body fat [see Warnings and Precautions (5.6) ] 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 [see Warnings and Precautions (5.1) ] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

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.