ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reaction is rash. In adults, theincidence of rash is 15% versus 6% with placebo, with Grade 3/4 rashoccurring in 2% of subjects. (6.1) In pediatric subjects the incidence of rash (all causality)was 21%. (6.1) To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reaction is rash. In adults, theincidence of rash is 15% versus 6% with placebo, with Grade 3/4 rashoccurring in 2% of subjects. (6.1) In pediatric subjects the incidence of rash (all causality)was 21%. (6.1) 6.1 Clinical Trial Experience. Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in theclinical trials of drug cannot be directly compared to rates inthe clinical trials of another drug and may not reflect the ratesobserved in clinical practice.Clinical Trial Experience inAdult PatientsThemost serious adverse reactions associated with VIRAMUNE are hepatitis,hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis,and hypersensitivity reactions. Hepatitis/hepatic failure may be isolatedor associated with signs of hypersensitivity which may include severerash or rash accompanied by fever, general malaise, fatigue, muscleor joint aches, blisters, oral lesions, conjunctivitis, facial edema,eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings andPrecautions (5.1, 5.2)].. Hepatic ReactionIn controlled clinical trials, symptomatichepatic events regardless of severity occurred in 4% (range 0% to11%) of subjects who received VIRAMUNE and 1% of subjects in controlgroups. Female gender and higher CD4+ cellcounts (greater than 250 cells/mm3 in womenand greater than 400 cells/mm3 in men)place patients at increased risk of these events [see Boxed Warning and Warnings and Precautions (5.1)].Asymptomatic transaminase elevations (AST or ALT greaterthan 5X ULN) were observed in 6% (range 0% to 9%) of subjects whoreceived VIRAMUNE and 6% of subjects in control groups. Co-infectionwith hepatitis or and/or increased transaminase elevations atthe start of therapy with VIRAMUNE are associated with greater riskof later symptomatic events (6 weeks or more after starting VIRAMUNE)and asymptomatic increases in AST or ALT.Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving VIRAMUNE than in controls (see Table 3).. Skin ReactionThe most common clinical toxicity of VIRAMUNEis rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most frequentlywithin the first 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 clinicaltrials (Trials 1037, 1038, 1046, and 1090), Grade and rashes werereported in 13% of subjects receiving VIRAMUNE compared to 6% receivingplacebo during the first weeks of therapy. Grade and rasheswere reported in 2% of VIRAMUNE recipients compared to less than 1%of subjects receiving placebo. Women tend to be at higher risk fordevelopment of VIRAMUNE-associated rash [see Boxed Warning and Warnings and Precautions (5.2)].Treatment-related, adverse experiences of moderate orsevere intensity observed in greater than 2% of subjects receivingVIRAMUNE in placebo-controlled trials are shown in Table 2.Table Percentage of Subjects with Moderate or Severe Drug-RelatedEvents in Adult Placebo-Controlled Trials1 Background therapy included3TC for all subjects and combinations of NRTIs and PIs. Subjects hadCD4+ cell counts less than 200 cells/mm3. Backgroundtherapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.Trial 10901 Trials 1037,1038, 10462 VIRAMUNEPlaceboVIRAMUNEPlacebo(n=1121)(n=1128)(n=253)(n=203)Median exposure (weeks)58522828Any adverse event15%11%32%13%Rash5272Nausea1194Granulocytopenia23<10Headache1<141Fatigue<1<154Diarrhea<1121Abdominal pain<1<120Myalgia<1012. Laboratory AbnormalitiesLiver enzyme test abnormalities(AST, ALT) were observed more frequently in subjects receiving VIRAMUNEthan in controls (Table 3). Asymptomatic elevations in GGT occur frequentlybut are not contraindication to continue VIRAMUNE therapy in theabsence of elevations in other liver enzyme tests. Other laboratoryabnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) wereobserved with similar frequencies in clinical trials comparing VIRAMUNEand control regimens (see Table 3).Table Percentage of Adult Subjects with Laboratory Abnormalities1 Background therapy included3TC for all subjects and combinations of NRTIs and PIs. Subjects hadCD4+ cell counts less than 200 cells/mm3. Backgroundtherapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.Trial 10901 Trials 1037,1038, 10462 VIRAMUNEPlaceboVIRAMUNEPlaceboLaboratory Abnormality(n=1121)(n=1128)(n=253)(n=203)Blood Chemistry SGPT (ALT) >250 U/L54144 SGOT (AST) >250 U/L4382 Bilirubin >2.5 mg/dL2222Hematology Hemoglobin <8.0 g/dL3400 Platelets <50,000/mm3 11<12 Neutrophils <750/mm3 131441ClinicalTrial Experience in Pediatric PatientsAdverse events were assessed in BI Trial 1100.1032 (ACTG245), double-blind, placebo-controlled trial of VIRAMUNE (n=305)in which pediatric subjects received combination treatment with VIRAMUNE.In this trial two subjects were reported to experience Stevens-Johnsonsyndrome or Stevens-Johnson/toxic epidermal necrolysis transitionsyndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180),an open-label trial of VIRAMUNE (n=37) in which subjects were followedfor 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 BI1100.892). The most frequently reported adverse events related toVIRAMUNE in pediatric subjects were similar to those observed in adults,with the exception of granulocytopenia, which was more commonly observedin children receiving both zidovudine and VIRAMUNE. Cases of allergicreaction, including one case of anaphylaxis, were also reported.The safety of VIRAMUNE was also examinedin BI Trial 1100.1368, an open-label, randomized clinical trial performedin South Africa in which 123 HIV-1 infected treatment-naive subjectsbetween months and 16 years of age received combination treatmentwith VIRAMUNE oral suspension, lamivudine and zidovudine for 48 weeks [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Rash (all causality) was reported in 21% of the subjects,4 (3%) of whom discontinued drug due to rash. All subjects experiencedthe rash early in the course of therapy (less than weeks) and resolvedupon nevirapine discontinuation. Other clinically important adverseevents (all causality) include neutropenia (9%), anemia (7%), andhepatotoxicity (2%) [see Use in Specific Populations (8.4) and Clinical Studies (14.2)].Safety information on use of VIRAMUNE in combinationtherapy in pediatric subjects weeks to less than months of agewas assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial.No unexpected safety findings were observed although granulocytopeniawas reported more frequently in this age group compared to the olderpediatric age groups and adults.. 6.2 Post-Marketing Experience. In addition to the adverse events identifiedduring clinical trials, the following adverse reactions have beenidentified during post-approval use of VIRAMUNE. Because these reactionsare reported voluntarily from population of uncertain size, it isnot always possible to reliably estimate their frequency or establisha causal relationship to drug exposure.Body as Whole: fever,somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulationof 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 associatedwith skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: Allergicreactions including anaphylaxis, angioedema, bullous eruptions, ulcerativestomatitis and urticaria have all been reported. In addition, hypersensitivitysyndrome and hypersensitivity reactions with rash associated withconstitutional findings such as fever, blistering, oral lesions, conjunctivitis,facial edema, muscle or joint aches, general malaise, fatigue, orsignificant hepatic abnormalities, drug reaction with eosinophiliaand systemic symptoms (DRESS) [see Warnings and Precautions (5.1)] plus one or more of thefollowing: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and/or renal dysfunction have been reported.In post-marketing surveillance anemia has been morecommonly observed in children although development of anemia due toconcomitant medication use cannot be ruled out.

BOXED WARNING SECTION.

WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKINREACTIONS. HEPATOTOXICITY:Severe, life-threatening,and in some cases fatal hepatotoxicity, particularly in the first18 weeks, has been reported in patients treated with VIRAMUNE. Insome cases, patients presented with non-specific prodromal signs orsymptoms of hepatitis and progressed to hepatic failure. These eventsare often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patientsat increased risk; women with CD4+ cellcounts greater than 250 cells/mm3, includingpregnant women receiving VIRAMUNE in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with VIRAMUNE use can occur in both genders,all CD4+ cell counts and at any time duringtreatment. Hepatic failure has also been reported in patients withoutHIV taking VIRAMUNE for post-exposure prophylaxis (PEP). Use of VIRAMUNEfor occupational and non-occupational PEP is contraindicated [see Contraindications (4)]. Patients with signs or symptoms of hepatitis, or with increasedtransaminases combined with rash or other systemic symptoms, mustdiscontinue VIRAMUNE and seek medical evaluation immediately [see Warnings and Precautions (5.1)].SKINREACTIONS:Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with VIRAMUNE. These have included cases of Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactionscharacterized by rash, constitutional findings, and organ dysfunction.Patients developing signs or symptoms of severe skin reactions orhypersensitivity reactions must discontinue VIRAMUNE and seek medicalevaluation immediately. Transaminase levels should be checked immediatelyfor all patients who develop rash in the first 18 weeks of treatment.The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has beenobserved to decrease the incidence of rash and must be followed [see Warnings and Precautions (5.2)].MONITORINGFOR HEPATOTOXICITY AND SKIN REACTIONS:Patients must be monitored intensively during thefirst 18 weeks of therapy with VIRAMUNE to detect potentially life-threateninghepatotoxicity or skin reactions. Extra vigilance is warranted duringthe first weeks of therapy, which is the period of greatest riskof these events. Do not restart VIRAMUNE following clinical hepatitis,or transaminase elevations combined with rash or other systemic symptoms,or following severe skin rash or hypersensitivity reactions. In somecases, hepatic injury has progressed despite discontinuation of treatment. WARNING: LIFE-THREATENING (INCLUDING FATAL)HEPATOTOXICITY and SKIN REACTIONSSee full prescribing informationfor complete boxed warning.Fatal and non-fatal hepatotoxicity have been reportedin patients taking VIRAMUNE. Discontinue immediately if clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur. Do not restart VIRAMUNE after recovery. (5.1) Fatal and non-fatal skin reactions, including Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactions,have been reported. Discontinue immediately if severe skin reactions,hypersensitivity reactions, or any rash with systemic symptoms occur.Check transaminase levels immediately for all patients who developa rash in the first 18 weeks of treatment. Do not restart VIRAMUNEafter recovery. (5.2) Monitoring during the first 18 weeks of therapy isessential. Extra vigilance is warranted during the first weeksof therapy, which is the period of greatest risk of these events. (5.1, 5.2) Fatal and non-fatal hepatotoxicity have been reportedin patients taking VIRAMUNE. Discontinue immediately if clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur. Do not restart VIRAMUNE after recovery. (5.1) Fatal and non-fatal skin reactions, including Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactions,have been reported. Discontinue immediately if severe skin reactions,hypersensitivity reactions, or any rash with systemic symptoms occur.Check transaminase levels immediately for all patients who developa rash in the first 18 weeks of treatment. Do not restart VIRAMUNEafter recovery. (5.2) Monitoring during the first 18 weeks of therapy isessential. Extra vigilance is warranted during the first weeksof therapy, which is the period of greatest risk of these events. (5.1, 5.2).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Nevirapine is an antiretroviral drug [see Microbiology (12.4)]. 12.3 Pharmacokinetics. Adults. Absorptionand BioavailabilityNevirapine is readily absorbed (greater than 90%) after oral administrationin healthy volunteers and in adults with HIV-1 infection. Absolutebioavailability in 12 healthy adults following single-dose administrationwas 93 +- 9% (mean +- SD) for 50 mg tablet and 91 +- 8% for an oralsolution. Peak plasma nevirapine concentrations of +- 0.4 mcg/mL(7.5 micromolar) were attained by hours following single 200 mgdose. Following multiple doses, nevirapine peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough nevirapine concentrations of 4.5 +- 1.9 mcg/mL (17 +- micromolar),(n=242) were attained at 400 mg per day. Nevirapine tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When VIRAMUNE (200 mg) was administered to24 healthy adults (12 female, 12 male), with either high-fat breakfast(857 kcal, 50 fat, 53% of calories from fat) or antacid (Maalox(R) 30 mL), the extent of nevirapine absorption (AUC)was comparable to that observed under fasting conditions. In separatetrial in HIV-1 infected subjects (n=6), nevirapine steady-state systemicexposure (AUC) was not significantly alteredby didanosine, which is formulated with an alkaline buffering agent.VIRAMUNE may be administered with or without food, antacid or didanosine.. DistributionNevirapine is highly lipophilic and is essentiallynonionized at physiologic pH. Following intravenous administrationto healthy adults, the apparent volume of distribution (Vdss) of nevirapinewas 1.21 +- 0.09 L/kg, suggesting that nevirapine is widely distributedin humans. Nevirapine readily crosses the placenta and is also foundin breast milk [see Use in Specific Populations (8.2)]. Nevirapine is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Nevirapine concentrations in human cerebrospinal fluid(n=6) were 45% (+-5%) of the concentrations in plasma; this ratio isapproximately equal to the fraction not bound to plasma protein.. Metabolism/EliminationIn vivo trials in humansand in vitro studies with human liver microsomeshave shown that nevirapine is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of nevirapine is mediated primarily by cytochromeP450 (CYP) isozymes from the CYP3A and CYP2B6 families, although otherisozymes may have secondary role. In mass balance/excretion trialin eight healthy male volunteers dosed to steady state with nevirapine200 mg given twice daily followed by single 50 mg dose of 14C-nevirapine, approximately 91.4 +- 10.5% of the radiolabeleddose was recovered, with urine (81.3 +- 11.1%) representing the primaryroute of excretion compared to feces (10.1 +- 1.5%). Greater than 80%of the radioactivity in urine was made up of glucuronide conjugatesof hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronideconjugation, and urinary excretion of glucuronidated metabolites representthe primary route of nevirapine biotransformation and eliminationin humans. Only small fraction (less than 5%) of the radioactivityin urine (representing less than 3% of the total dose) was made upof parent compound; therefore, renal excretion plays minor rolein elimination of the parent compound.Nevirapine is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6by approximately 20-25%, as indicated by erythromycin breath testresults and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediatedmetabolism leads to an approximately 1.5- to 2-fold increase in theapparent oral clearance of nevirapine as treatment continues froma single dose to two-to-four weeks of dosing with 200-400 mg per day.Autoinduction also results in corresponding decrease in the terminalphase half-life of nevirapine in plasma, from approximately 45 hours(single dose) to approximately 25-30 hours following multiple dosingwith 200-400 mg per day.. SpecificPopulations. Renal ImpairmentHIV-1 seronegative adults with mild (CrCl50-79 mL per min; n=7), moderate (CrCl 30-49 mL per min; n=6), orsevere (CrCl less than 30 mL per min; n=4) renal impairment receiveda single 200 mg dose of nevirapine in pharmacokinetic trial. Thesesubjects did not require dialysis. The trial included six additionalsubjects with renal failure requiring dialysis.In subjects with renal impairment (mild, moderate orsevere), there were no significant changes in the pharmacokineticsof nevirapine. However, subjects requiring dialysis exhibited 44%reduction in nevirapine AUC over one-week exposure period. Therewas also evidence of accumulation of nevirapine hydroxy-metabolitesin plasma in subjects requiring dialysis. An additional 200 mg dosefollowing each dialysis treatment is indicated [see Dosageand Administration (2.4) and Use inSpecific Populations (8.6)].. Hepatic ImpairmentIn steady-state trial comparing 46 subjectswith mild (n=17; expansion of some portal areas; Ishak Score 1-2),moderate (n=20; expansion of most portal areas with occasional portal-to-portaland portal-to-central bridging; Ishak Score 3-4), or severe (n=9;marked bridging with occasional cirrhosis without decompensation indicatingChild-Pugh A; Ishak Score 5-6) fibrosis as measure of hepatic impairment,the multiple dose pharmacokinetic disposition of nevirapine and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had nevirapine troughconcentrations above 9,000 mcg per mL (2-fold the usual mean trough).Therefore, patients with hepatic impairment should be monitored carefullyfor evidence of drug-induced toxicity [see Warnings and Precautions (5.1)]. The subjects studied werereceiving antiretroviral therapy containing VIRAMUNE 200 mg twicedaily for at least weeks prior to pharmacokinetic sampling, witha median duration of therapy of 3.4 years.In pharmacokinetic trial where HIV-1 negative cirrhoticsubjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B;n=4) hepatic impairment received single 200 mg dose of nevirapine,a significant increase in the AUC of nevirapine was observed in onesubject with Child-Pugh and ascites suggesting that patients withworsening hepatic function and ascites may be at risk of accumulatingnevirapine in the systemic circulation. Because nevirapine inducesits own metabolism with multiple dosing, this single-dose trial maynot reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.Do not administer nevirapine to patientswith moderate or severe (Child-Pugh Class or C, respectively) hepaticimpairment [see Contraindications (4), Warnings and Precautions (5.1),and Use in Specific Populations (8.7)].. GenderIn the multinational 2NN trial, population pharmacokineticsubstudy of 1077 subjects was performed that included 391 females.Female subjects showed 13.8% lower clearance of nevirapine thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of nevirapine, the effect of gender cannotsolely be explained by body size.. RaceAn evaluation of nevirapine plasma concentrations (pooleddata from several clinical trials) from HIV-1-infected subjects (27Black, 24 Hispanic, 189 Caucasian) revealed no marked difference innevirapine steady-state trough concentrations (median Cminss 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mLCaucasian) with long-term nevirapine treatment at 400 mg per day.However, the pharmacokinetics of nevirapine have not been evaluatedspecifically for the effects of ethnicity.Black subjects (n=80/group) in Trial 1100.1486 showedapproximately 30% to 35% higher trough concentrations than Caucasiansubjects (250-325 subjects/group) in both immediate-release VIRAMUNEand VIRAMUNE XR treatment groups over 96 weeks of treatment at 400mg per day.. Geriatric SubjectsNevirapine pharmacokinetics in HIV-1-infectedadults do not appear to change with age (range 18-68 years); however,nevirapine has not been extensively evaluated in subjects beyond theage of 55 years [see Use in Specific Populations (8.5)].. Pediatric SubjectsPharmacokinetic data for nevirapine havebeen derived from two sources: 48-week pediatric trial in SouthAfrica (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naivesubjects aged months to 16 years; and consolidated analysis offive Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising495 subjects aged 14 days to 19 years.BI Trial 1100.1368 studied the safety, efficacy, andpharmacokinetics of weight-based and body surface area (BSA)-baseddosing regimen of nevirapine. In the weight-based regimen, pediatricsubjects up to years of age received dose of mg/kg once dailyfor two weeks followed by mg per kg twice daily thereafter. Subjects8 years and older were dosed mg/kg once daily for two weeks followedby mg/kg twice daily thereafter. In the BSA regimen, all pediatricsubjects received 150 mg/m2 once dailyfor two weeks followed by 150 mg/m2 twicedaily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)]. Dosing of nevirapine at150 mg/m2 BID (after two-week lead-inof 150 mg/m2 QD) produced geometric meanor mean trough nevirapine concentrations between 4-6 mcg per mL (astargeted from adult data). In addition, the observed trough nevirapineconcentrations were comparable between the two dosing regimens studied(BSA- and weight-based methods).The consolidated analysis of Pediatric AIDS Clinical Trials Group(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluationof pediatric subjects less than months of age (n=17). The plasmanevirapine concentrations observed were within the range observedin adults and the remainder of the pediatric population, but weremore variable between subjects, particularly in the second month ofage. For dose recommendations for pediatric patients [seeDosage and Administration (2.2)].. Drug Interactions [see DrugInteractions (7)]Nevirapine induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE anddrugs primarily metabolized by CYP3A or CYP2B6 may result in decreasedplasma concentrations of these drugs and attenuate their therapeuticeffects.While primarily an inducerof cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibitthis system. Among human hepatic cytochrome P450s, nevirapine wascapable in vitro of inhibiting the 10-hydroxylationof (R)-warfarin (CYP3A). The estimated Ki forthe inhibition of CYP3A was 270 micromolar, concentration that isunlikely to be achieved in patients as the therapeutic range is lessthan 25 micromolar. Therefore, nevirapine may have minimal inhibitoryeffect on other substrates of CYP3A.Nevirapine does not appear to affect the plasma concentrationsof drugs that are substrates of other CYP450 enzyme systems, suchas 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.Table (see below) contains the results of drug interactiontrials performed with VIRAMUNE and other drugs likely to be co-administered.The effects of VIRAMUNE on the AUC, Cmax, andCmin of co-administered drugs are summarized.Table Drug Interactions: Changes in PharmacokineticParameters for Co-administered Drug in the Presence of VIRAMUNE (Allinteraction trials were conducted in HIV-1 positive subjects) Cmin below detectable levelof the assay Increase, Decrease, <=> No Effect For information regarding clinicalrecommendations, see Drug Interactions (7) b Pediatricsubjects ranging in age from months to 12 years. Parallel group design; for VIRAMUNE+lopinavir/ritonavir,n for lopinavir/ritonavir alone. Parallel group design; n=23 for atazanavir/ritonavir nevirapine,n=22 for atazanavir/ritonavir without nevirapine. Changes in atazanavirPK are relative to atazanavir/ritonavir 300/100 mg alone. Based on between-trial comparison. Based on historical controls.Co-administeredDrugDose of Co-administeredDrugDose Regimen ofVIRAMUNEn% Change of Co-administered Drug Pharmacokinetic Parameters (90%CI)AntiretroviralsAUCCmax Cmin Atazanavir/Ritonavira, 300/100 mg QDday4-13, then 400/100 mg QD, day 14-23200 mg BID day 1-23. Subjectswere treated with nevirapine prior to trial entry.23Atazanavir300/100mg42(52 to 29) Atazanavir300/100mg 28(40 to 14) Atazanavir300/100mg 72(80 to 60) Atazanavir400/100mg 19 (35 to 2) Atazanavir400/100mg 2(15 to 24) Atazanavir400/100mg 59 (73 to 40) Darunavir/Ritonavire 400/100 mg BID200 mg BID824 (3 to 57) 40 (14 to 73) (21 to 32) Didanosine100-150 mg BID200 mg QD 14 days; 200 mg BID 14 days18<=><=>Efavirenza 600 mg QD200 mg QD 14 days; 400 mg QD 14 days1728(34 to 14)12(23 to 1)32(35 to 19)Fosamprenavir1400 mg BID200 mg BID. Subjects were treated withnevirapine prior to trial entry.1733 (45 to 20) 25 (37 to 10) 35 (50 to 15) Fosamprenavir/Ritonavir700/100 mg BID200 mg BID. Subjects were treated withnevirapine prior to trial entry.1711(23 to 3) <=> 19 (32 to 4) Indinavira 800 mg q8H200 mg QD 14 days; 200 mg BID 14 days1931(39 to 22)15(24 to 4)44(53 to 33)Lopinavira, 300/75 mg/m2 (lopinavir/ritonavir) 7 mg/kg or mg/kg QD 2 weeks; BID 1week12, 15 22(44 to 9)14(36 to 16)55(75 to 19)Lopinavira 400/100 mg BID (lopinavir/ritonavir)200 mg QD 14 days; 200 mg BID >1 year22, 19 27(47 to 2)19(38 to 5)51(72 to 26)Maravirocf 300 mg SD200 mg BID81 (35 to 55)54 (6 to 151)<=> Nelfinavira 750 mg TID200 mg QD 14 days; 200 mg BID 14 days23<=><=>32(50 to 5)Nelfinavir-M8 metabolite62(70 to 53)59(68 to 48)66(74 to 55)Ritonavir600 mg BID200 mg QD 14 days; 200 mg BID 14 days18<=><=><=>Stavudine30-40 mg BID200 mg QD 14 days; 200 mg BID 14 days22<=><=>Zalcitabine0.125-0.25 mg TID200 mg QD 14 days; 200 mg BID 14 days6<=><=>Zidovudine100-200 mg TID200 mg QD 14 days; 200 mg BID 14 days1128(40 to 4)30(51 to 14)Other MedicationsAUCCmax Cmin Clarithromycina 500 mg BID200 mg QD 14 days; 200 mg BID 14 days1531(38 to 24)23(31 to 14)56(70 to 36)Metabolite 14-OH-clarithromycin42(16 to 73)47(21 to 80)<=>Ethinyl Estradiola and Norethindronea 0.035 mg(as Ortho-Novum(R) 1/35)200 mg QD 14 days; 200 mgBID 14 days1020(33 to 3)<=>1 mg(as Ortho-Novum(R) 1/35)19(30 to 7)16(27 to 3)Depomedroxy-Progesterone Acetate150 mg every months200 mg QD 14 days; 200 mg BID 14 days32<=><=><=>Fluconazole200 mg QD200 mg QD 14 days; 200 mg BID 14 days19<=><=><=>Ketoconazolea 400 mg QD200 mg QD 14 days; 200 mg BID 14 days2172(80 to 60)44(58 to 27)Methadonea Individual Subject Dosing200 mg QD 14 days; 200 mg BID >=7 days9In controlled pharmacokinetictrial with subjects receiving chronic methadone to whom steady-statenevirapine therapy was added, the clearance of methadone was increasedby 3-fold, resulting in symptoms of withdrawal, requiring dose adjustmentsin 10 mg segments, in of the subjects. Methadone did not haveany effect on nevirapine clearance.Rifabutina 150 or 300 mg QD200 mg QD 14 days; 200 mg BID 14 days1917(2 to 40)28(9 to 51)<=>Metabolite25-O-desacetyl-rifabutin24(16 to 84)29(2 to 68)22(14 to 74)Rifampina 600 mg QD200 mg QD 14 days; 200 mg BID x14 days1411(4 to 28)<=>Because of the design of the druginteraction trials (addition of 28 days of VIRAMUNE therapy to existingHIV-1 therapy), the effect of the concomitant drug on plasma nevirapinesteady-state concentrations was estimated by comparison to historicalcontrols.Administration of rifampinhad clinically significant effect on nevirapine pharmacokinetics,decreasing AUC and Cmax by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein nevirapine exposure, based on comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table on nevirapine pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and nevirapine.. 12.4 Microbiology. Mechanismof Action. Nevirapine is 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 activitiesby causing disruption of the enzymes catalytic site. The activityof nevirapine does not compete with template or nucleoside triphosphates.HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases, , or are not inhibited by nevirapine.. AntiviralActivity. The antiviral activity of nevirapine has been measured in varietyof cell lines including peripheral blood mononuclear cells, monocyte-derivedmacrophages, and lymphoblastoid cell lines. In an assay using humanembryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM againsta panel of 2923 wild-type isolates of HIV-1 that were primarily (93%)clade clinical isolates from the United States. The 99th percentile EC50 value was470 nM in this trial. The median EC50 valuewas 63 nM (range 14-302 nM, n=29) against clinical isolates of HIV-1clades A, B, C, D, F, G, and H, and circulating recombinant formsCRF01AE, CRF02AG and CRF12BF. Nevirapine had no antiviral activityin cell culture against group HIV-1 isolates (n=3) or HIV-2 isolates(n=3) replicating in cord blood mononuclear cells. Nevirapine in combinationwith efavirenz exhibited strong antagonistic anti-HIV-1 activity incell culture and was additive to antagonistic with the protease inhibitorritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activityof nevirapine was not antagonistic in combination with the NRTIs abacavir,didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine,and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir,nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity ofnevirapine was antagonized by the anti-HBV drug adefovir and by theanti-HCV drug ribavirin in cell culture.. Resistance. HIV-1 isolateswith reduced susceptibility (100- to 250-fold) to nevirapine emergein cell culture. Genotypic analysis showed mutations in the HIV-1RT gene encoding Y181C and/or V106A substitutions depending upon thevirus strain and cell line employed. Time to emergence of nevirapineresistance in cell culture was not altered when selection includednevirapine in combination with several other NNRTIs.Phenotypic and genotypic changes in HIV-1 isolatesfrom treatment-naive subjects receiving either nevirapine (n=24) ornevirapine and zidovudine (n=14) were monitored in Phase and trialsranging from to 12 weeks or longer. After week of nevirapine monotherapy,isolates from 3/3 subjects had decreased susceptibility to nevirapinein cell culture. One or more of the RT mutations resulting in aminoacid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A weredetected in HIV-1 isolates from some subjects as early as weeksafter therapy initiation. By week eight of nevirapine monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with greaterthan 100-fold decrease in susceptibility to nevirapine in cell culturecompared to baseline, and had one or more of the nevirapine-associatedRT resistance substitutions. Nineteen of these subjects (80%) hadisolates with Y181C substitutions regardless of dose.Genotypic analysis of isolates from antiretroviral-naivesubjects experiencing virologic failure (n=71) receiving nevirapineonce daily (n=25) or twice daily (n=46) in combination with lamivudineand stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25and 23/46 subjects, respectively, contained one or more of the followingNNRTI resistance-associated substitutions: Y181C, K101E, G190A/S,K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.For trial 1100.1486, genotypic analysiswas performed for baseline and on-therapy isolates from 23 and 34subjects who experienced virologic failure in the VIRAMUNE XR andimmediate-release VIRAMUNE treatment group, respectively. Nevirapineresistance-associated substitutions developed in the on-therapy isolatesof 78% (18/23) of the subjects who had virologic failures in the VIRAMUNEXR treatment group and 88% (30/34) of the subjects in the immediate-releaseVIRAMUNE treatment group, respectively. The Y181C nevirapine resistance-associatedsubstitution was found alone or in combination with other nevirapineresistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I,Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjectsfailing VIRAMUNE XR treatment and 25 subjects failing immediate-releaseVIRAMUNE treatment. On-therapy isolates from subject in VIRAMUNEXR treatment group developed novel amino acid substitution Y181Iand isolates from another subject in the immediate-release VIRAMUNEtreatment group developed novel amino acid substitution Y188N. Phenotypicanalysis showed that Y188N and Y181I substitutions conferred 103-and 22-fold reductions in susceptibility to nevirapine, respectively.. Cross-resistance. Rapid emergenceof HIV-1 strains which are cross-resistant to NNRTIs has been observedin cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistantto the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred22- and 7-fold reductions in susceptibility to delavirdine and efavirenz,respectively, but showed no decrease in susceptibility to etravirine.Similarly, the Y181I substitution reduced susceptibility to delavirdineand etravirine 3- and 8-fold, respectively, but did not reduce susceptibilityto efavirenz. However, nevirapine-resistant isolates were susceptibleto the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptibleto nevirapine in cell culture.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Patients. Trial BI 1090 was placebo-controlled,double-blind, randomized trial in 2249 HIV-1 infected subjects withless than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 comparedtreatment with VIRAMUNE lamivudine background therapy versus lamivudine+ background therapy in NNRTI-naive subjects. Treatment doses wereVIRAMUNE, 200 mg daily for two weeks followed by 200 mg twice dailyor placebo, and lamivudine, 150 mg twice daily. Other antiretroviralagents were given at approved doses. Initial background therapy (inaddition to lamivudine) was one NRTI in 1309 subjects (58%), two ormore 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-1infection, with median baseline CD4+ cellcount of 96 cells/mm3 and baseline HIV-1RNA of 4.58 log10 copies per mL (38,291 copiesper mL). Prior to entering the trial, 45% had previously experiencedan AIDS-defining clinical event. Eighty-nine percent had antiretroviraltreatment prior to entering the trial. BI 1090 was originally designedas clinical endpoint trial. Prior to unblinding the trial, the primaryendpoint was changed to proportion of subjects with HIV-1 RNA lessthan 50 copies per mL and not previously failed at 48 weeks. Treatmentresponse and outcomes are shown in Table 6.Table BI 1090 Outcomes Through 48 Weeks1 including change to open-labelnevirapine includes withdrawalof consent, lost to follow-up, non-compliance with protocol, otheradministrative reasonsOutcomeVIRAMUNE (N=1121)%Placebo (N=1128)%Responders at 48 weeks: HIV-1RNA <50 copies/mL 182Treatment Failure8298 Never suppressed viral load4566 Virologic failure afterresponse74 CDC category event ordeath1011 Added antiretroviral therapy1 while <50 copies/mL51 Discontinued trial therapydue to AE76 Discontinued trial <48weeks2 910The change from baseline in CD4+ cell count through one year of therapy was significantlygreater for the VIRAMUNE group compared to the placebo group for theoverall trial population (64 cells/mm3 versus22 cells/mm3, respectively), as well asfor subjects who entered the trial as treatment-naive or having receivedonly ZDV (85 cells/mm3 versus 25 cells/mm3, respectively).At two years into the trial, 16% of subjects on VIRAMUNE had experiencedclass CDC events as compared to 21% of subjects on the control arm.Trial BI 1046 (INCAS) was double-blind,placebo-controlled, randomized, three-arm trial with 151 HIV-1 infectedsubjects with CD4+ cell counts of 200-600cells/mm3 at baseline. BI 1046 comparedtreatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudineand zidovudine+didanosine. Treatment doses were VIRAMUNE at 200 mgdaily for two weeks followed by 200 mg twice daily or placebo, zidovudineat 200 mg three times daily, and didanosine at 125 or 200 mg twicedaily (depending on body weight). The subjects had mean baseline HIV-1RNA of 4.41 log10 copies/mL (25,704 copiesper mL) and mean baseline CD4+ cell countof 376 cells/mm3. The primary endpointwas the proportion of subjects with HIV-1 RNA less than 400 copiesper mL and not previously failed at 48 weeks. The virologic responderrates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine,19% for subjects treated with zidovudine+didanosine, and 0% for subjectstreated with VIRAMUNE+zidovudine.CD4+ cell counts in the VIRAMUNE+ZDV+ddIgroup increased above baseline by mean of 139 cells/mm3 at one year, significantly greater than the increaseof 87 cells/mm3 in the ZDV+ddI subjects.The VIRAMUNE+ZDV group mean decreased by cells/mm3 below baseline.. 14.2 Pediatric Patients. The pediatric safety and efficacy of VIRAMUNEwas examined in BI Trial 1100.1368, an open-label, randomized clinicaltrial performed in South Africa in which 123 HIV-1 infected treatment-naivesubjects between months and 16 years of age received VIRAMUNE oralsuspension for 48 weeks. Subjects were divided into age groups (3months to less than years, to less than years, to less than12 years, and 12 to less than or equal to 16 years) and randomizedto receive one of two VIRAMUNE doses, determined by different dosingmethods [body surface area (150 mg/m2)and weight-based dosing (4 or mg per kg)] in combination with zidovudineand lamivudine [see Adverse Reactions (6.1), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)]. The total daily dose of VIRAMUNE did notexceed 400 mg in either regimen. There were 66 subjects in the bodysurface area (BSA) dosing group and 57 subjects in the weight-based(BW) dosing group.Baseline demographicsincluded: 49% male; 81% Black and 19% Caucasian; 4% had previous exposureto ARVs. Subjects had median baseline HIV-1 RNA of 5.45 log10 copies per mL and median baseline CD4+ cell count of 527 cells/mm3 (range 37-2279). One hundred and five (85%) completed the 48-weekperiod while 18 (15%) discontinued prematurely. Of the subjects whodiscontinued prematurely, (7%) discontinued due to adverse reactionsand (2%) discontinued due to virologic failure. Overall the proportionof subjects who achieved and maintained an HIV-1 RNA less than 400copies per mL at 48 weeks was 47% (58/123).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION The 14-day lead-in period must be strictly followed; ithas been demonstrated to reduce the frequency of rash. (2.4, 5.2) If any patient experiences rash during the 14-day lead-inperiod, do not increase dose until the rash has resolved. Do not continuethe lead-in dosing regimen beyond 28 days. (2.4) If dosing is interrupted for greater than days, restart14-day lead-in dosing. (2.4) Total daily dose should not exceed 400 mg for anypatient.Adults(>=16 yrs)Pediatric Patients(>=15 days)First 14 days200 mg once daily150 mg/m2 once dailyAfter 14 days200 mg twice daily150 mg/m2 twice daily. The 14-day lead-in period must be strictly followed; ithas been demonstrated to reduce the frequency of rash. (2.4, 5.2) If any patient experiences rash during the 14-day lead-inperiod, do not increase dose until the rash has resolved. Do not continuethe lead-in dosing regimen beyond 28 days. (2.4) If dosing is interrupted for greater than days, restart14-day lead-in dosing. (2.4) 2.1 Adult Patients. The recommended dose for VIRAMUNE is one200 mg tablet daily for the first 14 days, followed by one 200 mgtablet twice daily, in combination with other antiretroviral agents.The 14-day lead-in period with VIRAMUNE 200 mg daily dosing must bestrictly followed as the lead-in period has been observed to decreasethe incidence of rash [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. If rash persists beyondthe 14-day lead-in period, do not dose escalate to 200 mg twice daily.The 200 mg once-daily dosing regimen should not be continued beyond28 days, at which point, an alternative regimen should be sought.For concomitantly administered antiretroviral therapy, the manufacturersrecommended dosage and monitoring should be followed.. 2.2 Pediatric Patients. The recommended oral dose for pediatricpatients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400mg for any patient. Table Calculation of the Volume of VIRAMUNE Oral Suspension(50 mg per mL) Required for Pediatric Dosing Based on Body Surfaceand Dose of 150 mg/m2 BSA range (m2)Volume (mL)0.06 0.121.250.12 0.252.50.25 0.4250.42 0.587.50.58 0.75100.75 0.9212.50.92 1.08151.08 1.2517.51.25+20VIRAMUNE suspension should be shakengently prior to administration. It is important to administer theentire measured dose of suspension by using an oral dosing syringeor dosing cup. An oral dosing syringe is recommended, particularlyfor volumes of mL or less. If dosing cup is used, it should bethoroughly rinsed with water and the rinse should also be administeredto the patient.. Formula Image. 2.3 Monitoring of Patients. Intensive clinical and laboratory monitoring,including liver enzyme tests, is essential at baseline and duringthe first 18 weeks of treatment with VIRAMUNE. The optimal frequencyof monitoring during this period has not been established. Some expertsrecommend clinical and laboratory monitoring more often than onceper month, and in particular, would include monitoring of liver enzymetests at baseline, prior to dose escalation, and at two weeks post-doseescalation. After the initial 18-week period, frequent clinical andlaboratory monitoring should continue throughout VIRAMUNE treatment [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed despite discontinuationof treatment.. 2.4 Dosage Adjustment. Patients with RashDiscontinue VIRAMUNE if patient experiencessevere rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2)]. Do not increase VIRAMUNE dose if patient experiencesmild to moderate rash without constitutional symptoms during the 14-daylead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved [seeWarnings and Precautions (5.2)]. The total duration of the once daily lead-in dosing period shouldnot exceed 28 days at which point an alternative regimen should besought.Patients withHepatic EventsIf clinical(symptomatic) hepatic event occurs, permanently discontinue VIRAMUNE.Do not restart VIRAMUNE after recovery [see Warnings and Precautions (5.1)].Patients with Dose InterruptionFor patients who interrupt VIRAMUNE dosingfor more than days, restart the recommended dosing, using one 200mg tablet daily (150 mg/m2/day in pediatricpatients) for the first 14 days (lead-in) followed by one 200 mg tablettwice daily (150 mg/m2 twice daily forpediatric patients). Patients with Renal ImpairmentPatients with CrCl greater than or equal to 20 mL permin do not require an adjustment in VIRAMUNE dosing. The pharmacokineticsof nevirapine have not been evaluated in patients with CrCl less than20 mL per min. An additional 200 mg dose of VIRAMUNE following eachdialysis treatment is indicated in patients requiring dialysis. Nevirapinemetabolites may accumulate in patients receiving dialysis; however,the clinical significance of this accumulation is not known [see Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Nevirapine is principally metabolized bythe liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapineis known to be an inducer of these enzymes. As result, drugs thatare metabolized by these enzyme systems may have lower than expectedplasma levels when co-administered with nevirapine.The specific pharmacokinetic changes that occur withco-administration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments aboutpossible dosage modifications based on established drug interactionsare listed in Table 4. The data in Tables and are based on theresults of drug interaction trials conducted in HIV-1 seropositivesubjects unless otherwise indicated. In addition to established druginteractions, there may be potential pharmacokinetic interactionsbetween nevirapine and other drug classes that are metabolized bythe cytochrome P450 system. These potential drug interactions arealso listed in Table 4. Although specific drug interaction trialsin HIV-1 seropositive subjects have not been conducted for some classesof drugs listed in Table 4, additional clinical monitoring may bewarranted when co-administering these drugs.The in vitro interaction between nevirapineand the antithrombotic agent warfarin is complex. As result, whengiving these drugs concomitantly, plasma warfarin levels may changewith the potential for increases in coagulation time. When warfarinis co-administered with nevirapine, anticoagulation levels shouldbe monitored frequently.Table Established and Potential Drug Interactions: Usewith Caution, Alteration in Dose or Regimen May Be Needed Due to DrugInteraction Established Drug Interactions: See Clinical Pharmacology(12.3), Table for Magnitude of Interaction. The interactionbetween VIRAMUNE and the drug was evaluated in clinical study. All other drug interactions shown are predicted.Drug NameEffect on Concentration of Nevirapine or Concomitant DrugClinicalCommentHIV AntiviralAgents: Protease Inhibitors (PIs)Atazanavir/Ritonavir Atazanavir Nevirapine Do not co-administer nevirapinewith atazanavir because nevirapine substantially decreases atazanavirexposure and there is potential risk for nevirapine-associated toxicitydue to increased nevirapine exposures. Fosamprenavir Amprenavir Nevirapine Co-administration of nevirapine andfosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir Amprenavir Nevirapine No dosing adjustments are requiredwhen nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavirtwice daily. The combination of nevirapine administered with fosamprenavir/ritonavironce daily has not been studied. Indinavir Indinavir The appropriate doses of thiscombination of indinavir and nevirapine with respect to efficacy andsafety have not been established. Lopinavir/Ritonavir Lopinavir Dosing in adult patients: dose adjustment of lopinavir/ritonavir to 500/125mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twicedaily is recommended when used in combination with nevirapine. Neitherlopinavir/ritonavir tablets nor oral solution should be administeredonce daily in combination with nevirapine. Dosingin pediatric patients: Please refer to theKaletra(R) prescribing information for dosingrecommendations based on body surface area and body weight. Neitherlopinavir/ritonavir tablets nor oral solution should be administeredonce daily in combination with nevirapine. Nelfinavir Nelfinavir M8 MetaboliteNelfinavir Cmin The appropriate doses of thecombination of nevirapine and nelfinavir with respect to safety andefficacy have not been established. Saquinavir/Ritonavir The interaction between nevirapineand saquinavir/ritonavir has not been evaluated The appropriatedoses of the combination of nevirapine and saquinavir/ritonavir withrespect to safety and efficacy have not been established. HIV AntiviralAgents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Efavirenz Efavirenz The appropriate doses of these combinationswith respect to safety and efficacy have not been established. DelavirdineEtravirineRilpivirine Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as thiscombination has not been shown to be beneficial. HepatitisC Antiviral AgentsBoceprevir Plasma concentrations of boceprevirmay be decreased due to induction of CYP3A4/5 by nevirapine. Nevirapine andboceprevir should not be coadministered because decreases in boceprevirplasma concentrations may result in reduction in efficacy. Telaprevir Plasma concentrationsof telaprevir may be decreased due to induction of CYP3A4 by nevirapineand plasma concentrations of nevirapine may be increased due to inhibitionof CYP3A4 by telaprevir. Nevirapine andtelaprevir should not be coadministered because changes in plasmaconcentrations of nevirapine, telaprevir, or both may result in areduction in telaprevir efficacy or an increase in nevirapine-associatedadverse events. Other AgentsAnalgesics:Methadone Methadone Methadone levels weredecreased; increased dosages may be required to prevent symptoms ofopiate withdrawal. Methadone-maintained patients beginning nevirapinetherapy should be monitored for evidence of withdrawal and methadonedose should be adjusted accordingly. Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combinationhave not been established. Antibiotics:Clarithromycin Clarithromycin 14-OH clarithromycin Clarithromycin exposure was significantlydecreased by nevirapine; however, 14-OH metabolite concentrationswere increased. Because clarithromycin active metabolite has reducedactivity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternativesto clarithromycin, such as azithromycin, should be considered. Rifabutin Rifabutin Rifabutin and its metabolite concentrationswere moderately increased. Due to high intersubject variability,however, some patients may experience large increases in rifabutinexposure and may be at higher risk for rifabutin toxicity. Therefore,caution should be used in concomitant administration. Rifampin Nevirapine Nevirapine and rifampin should notbe administered concomitantly because decreases in nevirapine plasmaconcentrations may reduce the efficacy of the drug. Physicians needingto treat patients co-infected with tuberculosis and using nevirapine-containingregimen may use rifabutin instead. Anticonvulsants:Carbamazepine, clonazepam, ethosuximidePlasma concentrationsof nevirapine and the anticonvulsant may be decreased.Usewith caution and monitor virologic response and levels of anticonvulsants.Antifungals:Fluconazole Nevirapine Because of the risk of increased exposureto nevirapine, caution should be used in concomitant administration,and patients should be monitored closely for nevirapine-associatedadverse events. Ketoconazole Ketoconazole Nevirapine and ketoconazole should notbe administered concomitantly because decreases in ketoconazole plasmaconcentrations may reduce the efficacy of the drug. Itraconazole Itraconazole Nevirapine and itraconazole shouldnot be administered concomitantly due to potential decreases in itraconazoleplasma concentrations that may reduce efficacy of the drug. Antithrombotics:WarfarinPlasma concentrationsmay be increased.Potential effecton anticoagulation. Monitoring of anticoagulation levels is recommended.Calcium Channel blockers:Diltiazem, nifedipine, verapamilPlasma concentrationsmay be decreased.Appropriate dosesfor these combinations have not been established.Cancer Chemotherapy:CyclophosphamidePlasma concentrationsmay be decreased.Appropriate dosesfor this combination have not been established.Ergot Alkaloids:ErgotaminePlasma concentrationsmay be decreased.Appropriate dosesfor this combination have not been established.Immunosuppressants:Cyclosporine, tacrolimus, sirolimusPlasma concentrationsmay be decreased.Appropriate dosesfor these combinations have not been established.Motility Agents:CisapridePlasma concentrationsmay be decreased.Appropriate dosesfor this combination have not been established.Opiate Agonists:FentanylPlasma concentrationsmay be decreased.Appropriate dosesfor this combination have not been established.Oral Contraceptives:Ethinyl estradiol and Norethindrone Ethinyl Estradiol Norethindrone Despite lower ethinyl estradioland norethindrone exposures when coadministered with nevirapine, literaturereports suggest that nevirapine has no effect on pregnancy rates amongHIV-infected women on combined oral contraceptives. When coadministeredwith VIRAMUNE, no dose adjustment of ethinyl estradiol or norethindroneis needed when used in combination for contraception. When these oral contraceptives are used for hormonal regulationduring VIRAMUNE therapy, the therapeutic effect of the hormonal therapyshould be monitored.. Co-administration of VIRAMUNE can alterthe concentrations of other drugs and other drugs may alter the concentrationof nevirapine. The potential for drug interactions must be consideredprior to and during therapy. (5.4, 7, 12.3).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approvedpatient labeling (Medication Guide).Hepatotoxicity and Skin Reactions Inform patientsof the possibility of severe liver disease or skin reactions associatedwith VIRAMUNE that may result in death. Instruct patients developingsigns or symptoms of liver disease or severe skin reactions to discontinueVIRAMUNE and seek medical attention immediately, including performanceof laboratory monitoring. Symptoms of liver disease include fatigue,malaise, anorexia, nausea, jaundice, acholic stools, liver tendernessor hepatomegaly. Symptoms of severe skin or hypersensitivity reactionsinclude rash accompanied by fever, general malaise, fatigue, muscleor 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 VIRAMUNE todetect potentially life-threatening hepatotoxicity and skin reactions.However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout VIRAMUNE treatment.Extra vigilance is warranted during the first weeks of therapy,which is the period of greatest risk of hepatic events. Advise patientswith signs and symptoms of hepatitis to discontinue VIRAMUNE and seekmedical evaluation immediately. If VIRAMUNE is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4+ cell count at initiationof VIRAMUNE therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatichepatic events, often associated with rash. Advise patients thatco-infection with hepatitis or and/or increased transaminasesat the start of therapy with VIRAMUNE are associated with greaterrisk of later symptomatic events (6 weeks or more after starting VIRAMUNE)and asymptomatic increases in AST or ALT [see Warnings andPrecautions (5.1)].The majority of rashes associatedwith VIRAMUNE occur within the first weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-inperiod, do not escalate the VIRAMUNE dose until the rash resolves.The total duration of the once-daily lead-in dosing period shouldnot exceed 28 days, at which point an alternative regimen may needto be started. Any patient experiencing rash should have their liverenzymes (AST, ALT) evaluated immediately. Patients with severe rashor hypersensitivity reactions should discontinue VIRAMUNE immediatelyand consult physician. VIRAMUNE should not be restarted followingsevere skin rash or hypersensitivity reaction. Women tend to be athigher risk for development of VIRAMUNE-associated rash [seeWarnings and Precautions (5.2)]. Administrationand Missed DosageInform patients to take VIRAMUNE everyday as prescribed. Advise patients not to alter the dose withoutconsulting their doctor. If dose is missed, patients should takethe next dose as soon as possible. However, if dose is skipped,the patient should not double the next dose.To avoid overdose, inform patients thatthey should never take immediate-release VIRAMUNE and extended-releaseVIRAMUNE XR concomitantly.Drug InteractionsVIRAMUNE may interactwith some drugs; therefore, advise patients to report to their doctorthe use of any other prescription, non-prescription medication orherbal products, particularly St. Johns wort [see Warningsand Precautions (5.4) and Drug Interactions (7)].Immune Reconstitution SyndromeAdvise patientsto inform their healthcare provider immediately of any signs or symptomsof infection, as inflammation from previous infection may occur soonafter combination antiretroviral therapy, including when VIRAMUNEis started [see Warnings and Precautions (5.5)].Fat RedistributionInform patientsthat redistribution or accumulation of body fat may occur in patientsreceiving antiretroviral therapy and that the cause and long-termhealth effects of these conditions are not known at this time [see Warnings and Precautions (5.6)].Pregnancy RegistryAdvise patients that there is pregnancyregistry that monitors pregnancy outcomes in women exposed to VIRAMUNEduring pregnancy [see Use in Specific Populations (8.1)]. LactationInstruct women with HIV-1 infectionnot to breastfeed because HIV-1 can be passed to the baby in the breastmilk [see Use in Specific Populations (8.2)].InfertilityAdvise females of reproductivepotential of the potential for impaired fertility from VIRAMUNE [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)] . Distributed by:Boehringer IngelheimPharmaceuticals, Inc.Ridgefield, CT 06877 USAProduct and trademark licensedfrom: Boehringer Ingelheim International GmbHThe other brands listed are trademarks oftheir respective owners and are not trademarks of Boehringer IngelheimPharmaceuticals, Inc.Copyright(C) 2019 Boehringer Ingelheim Pharmaceuticals, Inc. ALLRIGHTS RESERVEDOT1801ABJ022019.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Adults. Absorptionand BioavailabilityNevirapine is readily absorbed (greater than 90%) after oral administrationin healthy volunteers and in adults with HIV-1 infection. Absolutebioavailability in 12 healthy adults following single-dose administrationwas 93 +- 9% (mean +- SD) for 50 mg tablet and 91 +- 8% for an oralsolution. Peak plasma nevirapine concentrations of +- 0.4 mcg/mL(7.5 micromolar) were attained by hours following single 200 mgdose. Following multiple doses, nevirapine peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough nevirapine concentrations of 4.5 +- 1.9 mcg/mL (17 +- micromolar),(n=242) were attained at 400 mg per day. Nevirapine tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When VIRAMUNE (200 mg) was administered to24 healthy adults (12 female, 12 male), with either high-fat breakfast(857 kcal, 50 fat, 53% of calories from fat) or antacid (Maalox(R) 30 mL), the extent of nevirapine absorption (AUC)was comparable to that observed under fasting conditions. In separatetrial in HIV-1 infected subjects (n=6), nevirapine steady-state systemicexposure (AUC) was not significantly alteredby didanosine, which is formulated with an alkaline buffering agent.VIRAMUNE may be administered with or without food, antacid or didanosine.. DistributionNevirapine is highly lipophilic and is essentiallynonionized at physiologic pH. Following intravenous administrationto healthy adults, the apparent volume of distribution (Vdss) of nevirapinewas 1.21 +- 0.09 L/kg, suggesting that nevirapine is widely distributedin humans. Nevirapine readily crosses the placenta and is also foundin breast milk [see Use in Specific Populations (8.2)]. Nevirapine is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Nevirapine concentrations in human cerebrospinal fluid(n=6) were 45% (+-5%) of the concentrations in plasma; this ratio isapproximately equal to the fraction not bound to plasma protein.. Metabolism/EliminationIn vivo trials in humansand in vitro studies with human liver microsomeshave shown that nevirapine is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of nevirapine is mediated primarily by cytochromeP450 (CYP) isozymes from the CYP3A and CYP2B6 families, although otherisozymes may have secondary role. In mass balance/excretion trialin eight healthy male volunteers dosed to steady state with nevirapine200 mg given twice daily followed by single 50 mg dose of 14C-nevirapine, approximately 91.4 +- 10.5% of the radiolabeleddose was recovered, with urine (81.3 +- 11.1%) representing the primaryroute of excretion compared to feces (10.1 +- 1.5%). Greater than 80%of the radioactivity in urine was made up of glucuronide conjugatesof hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronideconjugation, and urinary excretion of glucuronidated metabolites representthe primary route of nevirapine biotransformation and eliminationin humans. Only small fraction (less than 5%) of the radioactivityin urine (representing less than 3% of the total dose) was made upof parent compound; therefore, renal excretion plays minor rolein elimination of the parent compound.Nevirapine is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6by approximately 20-25%, as indicated by erythromycin breath testresults and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediatedmetabolism leads to an approximately 1.5- to 2-fold increase in theapparent oral clearance of nevirapine as treatment continues froma single dose to two-to-four weeks of dosing with 200-400 mg per day.Autoinduction also results in corresponding decrease in the terminalphase half-life of nevirapine in plasma, from approximately 45 hours(single dose) to approximately 25-30 hours following multiple dosingwith 200-400 mg per day.. SpecificPopulations. Renal ImpairmentHIV-1 seronegative adults with mild (CrCl50-79 mL per min; n=7), moderate (CrCl 30-49 mL per min; n=6), orsevere (CrCl less than 30 mL per min; n=4) renal impairment receiveda single 200 mg dose of nevirapine in pharmacokinetic trial. Thesesubjects did not require dialysis. The trial included six additionalsubjects with renal failure requiring dialysis.In subjects with renal impairment (mild, moderate orsevere), there were no significant changes in the pharmacokineticsof nevirapine. However, subjects requiring dialysis exhibited 44%reduction in nevirapine AUC over one-week exposure period. Therewas also evidence of accumulation of nevirapine hydroxy-metabolitesin plasma in subjects requiring dialysis. An additional 200 mg dosefollowing each dialysis treatment is indicated [see Dosageand Administration (2.4) and Use inSpecific Populations (8.6)].. Hepatic ImpairmentIn steady-state trial comparing 46 subjectswith mild (n=17; expansion of some portal areas; Ishak Score 1-2),moderate (n=20; expansion of most portal areas with occasional portal-to-portaland portal-to-central bridging; Ishak Score 3-4), or severe (n=9;marked bridging with occasional cirrhosis without decompensation indicatingChild-Pugh A; Ishak Score 5-6) fibrosis as measure of hepatic impairment,the multiple dose pharmacokinetic disposition of nevirapine and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had nevirapine troughconcentrations above 9,000 mcg per mL (2-fold the usual mean trough).Therefore, patients with hepatic impairment should be monitored carefullyfor evidence of drug-induced toxicity [see Warnings and Precautions (5.1)]. The subjects studied werereceiving antiretroviral therapy containing VIRAMUNE 200 mg twicedaily for at least weeks prior to pharmacokinetic sampling, witha median duration of therapy of 3.4 years.In pharmacokinetic trial where HIV-1 negative cirrhoticsubjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B;n=4) hepatic impairment received single 200 mg dose of nevirapine,a significant increase in the AUC of nevirapine was observed in onesubject with Child-Pugh and ascites suggesting that patients withworsening hepatic function and ascites may be at risk of accumulatingnevirapine in the systemic circulation. Because nevirapine inducesits own metabolism with multiple dosing, this single-dose trial maynot reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.Do not administer nevirapine to patientswith moderate or severe (Child-Pugh Class or C, respectively) hepaticimpairment [see Contraindications (4), Warnings and Precautions (5.1),and Use in Specific Populations (8.7)].. GenderIn the multinational 2NN trial, population pharmacokineticsubstudy of 1077 subjects was performed that included 391 females.Female subjects showed 13.8% lower clearance of nevirapine thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of nevirapine, the effect of gender cannotsolely be explained by body size.. RaceAn evaluation of nevirapine plasma concentrations (pooleddata from several clinical trials) from HIV-1-infected subjects (27Black, 24 Hispanic, 189 Caucasian) revealed no marked difference innevirapine steady-state trough concentrations (median Cminss 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mLCaucasian) with long-term nevirapine treatment at 400 mg per day.However, the pharmacokinetics of nevirapine have not been evaluatedspecifically for the effects of ethnicity.Black subjects (n=80/group) in Trial 1100.1486 showedapproximately 30% to 35% higher trough concentrations than Caucasiansubjects (250-325 subjects/group) in both immediate-release VIRAMUNEand VIRAMUNE XR treatment groups over 96 weeks of treatment at 400mg per day.. Geriatric SubjectsNevirapine pharmacokinetics in HIV-1-infectedadults do not appear to change with age (range 18-68 years); however,nevirapine has not been extensively evaluated in subjects beyond theage of 55 years [see Use in Specific Populations (8.5)].. Pediatric SubjectsPharmacokinetic data for nevirapine havebeen derived from two sources: 48-week pediatric trial in SouthAfrica (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naivesubjects aged months to 16 years; and consolidated analysis offive Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising495 subjects aged 14 days to 19 years.BI Trial 1100.1368 studied the safety, efficacy, andpharmacokinetics of weight-based and body surface area (BSA)-baseddosing regimen of nevirapine. In the weight-based regimen, pediatricsubjects up to years of age received dose of mg/kg once dailyfor two weeks followed by mg per kg twice daily thereafter. Subjects8 years and older were dosed mg/kg once daily for two weeks followedby mg/kg twice daily thereafter. In the BSA regimen, all pediatricsubjects received 150 mg/m2 once dailyfor two weeks followed by 150 mg/m2 twicedaily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)]. Dosing of nevirapine at150 mg/m2 BID (after two-week lead-inof 150 mg/m2 QD) produced geometric meanor mean trough nevirapine concentrations between 4-6 mcg per mL (astargeted from adult data). In addition, the observed trough nevirapineconcentrations were comparable between the two dosing regimens studied(BSA- and weight-based methods).The consolidated analysis of Pediatric AIDS Clinical Trials Group(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluationof pediatric subjects less than months of age (n=17). The plasmanevirapine concentrations observed were within the range observedin adults and the remainder of the pediatric population, but weremore variable between subjects, particularly in the second month ofage. For dose recommendations for pediatric patients [seeDosage and Administration (2.2)].. Drug Interactions [see DrugInteractions (7)]Nevirapine induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE anddrugs primarily metabolized by CYP3A or CYP2B6 may result in decreasedplasma concentrations of these drugs and attenuate their therapeuticeffects.While primarily an inducerof cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibitthis system. Among human hepatic cytochrome P450s, nevirapine wascapable in vitro of inhibiting the 10-hydroxylationof (R)-warfarin (CYP3A). The estimated Ki forthe inhibition of CYP3A was 270 micromolar, concentration that isunlikely to be achieved in patients as the therapeutic range is lessthan 25 micromolar. Therefore, nevirapine may have minimal inhibitoryeffect on other substrates of CYP3A.Nevirapine does not appear to affect the plasma concentrationsof drugs that are substrates of other CYP450 enzyme systems, suchas 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.Table (see below) contains the results of drug interactiontrials performed with VIRAMUNE and other drugs likely to be co-administered.The effects of VIRAMUNE on the AUC, Cmax, andCmin of co-administered drugs are summarized.Table Drug Interactions: Changes in PharmacokineticParameters for Co-administered Drug in the Presence of VIRAMUNE (Allinteraction trials were conducted in HIV-1 positive subjects) Cmin below detectable levelof the assay Increase, Decrease, <=> No Effect For information regarding clinicalrecommendations, see Drug Interactions (7) b Pediatricsubjects ranging in age from months to 12 years. Parallel group design; for VIRAMUNE+lopinavir/ritonavir,n for lopinavir/ritonavir alone. Parallel group design; n=23 for atazanavir/ritonavir nevirapine,n=22 for atazanavir/ritonavir without nevirapine. Changes in atazanavirPK are relative to atazanavir/ritonavir 300/100 mg alone. Based on between-trial comparison. Based on historical controls.Co-administeredDrugDose of Co-administeredDrugDose Regimen ofVIRAMUNEn% Change of Co-administered Drug Pharmacokinetic Parameters (90%CI)AntiretroviralsAUCCmax Cmin Atazanavir/Ritonavira, 300/100 mg QDday4-13, then 400/100 mg QD, day 14-23200 mg BID day 1-23. Subjectswere treated with nevirapine prior to trial entry.23Atazanavir300/100mg42(52 to 29) Atazanavir300/100mg 28(40 to 14) Atazanavir300/100mg 72(80 to 60) Atazanavir400/100mg 19 (35 to 2) Atazanavir400/100mg 2(15 to 24) Atazanavir400/100mg 59 (73 to 40) Darunavir/Ritonavire 400/100 mg BID200 mg BID824 (3 to 57) 40 (14 to 73) (21 to 32) Didanosine100-150 mg BID200 mg QD 14 days; 200 mg BID 14 days18<=><=>Efavirenza 600 mg QD200 mg QD 14 days; 400 mg QD 14 days1728(34 to 14)12(23 to 1)32(35 to 19)Fosamprenavir1400 mg BID200 mg BID. Subjects were treated withnevirapine prior to trial entry.1733 (45 to 20) 25 (37 to 10) 35 (50 to 15) Fosamprenavir/Ritonavir700/100 mg BID200 mg BID. Subjects were treated withnevirapine prior to trial entry.1711(23 to 3) <=> 19 (32 to 4) Indinavira 800 mg q8H200 mg QD 14 days; 200 mg BID 14 days1931(39 to 22)15(24 to 4)44(53 to 33)Lopinavira, 300/75 mg/m2 (lopinavir/ritonavir) 7 mg/kg or mg/kg QD 2 weeks; BID 1week12, 15 22(44 to 9)14(36 to 16)55(75 to 19)Lopinavira 400/100 mg BID (lopinavir/ritonavir)200 mg QD 14 days; 200 mg BID >1 year22, 19 27(47 to 2)19(38 to 5)51(72 to 26)Maravirocf 300 mg SD200 mg BID81 (35 to 55)54 (6 to 151)<=> Nelfinavira 750 mg TID200 mg QD 14 days; 200 mg BID 14 days23<=><=>32(50 to 5)Nelfinavir-M8 metabolite62(70 to 53)59(68 to 48)66(74 to 55)Ritonavir600 mg BID200 mg QD 14 days; 200 mg BID 14 days18<=><=><=>Stavudine30-40 mg BID200 mg QD 14 days; 200 mg BID 14 days22<=><=>Zalcitabine0.125-0.25 mg TID200 mg QD 14 days; 200 mg BID 14 days6<=><=>Zidovudine100-200 mg TID200 mg QD 14 days; 200 mg BID 14 days1128(40 to 4)30(51 to 14)Other MedicationsAUCCmax Cmin Clarithromycina 500 mg BID200 mg QD 14 days; 200 mg BID 14 days1531(38 to 24)23(31 to 14)56(70 to 36)Metabolite 14-OH-clarithromycin42(16 to 73)47(21 to 80)<=>Ethinyl Estradiola and Norethindronea 0.035 mg(as Ortho-Novum(R) 1/35)200 mg QD 14 days; 200 mgBID 14 days1020(33 to 3)<=>1 mg(as Ortho-Novum(R) 1/35)19(30 to 7)16(27 to 3)Depomedroxy-Progesterone Acetate150 mg every months200 mg QD 14 days; 200 mg BID 14 days32<=><=><=>Fluconazole200 mg QD200 mg QD 14 days; 200 mg BID 14 days19<=><=><=>Ketoconazolea 400 mg QD200 mg QD 14 days; 200 mg BID 14 days2172(80 to 60)44(58 to 27)Methadonea Individual Subject Dosing200 mg QD 14 days; 200 mg BID >=7 days9In controlled pharmacokinetictrial with subjects receiving chronic methadone to whom steady-statenevirapine therapy was added, the clearance of methadone was increasedby 3-fold, resulting in symptoms of withdrawal, requiring dose adjustmentsin 10 mg segments, in of the subjects. Methadone did not haveany effect on nevirapine clearance.Rifabutina 150 or 300 mg QD200 mg QD 14 days; 200 mg BID 14 days1917(2 to 40)28(9 to 51)<=>Metabolite25-O-desacetyl-rifabutin24(16 to 84)29(2 to 68)22(14 to 74)Rifampina 600 mg QD200 mg QD 14 days; 200 mg BID x14 days1411(4 to 28)<=>Because of the design of the druginteraction trials (addition of 28 days of VIRAMUNE therapy to existingHIV-1 therapy), the effect of the concomitant drug on plasma nevirapinesteady-state concentrations was estimated by comparison to historicalcontrols.Administration of rifampinhad clinically significant effect on nevirapine pharmacokinetics,decreasing AUC and Cmax by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein nevirapine exposure, based on comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table on nevirapine pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and nevirapine.

SPL MEDGUIDE SECTION.

This Medication Guide has been approvedby the U.S. Food and Drug AdministrationRevised: October 2019MEDICATIONGUIDEVIRAMUNE(R) (VIH-rah-mune)(nevirapine)oral suspensionVIRAMUNE(R) (VIH-rah-mune)(nevirapine)tabletsVIRAMUNE XR(R) (VIH-rah-mune)(nevirapine)extended-release tabletsWhat is the most importantinformation should know about VIRAMUNEVIRAMUNE can cause severe liver and skin problems that may lead todeath. These problems can happen at any time during treatment, butyour risk is higher during the first 18 weeks of treatment.VIRAMUNE can cause serious side effects, including:Severe liver problems. Some people taking VIRAMUNEmay develop severe liver problems that can lead to liver failure andthe need for liver transplant, or death. If you have liver problemsyou may get rash.Women have higher risk of developing liver problems duringtreatment with VIRAMUNE than men.People who have abnormal liver test results before startingVIRAMUNE and people with hepatitis or also have greater riskof getting liver problems. People who have higherCD4+ cell counts when they begin VIRAMUNEhave higher risk of liver problems, especially: Women with CD4+ counts higherthan 250 cells/mm3. This group has thehighest risk.Men with CD4+ counts higher than400 cells/mm3. Stop takingVIRAMUNE and call your doctor right away if you have any of the followingsymptoms of liver problems with or without skin rash: dark (tea colored) urinelight-colored bowel movements (stools)feeling sick to your stomach (nausea)pain or tenderness on your right side below your ribsloss of appetiteyellowing of your skin or whites of your eyesfeverfeel unwell or like you have the flutirednessSevere skin reactions and rash. Some skinreactions and rashes may be severe, life-threatening, and in somepeople, may lead to death. Most severe skin reactions and rashes happenin the first weeks of treatment with VIRAMUNE.Women have higher risk of developing rash during treatmentwith VIRAMUNE than men. Stop taking VIRAMUNE andcall your doctor right away if you get rash with any of the followingsymptoms: blistersred or inflamed eyes, like pink eye (conjunctivitis)swelling of your facefeel unwell or like you have the flumuscle or joint achesmouth soresfevertirednessYour doctor should do blood tests often to check your liverfunction and check for severe skin reactions during the first 18 weeksof treatment with VIRAMUNE. You should continue to see your doctorand have your liver checked regularly during your treatment with VIRAMUNE.It is important for you to keep all of your doctor appointments.If your doctor tells you to stop treatment with VIRAMUNEbecause you have had any of the severe liver or skin symptoms listedabove, you should never take VIRAMUNE again.See What are the possible side effects of VIRAMUNEfor more information about side effects.What is VIRAMUNEVIRAMUNE tablets and VIRAMUNE oral solution are prescriptionHIV-1 medicines used with other HIV-1 medicines to treat HIV-1 (HumanImmunodeficiency Virus 1) in adults and in children 15 days of ageor older. HIV-1 is the virus that causes AIDS (Acquired Immune DeficiencySyndrome).VIRAMUNE XR extended-release tablets is prescriptionmedicine used with other HIV-1 medicines to treat HIV-1 (Human ImmunodeficiencyVirus 1) in adults and in children years of age or older based onthe childs weight and height.If you are woman with CD4+ countshigher than 250 cells/mm3 or man withCD4+ counts higher than 400 cells/mm3, you and your doctor will decide if starting VIRAMUNEis right for you.VIRAMUNE XR extended-release tablets are not recommendedfor use in children less than years of age. Do not takeVIRAMUNE:if you have liver problems.as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens. VIRAMUNE is only for people diagnosedwith HIV-1. If you have not been diagnosed as HIV positive, then donot take VIRAMUNE.Before takingVIRAMUNE, tell your doctor about all your or your childs medicalconditions, including if you or your child:have or have had hepatitis (inflammation of your liver)or problems with your liver. See What is the most importantinformation should know about VIRAMUNE receive dialysishave trouble swallowing pillsare pregnant or plan to become pregnant. It is not knownif VIRAMUNE will harm your unborn baby. PregnancyRegistry: There is pregnancy registry for women who takeVIRAMUNE during pregnancy. The purpose of the registry is to collectinformation about the health of you and your baby. Talk to your doctorabout how you can take part in this registry.are breastfeeding or plan to breastfeed. VIRAMUNE can passinto your breast milk and may harm your baby. You should not breastfeedif you have HIV-1 because of the risk of passing HIV-1 to your baby.Do not breastfeed during treatment with VIRAMUNE. Talk to your doctorabout the best way to feed your baby.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins andherbal supplements. Especially tell your doctor if you takeSt. Johns wort.Some medicines interact with VIRAMUNE. Keep list of yourmedicines to show your doctor or pharmacist.You can ask your doctor or pharmacist for list of medicinesthat interact with VIRAMUNE.Do not start taking new medicine without tellingyour doctor. Your doctor can tell you if it is safe to takeVIRAMUNE with other medicines.How shouldI take VIRAMUNETake VIRAMUNE exactly as your doctor tells you totake it. Do not change your dose unless your doctor tells you to.VIRAMUNE is always taken in combination with other antiretroviralmedicines.VIRAMUNE comes in three different forms. Your doctor willprescribe the form of VIRAMUNE that is right for you.VIRAMUNE tabletsVIRAMUNE oral suspensionVIRAMUNE XR extended-release tablets You should not take more than one form of VIRAMUNE at thesame time. Talk to your doctor if you have any questions.If your child is prescribed VIRAMUNE, your childs doctorwill tell you exactly how VIRAMUNE should be taken.VIRAMUNE can be taken with or without food.Swallow VIRAMUNE XR extended-release tablets whole. Do notchew, crush, or divide VIRAMUNE XR extended-release tablets.Do not miss dose of VIRAMUNE. If you miss dose of VIRAMUNE,take the missed dose as soon as you remember. If it is almost timefor your next dose, do not take the missed dose. You should take thenext dose at your regular time. Do not take doses at the same time.If you stop taking VIRAMUNE for more than days, ask yourdoctor how much to take before you start taking it again. You mayneed to begin taking the VIRAMUNE starting dose again, which is taken1 time each day for 14 days.Starting VIRAMUNEtablets:Your doctor should start you with dose each day to loweryour chance of getting serious rash. It is important thatyou only take dose of VIRAMUNE each day for the first 14 days. Call your doctor right away if you get skin rashduring the first 14 days of VIRAMUNE treatment.Do not increase your dose to times day if youhave rash.You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of VIRAMUNE. Day 15, you will take VIRAMUNE tablet times day.Starting VIRAMUNEXR extended-release tablets when this is the first time you are takingany form of VIRAMUNE:Your doctor should start you with dose of VIRAMUNE tabletsor oral suspension each day to lower your risk of getting seriousrash. It is important that you only take dose of VIRAMUNEeach day for the first 14 days. Call your doctor right away if you get skin rashduring the first 14 days of VIRAMUNE treatment.You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of VIRAMUNE.Do not start VIRAMUNE XR extended-release tabletsif you have rash. Day 15, take VIRAMUNE XR extended-release tablets timea day as prescribed by your doctor.Switching from VIRAMUNE tablets or oral suspension toVIRAMUNE XR extended-release tablets:Take VIRAMUNE XR extended-release tablets time day asprescribed by your doctor.You may sometimes pass soft mass in your stools (bowelmovement) that looks like your VIRAMUNE XR extended-release tablets.This will not affect the way your medicine works.If you take VIRAMUNE oral suspension:If you or your child takes VIRAMUNE oral suspension (liquid),shake it gently before each use. Use an oral dosing syringe or dosingcup to measure the right dose. The oral dosing syringe and dosingcup are not provided with VIRAMUNE oral suspension. Ask your pharmacistfor syringe or cup if you do not have one.After drinking the medicine, fill the dosing cup with waterand drink it to make sure you get all the medicine.If the dose is less than teaspoon (5 mL), use the syringeinstead of the dosing cup.What are thepossible side effects of VIRAMUNEVIRAMUNEmay cause serious side effects, including:See What is the most important information should know about VIRAMUNEChanges in your immune system (Immune ReconstitutionSyndrome) can happen when you start taking HIV-1 medicines.Your immune system may get stronger and begin to fight infectionsthat have been hidden in your body for long time. Tell your doctorright away if you start having new symptoms after starting your HIV-1medicine.Changes in body fat can happen in people whotake HIV-1 medicines. These changes may include increased amount offat in the upper back and neck (buffalo hump), breast, and aroundthe middle of your body (trunk). Loss of fat from your legs, arms,and face may also happen. The exact cause and long-term health effectsof these conditions are not known.The most common side effect of VIRAMUNE is rash.VIRAMUNE may cause decreased fertility in females. Talkto your doctor if you have concerns about fertility.Theseare not all the possible side effects of VIRAMUNE. For more information,ask your doctor or pharmacist.Call your doctor for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How shouldI store VIRAMUNEStore VIRAMUNE at room temperature between 68F to 77F(20C to 25C).Keep VIRAMUNE and all medicines out of the reach of children.General informationabout the safe and effective use of VIRAMUNE.Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use VIRAMUNE for condition for which itwas not prescribed. Do not give VIRAMUNE to other people, even ifthey have the same condition you have. It may harm them. You can askyour pharmacist or doctor for information about VIRAMUNE that is writtenfor health professionals.What are the ingredientsin VIRAMUNEActive ingredient: nevirapine Inactive ingredients: VIRAMUNE tablets: microcrystalline cellulose, lactose monohydrate, povidone, sodiumstarch glycolate, colloidal silicon dioxide, and magnesium stearate VIRAMUNE oral suspension: carbomer 934P, methylparaben,propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide,and purified water VIRAMUNE XR tablets: lactosemonohydrate, hypromellose, iron oxide, and magnesium stearate For current prescribing information for VIRAMUNE orVIRAMUNE XR, scan the codes below or for additional information youmay also call Boehringer Ingelheim Pharmaceuticals, Inc., at 1-800-542-6257,(TTY) 1-800-459-9906.VIRAMUNE tablets and oralsuspensionVIRAMUNE XR extended-release tabletsCopyright (C) 2019 BoehringerIngelheim International GmbH.Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877,USAProduct and trademark licensed from: Boehringer IngelheimInternational GmbHALL RIGHTS RESERVEDOT1801ABJ022019. Severe liver problems. Some people taking VIRAMUNEmay develop severe liver problems that can lead to liver failure andthe need for liver transplant, or death. If you have liver problemsyou may get rash.Women have higher risk of developing liver problems duringtreatment with VIRAMUNE than men.People who have abnormal liver test results before startingVIRAMUNE and people with hepatitis or also have greater riskof getting liver problems. People who have higherCD4+ cell counts when they begin VIRAMUNEhave higher risk of liver problems, especially: Women with CD4+ counts higherthan 250 cells/mm3. This group has thehighest risk.Men with CD4+ counts higher than400 cells/mm3. Stop takingVIRAMUNE and call your doctor right away if you have any of the followingsymptoms of liver problems with or without skin rash: Women have higher risk of developing liver problems duringtreatment with VIRAMUNE than men.. People who have abnormal liver test results before startingVIRAMUNE and people with hepatitis or also have greater riskof getting liver problems. People who have higherCD4+ cell counts when they begin VIRAMUNEhave higher risk of liver problems, especially: Women with CD4+ counts higherthan 250 cells/mm3. This group has thehighest risk.. Men with CD4+ counts higher than400 cells/mm3. Stop takingVIRAMUNE and call your doctor right away if you have any of the followingsymptoms of liver problems with or without skin rash: dark (tea colored) urine. light-colored bowel movements (stools). feeling sick to your stomach (nausea). pain or tenderness on your right side below your ribs. loss of appetite. yellowing of your skin or whites of your eyes. fever. feel unwell or like you have the flu. tiredness. Severe skin reactions and rash. Some skinreactions and rashes may be severe, life-threatening, and in somepeople, may lead to death. Most severe skin reactions and rashes happenin the first weeks of treatment with VIRAMUNE.Women have higher risk of developing rash during treatmentwith VIRAMUNE than men. Stop taking VIRAMUNE andcall your doctor right away if you get rash with any of the followingsymptoms: Women have higher risk of developing rash during treatmentwith VIRAMUNE than men. Stop taking VIRAMUNE andcall your doctor right away if you get rash with any of the followingsymptoms: blisters. red or inflamed eyes, like pink eye (conjunctivitis). swelling of your face. feel unwell or like you have the flu. muscle or joint aches. mouth sores. fever. tiredness. Your doctor should do blood tests often to check your liverfunction and check for severe skin reactions during the first 18 weeksof treatment with VIRAMUNE. You should continue to see your doctorand have your liver checked regularly during your treatment with VIRAMUNE.It is important for you to keep all of your doctor appointments.. If your doctor tells you to stop treatment with VIRAMUNEbecause you have had any of the severe liver or skin symptoms listedabove, you should never take VIRAMUNE again.. If you are woman with CD4+ countshigher than 250 cells/mm3 or man withCD4+ counts higher than 400 cells/mm3, you and your doctor will decide if starting VIRAMUNEis right for you.. VIRAMUNE XR extended-release tablets are not recommendedfor use in children less than years of age.. if you have liver problems.. as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens. VIRAMUNE is only for people diagnosedwith HIV-1. If you have not been diagnosed as HIV positive, then donot take VIRAMUNE.. have or have had hepatitis (inflammation of your liver)or problems with your liver. See What is the most importantinformation should know about VIRAMUNE receive dialysis. have trouble swallowing pills. are pregnant or plan to become pregnant. It is not knownif VIRAMUNE will harm your unborn baby. PregnancyRegistry: There is pregnancy registry for women who takeVIRAMUNE during pregnancy. The purpose of the registry is to collectinformation about the health of you and your baby. Talk to your doctorabout how you can take part in this registry.. are breastfeeding or plan to breastfeed. VIRAMUNE can passinto your breast milk and may harm your baby. You should not breastfeedif you have HIV-1 because of the risk of passing HIV-1 to your baby.Do not breastfeed during treatment with VIRAMUNE. Talk to your doctorabout the best way to feed your baby.. Some medicines interact with VIRAMUNE. Keep list of yourmedicines to show your doctor or pharmacist.. You can ask your doctor or pharmacist for list of medicinesthat interact with VIRAMUNE.. Do not start taking new medicine without tellingyour doctor. Your doctor can tell you if it is safe to takeVIRAMUNE with other medicines.. Take VIRAMUNE exactly as your doctor tells you totake it. Do not change your dose unless your doctor tells you to.. VIRAMUNE is always taken in combination with other antiretroviralmedicines.. VIRAMUNE comes in three different forms. Your doctor willprescribe the form of VIRAMUNE that is right for you.VIRAMUNE tabletsVIRAMUNE oral suspensionVIRAMUNE XR extended-release tablets VIRAMUNE tablets. VIRAMUNE oral suspension. VIRAMUNE XR extended-release tablets. You should not take more than one form of VIRAMUNE at thesame time. Talk to your doctor if you have any questions.. If your child is prescribed VIRAMUNE, your childs doctorwill tell you exactly how VIRAMUNE should be taken.. VIRAMUNE can be taken with or without food.. Swallow VIRAMUNE XR extended-release tablets whole. Do notchew, crush, or divide VIRAMUNE XR extended-release tablets.. Do not miss dose of VIRAMUNE. If you miss dose of VIRAMUNE,take the missed dose as soon as you remember. If it is almost timefor your next dose, do not take the missed dose. You should take thenext dose at your regular time. Do not take doses at the same time.. If you stop taking VIRAMUNE for more than days, ask yourdoctor how much to take before you start taking it again. You mayneed to begin taking the VIRAMUNE starting dose again, which is taken1 time each day for 14 days.. Your doctor should start you with dose each day to loweryour chance of getting serious rash. It is important thatyou only take dose of VIRAMUNE each day for the first 14 days. Call your doctor right away if you get skin rashduring the first 14 days of VIRAMUNE treatment.Do not increase your dose to times day if youhave rash.You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of VIRAMUNE. Call your doctor right away if you get skin rashduring the first 14 days of VIRAMUNE treatment.. Do not increase your dose to times day if youhave rash.. You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of VIRAMUNE.. Day 15, you will take VIRAMUNE tablet times day.. Your doctor should start you with dose of VIRAMUNE tabletsor oral suspension each day to lower your risk of getting seriousrash. It is important that you only take dose of VIRAMUNEeach day for the first 14 days. Call your doctor right away if you get skin rashduring the first 14 days of VIRAMUNE treatment.You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of VIRAMUNE.Do not start VIRAMUNE XR extended-release tabletsif you have rash. Call your doctor right away if you get skin rashduring the first 14 days of VIRAMUNE treatment.. You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of VIRAMUNE.. Do not start VIRAMUNE XR extended-release tabletsif you have rash.. Day 15, take VIRAMUNE XR extended-release tablets timea day as prescribed by your doctor.. Take VIRAMUNE XR extended-release tablets time day asprescribed by your doctor.. You may sometimes pass soft mass in your stools (bowelmovement) that looks like your VIRAMUNE XR extended-release tablets.This will not affect the way your medicine works.. If you or your child takes VIRAMUNE oral suspension (liquid),shake it gently before each use. Use an oral dosing syringe or dosingcup to measure the right dose. The oral dosing syringe and dosingcup are not provided with VIRAMUNE oral suspension. Ask your pharmacistfor syringe or cup if you do not have one.. After drinking the medicine, fill the dosing cup with waterand drink it to make sure you get all the medicine.. If the dose is less than teaspoon (5 mL), use the syringeinstead of the dosing cup.. Changes in your immune system (Immune ReconstitutionSyndrome) can happen when you start taking HIV-1 medicines.Your immune system may get stronger and begin to fight infectionsthat have been hidden in your body for long time. Tell your doctorright away if you start having new symptoms after starting your HIV-1medicine.. Changes in body fat can happen in people whotake HIV-1 medicines. These changes may include increased amount offat in the upper back and neck (buffalo hump), breast, and aroundthe middle of your body (trunk). Loss of fat from your legs, arms,and face may also happen. The exact cause and long-term health effectsof these conditions are not known.. Store VIRAMUNE at room temperature between 68F to 77F(20C to 25C).. viramune-tablets-and-oral-suspension-qr-code. viramune-xr-qr-code.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Women infected with HIV-1 should be instructednot to breastfeed due to the potential for HIV-1 transmission. (8.2) No dose adjustment is required for patients with renal impairmentwith creatinine clearance greater than or equal to 20 mL per min.Patients on dialysis receive an additional dose of 200 mg followingeach dialysis treatment. (2.4, 8.6) Monitor patients with hepatic fibrosis or cirrhosis carefullyfor evidence of drug-induced toxicity. Do not administer VIRAMUNEto patients with Child-Pugh or C. (5.1, 8.7) Lactation: Women infected with HIV-1 should be instructednot to breastfeed due to the potential for HIV-1 transmission. (8.2) No dose adjustment is required for patients with renal impairmentwith creatinine clearance greater than or equal to 20 mL per min.Patients on dialysis receive an additional dose of 200 mg followingeach dialysis treatment. (2.4, 8.6) Monitor patients with hepatic fibrosis or cirrhosis carefullyfor evidence of drug-induced toxicity. Do not administer VIRAMUNEto patients with Child-Pugh or C. (5.1, 8.7) 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposureregistry that monitors pregnancy outcomes in women exposed to nevirapineduring pregnancy. Healthcare providers are encouraged to registerpatients by calling the Antiretroviral Pregnancy Registry (APR) at1-800-258-4263.Risk SummaryAvailable data from the APR show no differencein the risk of overall major birth defects for nevirapine comparedwith the background rate for major birth defects of 2.7% in the U.S.reference population of the Metropolitan Atlanta Congenital DefectsProgram (MACDP) [see Data]. The rate of miscarriage is not reported in the APR. Theestimated background rate of miscarriage in clinically recognizedpregnancies in the U.S. general population is 15-20%. The backgroundrisk of birth defects and miscarriage for the indicated populationis unknown. Methodological limitations of the APR include the useof MACDP as the external comparator group. The MACDP population isnot disease-specific, evaluates women and infants from limited geographicarea, and does not include outcomes for births that occurred at <20weeks gestation.In literature reports, immediate-release nevirapine exposure (Cmin) can be up to 29% lower during pregnancy. However,as this reduction was not found to be clinically meaningful, doseadjustment is not necessary [see Data].There is risk for severe hepatic events in pregnant women exposedto VIRAMUNE [see Clinical Considerations]. In animal reproduction studies, no evidence of adversedevelopmental outcomes were observed following oral administrationof nevirapine during organogenesis in the rat and rabbit, at systemicexposures (AUC) to nevirapine approximately equal (rats) and 50% higher(rabbits) than the exposure in humans at the recommended 400 mg dailydose [see Data]. Clinical ConsiderationsMaternal adverse reactionsSevere hepaticevents, including fatalities, have been reported in pregnant womenreceiving chronic VIRAMUNE therapy as part of combination treatmentof HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate VIRAMUNE unless the benefit outweighsthe risk. It is unclear if pregnancy augments the risk observed innon-pregnant women [see Warnings and Precautions (5.1)]. DataHuman DataBased on prospectivereports to the APR of over 2600 exposures to nevirapine during pregnancyresulting in live births (including over 1100 exposed in the firsttrimester), there was no difference between nevirapine and overallbirth defects compared with the background birth defect rate of 2.7%in the U.S. reference population of the MACDP. The prevalence of birthdefects in live births was 2.8% (95% CI: 1.9 %, 4.0%) following firsttrimester exposure to nevirapine-containing regimens and 3.2% (95%CI: 2.4%, 4.3%) for second/third trimester exposure to nevirapine-containingregimens. Thereare several literature reports of chronic administration of immediate-releasenevirapine during pregnancy, in which nevirapine pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in nevirapine Cmin duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.Animal DataNevirapine was administered orally to pregnantrats (at 0, 12.5, 25, and 50 mg per kg per day) and rabbits (at 0,30, 100, and 300 mg per kg per day) through organogenesis (on gestationdays through 16, and through 18, respectively). No adverse developmentaleffects were observed at doses producing systemic exposures (AUC)approximately equivalent to (rats) or approximately 50% higher (rabbits)than human exposure at the recommended daily dose. In rats, decreasedfetal body weights were observed at maternally toxic dose at anexposure approximately 50% higher than the recommended daily dose.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Preventionrecommend that HIV-1 infected mothers in the United States not breastfeedtheir infants to avoid risking postnatal transmission of HIV-1 infection.Published data report that nevirapine is present in human milk [see Data]. Thereare limited data on the effects of nevirapine on the breastfed infant.There is no information on the effects of nevirapine on milk production.Because of the potential for (1) HIV-1 transmission (in HIV-negativeinfants), (2) developing viral resistance (in HIV-positive infants),and (3) serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving VIRAMUNE.DataBased on five publications,immediate-release nevirapine was excreted in breast-milk at medianconcentrations ranging from 4080 to 6795 ng/mL, and the median maternalbreast-milk to maternal plasma concentration ratio range was 59 to88%. Reported infant nevirapine median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated nevirapine doseof 704 to 682 ug/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended nevirapine dose for infants.Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to nevirapine through breastmilk.. 8.3 Females and Malesof Reproductive Potential. InfertilityLimited human dataare insufficient to determine the risk of infertility in humans. Basedon results from animal fertility studies conducted in rats, VIRAMUNEmay reduce fertility in females of reproductive potential. It is notknown if these effects on fertility are reversible [see NonclinicalToxicology (13.1)]. 8.4 Pediatric Use. Thesafety, pharmacokinetic profile, and virologic and immunologic responsesof VIRAMUNE have been evaluated in HIV-1 infected pediatric subjectsage months to 18 years [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. The safety and pharmacokineticprofile of VIRAMUNE has been evaluated in HIV-1 infected pediatricsubjects age 15 days to less than months [see Adverse Reactions (6.1) and Clinical Studies (14.2)].The most frequently reported adverse events relatedto VIRAMUNE in pediatric subjects were similar to those observed inadults, with the exception of granulocytopenia, which was more commonlyobserved in children receiving both zidovudine and VIRAMUNE [see Adverse Reactions (6.1) andClinical Studies (14.2)].. 8.5 Geriatric Use. Clinicaltrials of VIRAMUNE did not include sufficient numbers of subjectsaged 65 and older to determine whether elderly subjects respond differentlyfrom younger subjects. In general, dose selection for an elderly patientshould be cautious, reflecting the greater frequency of decreasedhepatic, renal or cardiac function, and of concomitant disease orother drug therapy.. 8.6 Renal Impairment. In subjects with renal impairment (mild,moderate or severe), there were no significant changes in the pharmacokineticsof nevirapine. Nevirapine is extensively metabolized by the liverand 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 CrClgreater than or equal to 20 mL per min. The pharmacokinetics of nevirapinehave not been evaluated in patients with CrCl less than 20 mL permin. In patients undergoing chronic hemodialysis, an additional 200mg dose following each dialysis treatment is indicated [seeDosage and Administration (2.4) andClinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. Because increased nevirapine levels andnevirapine accumulation may be observed in patients with serious liverdisease, do not administer VIRAMUNE to patients with moderate or severe(Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4), Warningsand Precautions (5.1), and ClinicalPharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Monitor patients for immune reconstitution syndrome andfat redistribution. (5.5, 5.6) Monitor patients for immune reconstitution syndrome andfat redistribution. (5.5, 5.6) 5.1 Hepatotoxicity andHepatic Impairment. Severe,life-threatening, and in some cases fatal hepatotoxicity, includingfulminant and cholestatic hepatitis, hepatic necrosis and hepaticfailure, have been reported in patients treated with VIRAMUNE. Incontrolled clinical trials, symptomatic hepatic events regardlessof severity occurred in 4% (range 0% to 11%) of subjects who receivedVIRAMUNE and 1% of subjects in control groups.The risk of symptomatic hepatic events regardless ofseverity was greatest in the first weeks of therapy. The risk continuedto be greater in the VIRAMUNE groups compared to controls through18 weeks of treatment. However, hepatic events may occur at any timeduring 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 initiallyabnormal serum transaminase levels. Rash was observed in approximatelyhalf of the subjects with symptomatic hepatic adverse events. Feverand flu-like symptoms accompanied some of these hepatic events. Someevents, particularly those with rash and other symptoms, have progressedto hepatic failure with transaminase elevation, with or without hyperbilirubinemia,hepatic encephalopathy, prolonged partial thromboplastin time, oreosinophilia. Rhabdomyolysis has been observed in some patients experiencingskin and/or liver reactions associated with VIRAMUNE use. Hepatitis/hepaticfailure may be associated with signs of hypersensitivity which caninclude severe rash or rash accompanied by fever, general malaise,fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction. Patients with signs or symptoms of hepatitis mustbe advised to discontinue VIRAMUNE and immediately seek medical evaluation,which should include liver enzyme tests.The first 18 weeks of therapy with VIRAMUNEare critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateninghepatic events. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout VIRAMUNE treatment. Transaminases should be checked immediately if patientexperiences signs or symptoms suggestive of hepatitis and/or hypersensitivityreaction. Transaminases should also be checked immediately for allpatients who develop rash in the first 18 weeks of treatment. Physiciansand patients should be vigilant for the appearance of signs or symptomsof hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice,bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Thediagnosis of hepatotoxicity should be considered in this setting,even if transaminases are initially normal or alternative diagnosesare possible [see Dosage and Administration (2.3)].If clinical hepatitis or transaminase elevations combinedwith rash or other systemic symptoms occur, permanently discontinueVIRAMUNE. Do not restart VIRAMUNE after recovery. In some cases, hepaticinjury progresses despite discontinuation of treatment.The patients at greatest risk of hepaticevents, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first weeksof treatment, women have 3-fold higher risk than men for symptomatic,often rash-associated, hepatic events (6% versus 2%), and patientswith higher CD4+ cell counts at initiationof VIRAMUNE therapy are at higher risk for symptomatic hepatic eventswith VIRAMUNE. In retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had 12-fold higher risk of symptomatic hepaticadverse 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 monitoredfor hepatotoxicity since symptomatic hepatic adverse events have beenreported at all CD4+ cell counts. Co-infectionwith hepatitis or and/or increased transaminase elevations atthe start of therapy with VIRAMUNE are associated with greater riskof later symptomatic events (6 weeks or more after starting VIRAMUNE)and asymptomatic increases in AST or ALT.In addition, serious hepatotoxicity (including liverfailure requiring transplantation in one instance) has been reportedin HIV-1 uninfected individuals receiving multiple doses of VIRAMUNEin the setting of post-exposure prophylaxis (PEP), an unapproved use.Use of VIRAMUNE for occupational and non-occupational PEP is contraindicated [see Contraindications (4)].Increased nevirapine troughconcentrations have been observed in some patients with hepatic fibrosisor cirrhosis. Therefore, carefully monitor patients with either hepaticfibrosis or cirrhosis for evidence of drug-induced toxicity. Do notadminister nevirapine to patients with moderate or severe (Child-PughClass or C, respectively) hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].. 5.2 Skin Reactions. Severe and life-threatening skin reactions,including fatal cases, have been reported, occurring most frequentlyduring the first weeks of therapy. These have included cases ofStevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivityreactions characterized by rash, constitutional findings, and organdysfunction including hepatic failure. Rhabdomyolysis has been observedin some patients experiencing skin and/or liver reactions associatedwith VIRAMUNE use. In controlled clinical trials, Grade and rasheswere reported during the first weeks in 2% of VIRAMUNE recipientscompared to less than 1% of placebo subjects.Patients developing signs or symptoms of severe skinreactions or hypersensitivity reactions (including, but not limitedto, severe rash or rash accompanied by fever, general malaise, fatigue,muscle or joint aches, blisters, oral lesions, conjunctivitis, facialedema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and renal dysfunction) must permanently discontinue VIRAMUNE and seekmedical evaluation immediately. Do not restart VIRAMUNE followingsevere skin rash, skin rash combined with increased transaminasesor other symptoms, or hypersensitivity reaction.The first 18 weeks of therapy with VIRAMUNEare critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateningskin reactions. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout VIRAMUNE treatment. In addition, the 14-day lead-inperiod with VIRAMUNE 200 mg daily dosing has been demonstrated toreduce the frequency of rash [see Dosage and Administration(2.1)].If patients present with suspected VIRAMUNE-associatedrash, measure transaminases immediately. Permanently discontinue VIRAMUNEin patients with rash-associated transaminase elevations [seeWarnings and Precautions (5.1)].Therapy with VIRAMUNE mustbe initiated with 14-day lead-in period of 200 mg per day (150 mg/m2 per day in pediatric patients), which has been shownto reduce the frequency of rash. Discontinue VIRAMUNE if patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase VIRAMUNE dose to patient experiencinga mild to moderate rash without constitutional symptoms during the14-day lead-in period of 200 mg per day (150 mg/m2/day in pediatric patients) until the rash has resolved. The totalduration of the once-daily lead-in dosing period must not exceed 28days at which point an alternative regimen should be sought [see Dosage and Administration (2.4)]. Patients must be monitored closely if isolated rash ofany severity occurs. Delay in stopping VIRAMUNE treatment after theonset of rash may result in more serious reaction.Women appear to be at higher risk than men of developingrash with VIRAMUNE.In clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of VIRAMUNE administration) was associated with an increase inincidence and severity of rash during the first weeks of VIRAMUNEtherapy. Therefore, use of prednisone to prevent VIRAMUNE-associatedrash is not recommended.. 5.3 Resistance. VIRAMUNE must not be used as single agentto treat HIV-1 or added on as sole agent to failing regimen. Resistantvirus emerges rapidly when nevirapine is administered as monotherapy.The choice of new antiretroviral agents to be used in combinationwith nevirapine should take into consideration the potential for crossresistance. When discontinuing an antiretroviral regimen containingVIRAMUNE, the long half-life of nevirapine should be taken into account;if antiretrovirals with shorter half-lives than VIRAMUNE are stoppedconcurrently, low plasma concentrations of nevirapine alone may persistfor week or longer and virus resistance may subsequently develop [see Microbiology (12.4)].. 5.4 Drug Interactions. See Table for listings of establishedand potential drug interactions [see Drug Interactions (7)].Concomitant use of St. Johns wort (Hypericumperforatum) or St. Johns wort-containing products and VIRAMUNEis not recommended. Co-administration of St. Johns wort with non-nucleosidereverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of VIRAMUNE and lead to loss of virologic responseand possible resistance to VIRAMUNE or to the class of NNRTIs. Co-administrationof VIRAMUNE and efavirenz is not recommended as this combination hasbeen associated with an increase in adverse reactions and no improvementin efficacy.. 5.5 Immune ReconstitutionSyndrome Immune reconstitutionsyndrome has been reported in patients treated with combination antiretroviraltherapy, including VIRAMUNE. During the initial phase of combinationantiretroviral treatment, patients whose immune system responds maydevelop an inflammatory response to indolent or residual opportunisticinfections (such as Mycobacterium avium infection,cytomegalovirus, Pneumocystis jiroveci pneumonia,or tuberculosis), which may necessitate further evaluation and treatment.Autoimmune disorders (such as Gravesdisease, polymyositis, and Guillain-Barre syndrome) have also beenreported to occur in the setting of immune reconstitution, however,the time to onset is more variable, and can occur many months afterinitiation of treatment.. 5.6 Fat Redistribution. Redistribution/accumulation of body fatincluding central obesity, dorsocervical fat enlargement (buffalohump), peripheral wasting, facial wasting, breast enlargement, andcushingoid appearance have been observed in patients receiving antiretroviraltherapy. The mechanism and long-term consequences of these eventsare currently unknown. causal relationship has not been established.