ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adult patients: The most common adverse reaction is rash.During the lead-in period with immediate-release VIRAMUNE, the incidenceof Grade or higher drug-related rash in adults is 3%. After thelead-in period the incidence of Grade or higher drug-related rashin subjects taking VIRAMUNE XR is 3%. The incidence of Grade orhigher drug-related clinical hepatitis after the lead-in phase was2%. (6.1) Pediatric patients: The incidence of Grade or higher drug-relatedrash was 1%. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adult patients: The most common adverse reaction is rash.During the lead-in period with immediate-release VIRAMUNE, the incidenceof Grade or higher drug-related rash in adults is 3%. After thelead-in period the incidence of Grade or higher drug-related rashin subjects taking VIRAMUNE XR is 3%. The incidence of Grade orhigher drug-related clinical hepatitis after the lead-in phase was2%. (6.1) Pediatric patients: The incidence of Grade or higher drug-relatedrash was 1%. (6.1) 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trialsof drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in clinicalpractice.Clinical Trial Experience in Adult PatientsThe most serious adverse reactions associatedwith nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome,toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepaticfailure may be isolated or associated with signs of hypersensitivitywhich may include severe rash or rash accompanied by fever, generalmalaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction [see BoxedWarning and Warnings and Precautions (5.1, 5.2)].The most common clinical toxicityof nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warningsand Precautions (5.2)]. Rash occurs most frequently within the first weeks of therapy.Rashes are usually mild to moderate, maculopapular erythematous cutaneouseruptions, with or without pruritus, located on the trunk, face andextremities. The safety databasein VIRAMUNE XR clinical trials contains data from 800 subjects treatedwith VIRAMUNE XR and 654 subjects treated with immediate release VIRAMUNE.. Trial 1100.1486 (VERxVE)In Trial 1100.1486 (VERxVE)treatment-naive subjects received lead-in dose of immediate-releaseVIRAMUNE 200 mg once daily for 14 days (n=1068) and then were randomizedto receive either immediate-release VIRAMUNE 200 mg twice daily (n=506)or VIRAMUNE XR 400 mg once daily (n=505). All subjects received tenofovir+ emtricitabine as background therapy. Subjects were enrolled withCD4+ counts less than 250 cells/mm3 for women and less than 400 cells/mm3 for men [see Indications and Usage (1)]. Data on potentialsymptoms of hepatic events were prospectively collected in this trial.The safety data include all subject visits up to the time of the lastsubjects completion of the 96-week endpoint in the trial (mean observationperiod 98 weeks).After the lead-inperiod, the incidence of any hepatic event was 9% in the immediate-releaseVIRAMUNE group and 6% in the VIRAMUNE XR group; the incidence of symptomatichepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE or ALT/AST elevation was 8% in both theimmediate-release VIRAMUNE group and VIRAMUNE XR group. Overall, therewas comparable incidence of symptomatic hepatic events among menand women enrolled in VERxVE.Severe or life-threatening rash considered to be related to nevirapinetreatment occurred in 1% of subjects during the lead-in phase withimmediate-release VIRAMUNE, and in 1% of subjects in either treatmentgroup during the randomization phase. In addition, six cases of Stevens-Johnsonsyndrome were reported in the trial; all but one occurred within thefirst 30 days of nevirapine treatment.No Grade or above adverse reactions judged to be relatedto treatment by the investigator occurred in more than 2% of subjectsduring the 14-day lead-in with immediate-release VIRAMUNE (200 mgonce daily), except for rash which occurred in 4% of subjects. Adverse reactions of at least moderate intensity(Grades or above) 2% or more of treatment-naive subjects receivingeither immediate-release VIRAMUNE or VIRAMUNE XR after randomizationin Trial 1100.1486 are shown in Table 1.Table Selected Clinical Adverse Drug Reactions of at leastModerate Intensity (Grade or above) Occurring in 2% or more of AdultSubjects- Week 96 Analysis of Trial 1100.14861 Excludes laboratory abnormalitiesreported as ADRs Mean observationperiod 98 weeks. Rash includesterms rash, rash maculo-papular, erythema nodosum, rash erythematous,rash papular, skin reaction, Stevens-Johnson syndrome, drug reactionwith eosinophilia and systemic symptoms (DRESS). Clinical hepatitis includes terms hepatitis, hepatotoxicity,hepatitis acute, liver disorder, hepatitis toxic, hepatic failure,jaundice.Adverse DrugReactionVIRAMUNE Immediate-ReleaseN=506 (%)VIRAMUNE XRN=505 (%)Rash2 45Diarrhea44Headache44Clinical Hepatitis3 42Abdominal Pain23Arthralgia22Pyrexia21Nausea21Fatigue22. Laboratory AbnormalitiesLiver enzyme test abnormalities(AST, ALT) were observed in subjects receiving VIRAMUNE XR. Asymptomaticelevations in GGT occur frequently but are not contraindicationto continue therapy with nevirapine in the absence of elevations inother liver enzyme tests. Laboratory abnormalities that occurred intrial 1100.1486 are shown in Table 2.Table Grade to Grade Laboratory Abnormalities thatRepresent Worsening from Baseline Observed in at least 5% of Subjectsin Either Treatment Group Trial 1100.1486Laboratory Parameter (unit)LimitVIRAMUNE Immediate-Release (%)(N=506)VIRAMUNE XR(%)(N=505)Chemistry SGPT/ALT (U/L) Grade 22.6-5.0 ULN1310Grade 35.1-10.0 ULN34Grade 4>10.0 ULN42SGOT/AST (U/L) Grade 22.6-5.0 ULN97Grade 35.1-10.0 ULN23Grade 4>10.0 ULN22Amylase (U/L) Grade 21.6-2.0 ULN45Grade 32.1-5.0 ULN42Grade 4>5.0 ULN0<1Phosphate (mg/dL) Grade 22.0-2.4 ULN3833Grade 31.0-1.9 ULN67Grade 4<1.0 ULN<10Hematology Neutrophils Grade 2750-999/mm3 74Grade 3500-749/mm3 22Grade 4<500/mm3 11Lipids LDL (mg/dL) Grade 2160-190 mg/dL1515Grade 3>190 mg/dL55Cholesterol (mg/dL) Grade 2240-300 mg/dL1819Grade 3>300 mg/dL43. Trial 1100.1526 (TRANxITION)In Trial 1100.1526 (TRANxITION)subjects on immediate-release VIRAMUNE 200 mg twice daily for at least18 weeks were randomized to either receive VIRAMUNE XR 400 mg oncedaily (n=295) or remain on their immediate-release VIRAMUNE treatment(n=148). Adverse reactions observed for VIRAMUNE XR subjects (48 weekanalysis) were similar to those observed in trial 1100.1486, as displayedin Table 1.Clinical Trial Experience in Pediatric PatientsAdverse reactions were assessedin Trial 1100.1518, an open-label, multiple-dose, non-randomized,cross-over trial to evaluate the safety and steady-state pharmacokineticparameters of VIRAMUNE XR tablets in HIV-1-infected pediatric subjects3 to less than 18 years of age. Safety was further examined in anoptional extension phase of the trial. Forty subjects who completedthe pharmacokinetic part of the trial were treated with VIRAMUNE XRonce daily in combination with other antiretrovirals for medianduration of 33 weeks. The most frequently reported adverse reactionsrelated to VIRAMUNE XR in pediatric subjects were similar to thoseobserved in adults. In pediatric subjects the incidence of Grade2 or higher drug-related rash was 1%. There were no adverse reactionsof Grade or above which were considered to be related to treatmentby the investigator that occurred in more than 1% of subjects [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3),and Clinical Studies (14.2)].. 6.2 Post-Marketing Experience. The following adverse reactions have beenidentified during post-approval use of immediate-release VIRAMUNE.Because these reactions are reported voluntarily from populationof uncertain size, it is not always possible to reliably estimatetheir frequency or establish 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 [see Warnings and Precautions (5.1)] plus one or more of thefollowing: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and/or renal dysfunction have been reported.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Animal studies have shown that nevirapine is widelydistributed to nearly all tissues and readily crosses the blood-brainbarrier.

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 nevirapine. 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 nevirapine in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with nevirapine 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 nevirapine for post-exposure prophylaxis (PEP). Use ofnevirapine for 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 nevirapine 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 nevirapine. These have included cases ofStevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivityreactions characterized by rash, constitutional findings, and organdysfunction. Patients developing signs or symptoms of severe skinreactions or hypersensitivity reactions must discontinue nevirapineand seek medical evaluation immediately. Transaminase levels shouldbe checked immediately for all patients who develop rash in thefirst 18 weeks of treatment. The 14-day lead-in period with immediate-releaseVIRAMUNE 200 mg daily dosing has been observed to decrease the incidenceof rash and must be followed [see Warnings and Precautions (5.2)].MONITORING FOR HEPATOXICITY AND SKIN REACTIONS:Patients must be monitoredintensively during the first 18 weeks of therapy with nevirapine todetect potentially life-threatening hepatotoxicity or skin reactions.Extra vigilance is warranted during the first weeks of therapy,which is the period of greatest risk of these events. Do not restartnevirapine following clinical hepatitis, or transaminase elevationscombined with rash or other systemic symptoms, or following severeskin rash or hypersensitivity reactions. In some cases, hepatic injuryhas progressed despite discontinuation of treatment.. WARNING: LIFE-THREATENING (INCLUDING FATAL)HEPATOTOXICITY and SKIN REACTIONSSee full prescribinginformation for complete boxed warning.Fatal and non-fatal hepatotoxicity havebeen reported in patients taking VIRAMUNE XR. Discontinue immediatelyif clinical hepatitis or transaminase elevations combined with rashor other systemic symptoms occur. Do not restart VIRAMUNE XR afterrecovery. (5.1) Fatal and non-fatal skin reactions, includingStevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivityreactions, have been reported. Discontinue immediately if severe skinreactions, hypersensitivity reactions, or any rash with systemic symptomsoccur. Check transaminase levels immediately for all patients whodevelop rash in the first 18 weeks of treatment. Do not restartVIRAMUNE XR after recovery. (5.2) Monitoring during the first 18 weeks oftherapy is essential. Extra vigilance is warranted during the first6 weeks of therapy, which is the period of greatest risk of theseevents. (5.1, 5.2) Fatal and non-fatal hepatotoxicity havebeen reported in patients taking VIRAMUNE XR. Discontinue immediatelyif clinical hepatitis or transaminase elevations combined with rashor other systemic symptoms occur. Do not restart VIRAMUNE XR afterrecovery. (5.1) Fatal and non-fatal skin reactions, includingStevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivityreactions, have been reported. Discontinue immediately if severe skinreactions, hypersensitivity reactions, or any rash with systemic symptomsoccur. Check transaminase levels immediately for all patients whodevelop rash in the first 18 weeks of treatment. Do not restartVIRAMUNE XR after recovery. (5.2) Monitoring during the first 18 weeks oftherapy is essential. Extra vigilance is warranted during the first6 weeks of therapy, which is the period of greatest risk of theseevents. (5.1, 5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies in mice and rats werecarried out with nevirapine. Mice were dosed with 0, 50, 375 or 750mg/kg/day for two years. Hepatocellular adenomas and carcinomas wereincreased at all doses in males and at the two high doses in females.In studies in which rats were administered nevirapine at doses of0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellularadenomas was seen in males at all doses and in females at the highdose. The systemic exposure (based on AUCs) at all doses in the twoanimal studies was lower than that measured in humans at the 200 mgtwice daily dose of immediate-release VIRAMUNE. The mechanism of thecarcinogenic potential is unknown.MutagenesisHowever, ingenetic toxicology assays, nevirapine showed no evidence of mutagenicor clastogenic activity in battery of in vitro and in vivo studies. These included microbial assays for genemutation (Ames: Salmonella strains and E. coli),mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assaysusing Chinese hamster ovary cell line and mouse bone marrow micronucleusassay following oral administration. Given the lack of genotoxic activityof nevirapine, the relevance to humans of hepatocellular neoplasmsin nevirapine-treated mice and rats is not known.Impairment of FertilityIn reproductive toxicology studies, evidence of impairedfertility was seen in female rats at doses providing systemic exposure,based on AUC, approximately equivalent to that provided with the recommendedclinical dose.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Nevirapine is an antiretroviral drug [see Microbiology (12.4)]. 12.3 Pharmacokinetics. Adults. Absorption and BioavailabilityThe single-dose pharmacokinetics of VIRAMUNEXR was studied in 17 healthy volunteers. Nevirapine was absorbed witha median tmax of approximately 24 hrs. Themean Cmax and AUC0- of nevirapine were 2060 ng per mL and 161,000 nghr/mL, respectively.The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg ofimmediate-release VIRAMUNE, was approximately 75%.The multiple-dose pharmacokinetics of VIRAMUNE XR wasstudied in 24 HIV-1 infected subjects who switched from chronic VIRAMUNEIR to VIRAMUNE XR. The mean nevirapine AUC0-24,ss and Cmin,ss after 19 days of VIRAMUNE XRdosing under fasted conditions were 82,000 nghr/mL and 2920 ng permL, respectively. When VIRAMUNE XR was administered under fed conditions,the mean nevirapine AUC0-24,ss and Cmin,ss were 96,700 nghr/mL and 3150 ng per mL, respectively.The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg ofimmediate-release VIRAMUNE, under fasted and fed conditions, was 80%and 94%, respectively. The difference in the bioavailability of nevirapine,when VIRAMUNE XR is dosed under fasted or fed conditions, is not consideredclinically relevant. VIRAMUNE XR can be taken with or without food.. DistributionNevirapine is highly lipophilicand is essentially nonionized at physiologic pH. Following intravenousadministration to healthy adults, the apparent volume of distribution(Vdss) of nevirapine was 1.21 +- 0.09 L/kg, suggesting that nevirapineis widely distributed in humans. Nevirapine readily crosses the placentaand is also found in breast milk [see Use in SpecificPopulations (8.2)]. Nevirapine is about 60% bound to plasma proteins in the plasmaconcentration range of 1-10 mcg per mL. Nevirapine concentrationsin human cerebrospinal fluid (n=6) were 45% (+-5%) of the concentrationsin plasma; this ratio is approximately equal to the fraction not boundto plasma protein.. Metabolism/EliminationIn vivo studies in humans and 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 microsomessuggest that oxidative metabolism of nevirapine is mediated primarilyby cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families,although other isozymes may have secondary role. In mass balance/excretiontrial in eight healthy male volunteers dosed to steady state withimmediate-release VIRAMUNE 200 mg given twice daily followed by asingle 50 mg dose of 14C-nevirapine, approximately91.4 +- 10.5% of the radiolabeled dose was recovered, with urine (81.3+- 11.1%) representing the primary route of excretion compared to feces(10.1 +- 1.5%). Greater than 80% of the radioactivity in urine wasmade up of glucuronide conjugates of hydroxylated metabolites. Thuscytochrome P450 metabolism, glucuronide conjugation, and urinary excretionof glucuronidated metabolites represent the primary route of nevirapinebiotransformation and elimination in humans. Only small fraction(less than 5%) of the radioactivity in urine (representing less than3% of the total dose) was made up of parent compound; therefore, renalexcretion plays minor role in elimination of the parent compound.Nevirapine is an inducer of hepatic cytochromeP450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3Aand CYP2B6 by approximately 20-25%, as indicated by erythromycin breathtest results and urine metabolites. Autoinduction of CYP3A and CYP2B6mediated metabolism leads to an approximately 1.5- to 2-fold increasein the apparent oral clearance of nevirapine as treatment continuesfrom single dose to two-to-four weeks of dosing with 200-400 mgper day of immediate-release VIRAMUNE. Autoinduction also resultsin corresponding decrease in the terminal phase half-life of nevirapinein plasma, from approximately 45 hours (single dose) to approximately25-30 hours following multiple dosing with 200-400 mg per day.. SpecificPopulations. Renal ImpairmentHIV-1 seronegative adults withmild (CrCl 50-79 mL per min; n=7), moderate (CrCl 30-49 mL per min;n=6), or severe (CrCl less than 30 mL per min; n=4) renal impairmentreceived single 200 mg dose of immediate-release VIRAMUNE in pharmacokinetictrial. These subjects did not require dialysis. The trial includedsix additional subjects with renal failure requiring dialysis.In subjects with renal impairment (mild,moderate or severe), 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 doseof immediate-release VIRAMUNE following each dialysis treatment isindicated [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. VIRAMUNE XRhas not been studied in patients with renal dysfunction.. Hepatic ImpairmentIn steady-state trial comparing46 subjects with mild (n=17; expansion of some portal areas; IshakScore 1-2), moderate (n=20; expansion of most portal areas with occasionalportal-to-portal and portal-to-central bridging; Ishak Score 3-4),or severe (n=9; marked bridging with occasional cirrhosis withoutdecompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosisas measure of hepatic impairment, the multiple dose pharmacokineticdisposition of nevirapine and its five oxidative metabolites werenot altered. However, approximately 15% of these subjects with hepaticfibrosis had nevirapine trough concentrations above 9,000 mcg permL (2-fold the usual mean trough). Therefore, patients with hepaticimpairment should be monitored carefully for evidence of drug-inducedtoxicity [see Warnings and Precautions (5.1)]. The subjectsstudied were receiving antiretroviral therapy containing immediate-releaseVIRAMUNE 200 mg twice daily for at least weeks prior to pharmacokineticsampling, with median duration of therapy of 3.4 years.In pharmacokinetic trial where HIV-1negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate(Child-Pugh B; n=4) hepatic impairment received single 200 mg doseof immediate-release VIRAMUNE, significant increase in the AUC ofnevirapine was observed in one subject with Child-Pugh and ascitessuggesting that patients with worsening hepatic function and ascitesmay be at risk of accumulating nevirapine in the systemic circulation.Because nevirapine induces its own metabolism with multiple dosing,this single-dose trial may not reflect the impact of hepatic impairmenton multiple-dose pharmacokinetics.Do not administer nevirapine to patients with moderate or severe(Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1),and Use in Specific Populations (8.7)]. VIRAMUNE XR has not been evaluated in patientswith hepatic impairment.. GenderIn the multinational 2NN trial of immediate-releaseVIRAMUNE, population pharmacokinetic substudy of 1077 subjects wasperformed that included 391 females. Female subjects showed 13.8%lower clearance of nevirapine than did men. Since neither body weightnor Body Mass Index (BMI) had an influence on the clearance of nevirapine,the effect of gender cannot solely be explained by body size.The effects of gender on the pharmacokineticsof VIRAMUNE XR have been investigated in Trial 1100.1486. Female subjectstend to have higher (approximately 20 30%) trough concentrationsin both VIRAMUNE XR and immediate-release VIRAMUNE treatment groups.. RaceAn evaluation of nevirapine plasma concentrations(pooled data from several clinical trials) from HIV-1-infected subjects(27 Black, 24 Hispanic, 189 Caucasian) revealed no marked differencein nevirapine steady-state trough concentrations (median Cminss 4.7 mcg per mL Black, 3.8 mcg per mL Hispanic,4.3 mcg per mL Caucasian) with long-term treatment with immediate-releaseVIRAMUNE at 400 mg per day. However, the pharmacokinetics of nevirapinehave not been evaluated specifically for the effects of ethnicity.Black subjects (n=80/group) in Trial 1100.1486showed approximately 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 PatientsNevirapine pharmacokineticsin HIV-1-infected adults do not appear to change with age (range 18-68years); however, nevirapine has not been extensively evaluated inpatients beyond the age of 65 years [see Use inSpecific Populations (8.5)].PediatricPatientsThe pharmacokineticsof VIRAMUNE XR were assessed in HIV-1 infected children to lessthan 18 years of age. Children enrolled received weight or body surfacearea dose-adjusted immediate-release VIRAMUNE in combination withother antiretrovirals for minimum of 18 weeks and then were switchedto VIRAMUNE XR tablets in combination with other antiretrovirals for10 days, after which steady-state pharmacokinetic parameters weredetermined.Overall, the meansystemic nevirapine exposures in children to less than 18 yearsof age following administration of VIRAMUNE XR and immediate-releaseVIRAMUNE were similar. Based on intensive PK data (N=17), the observedgeometric mean ratios of VIRAMUNE XR to immediate-release VIRAMUNEwere approximately 97% for Cmin,ss and 94%for AUCss with 90% confidence intervals within80% 125%; the ratio for Cmax,ss was lowerand consistent with once daily extended-release dosage form.Trial 1100.1518 did not provide sufficientpharmacokinetic data for children to less than years of age tosupport the use of VIRAMUNE XR in this age group.. Drug Interactions[see Drug Interactions (7)]Nevirapineinduces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administrationof VIRAMUNE XR and drugs primarily metabolized by CYP3A or CYP2B6may result in decreased plasma concentrations of these drugs and attenuatetheir therapeutic effects.Whileprimarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapinemay also inhibit this system. Among human hepatic cytochrome P450s,nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). Theestimated Ki for the inhibition of CYP3A was270 micromolar, concentration that is unlikely to be achieved inpatients as the therapeutic range is less than 25 micromolar. Therefore,nevirapine may have minimal inhibitory effect on other substratesof CYP3A.Nevirapine does notappear to affect the plasma concentrations of drugs that are substratesof other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or2C19.Table (see below) containsthe results of drug interaction trials performed with immediate-releaseVIRAMUNE and other drugs likely to be co-administered. The effectsof nevirapine on the AUC, Cmax, and Cmin of co-administered drugs are summarized. Resultsof drug interaction studies with immediate-release VIRAMUNE are expectedto also apply to VIRAMUNE XR.Table Drug Interactions: Changes in Pharmacokinetic Parametersfor Co-administered Drug in the Presence of Immediate-Release VIRAMUNE(All interaction studies 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)]. Pediatric subjects ranging in age from months to12 years. Parallel group design;n for VIRAMUNE+lopinavir/ritonavir, for lopinavir/ritonavir alone. Parallel group design; n=23 for atazanavir/ritonavir+ nevirapine, n=22 for atazanavir/ritonavir without nevirapine. Changesin atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. Based on between-trial comparison. Based on historical controls.Co-administeredDrugDose of Co-administeredDrugDose Regimen ofimmediate-release VIRAMUNEn% 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 entry1711(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 metabolite 62(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-clarithromycin 42(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-ProgesteroneAcetate150 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-rifabutin 24(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 Table4 on nevirapine pharmacokinetics was not significant. No significantinteraction was observed when tipranavir was co-administered withlow-dose ritonavir and nevirapine.. 12.4 Microbiology. Mechanism of Action. Nevirapine is non-nucleoside reversetranscriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directlyto reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependentDNA polymerase activities by causing disruption of the enzymescatalytic site. The activity of nevirapine does not compete with templateor nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases(such as human DNA polymerases , or are not inhibited bynevirapine.. 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 theVIRAMUNE XR treatment group and 88% (30/34) of the subjects in theimmediate-release VIRAMUNE treatment group, respectively. The Y181Cnevirapine resistance-associated substitution was found alone or incombination with other nevirapine resistance-associated substitutions(K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H,F227L, M230L) in isolates from 14 subjects failing VIRAMUNE XR treatmentand 25 subjects failing immediate-release VIRAMUNE treatment. On-therapyisolates from subject in VIRAMUNE XR treatment group developed anovel amino acid substitution Y181I and isolates from another subjectin the immediate-release VIRAMUNE treatment group developed novelamino acid substitution Y188N. Phenotypic analysis showed that Y188Nand Y181I substitutions conferred 103- and 22-fold reductions in susceptibilityto 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. The clinical efficacy of VIRAMUNE XR isbased on 96-week data from an ongoing, randomized, double-blind, double-dummyPhase trial (Trial 1100.1486, VERxVE) in treatment-naive subjectsand on 48-week data in an ongoing, randomized, open-label trial insubjects who switched from immediate-release VIRAMUNE tablets administeredtwice daily to VIRAMUNE XR tablets administered once daily (Trial1100.1526, TRANxITION).. Treatment-naiveSubjects. Trial 1100.1486 (VERxVE) is Phase trial in which treatment-naivesubjects received immediate-release VIRAMUNE 200 mg once daily for14 days and then were randomized to receive either immediate-releaseVIRAMUNE 200 mg twice daily or VIRAMUNE XR 400 mg once daily. Allsubjects received tenofovir emtricitabine as background therapy.Randomization was stratified by screening HIV-1 RNA level (less thanor equal to 100,000 copies per mL and greater than 100,000 copiesper mL). Subject demographic and baseline disease characteristicswere balanced between the two treatment groups. With respect to demographics:85% of the subjects were male, 75% were white, 20% were black, andapproximately 29% were from North America. With respect to baselinedisease characteristics: mean viral load was 4.7 log10 copies per mL, mean CD4+ cell count was228 cells/mm3 and 73% of subjects had cladeB HIV-1 subtype. Approximately two-thirds of the subjects had baselineHIV-RNA level of less than or equal to 100,000 copies per mL.Table describes week 96 outcomes in theTrial 1100.1486 (VERxVE). These outcomes include all subjects whowere randomized after the 14 day lead-in with immediate-release VIRAMUNEand received at least one dose of blinded study medication.Table Outcomes at Week 96 in Trial 1100.1486Includes subjects who changed optimized backgroundtherapy (OBT) to new class or changed OBT not permitted per protocolor due to lack of efficacy prior to Week 96, subjects who discontinuedprior to Week 96 for lack or loss of efficacy and subjects with HIVRNA greater than or equal to 50 copies/mL in the Week 96 window.Includes subjects who discontinued due to adverse events or deathat any time point from Day through the Week 96 window if this resultedin no virologic data on treatment during the specified window.Other includes: withdrew consent, lost to follow-up, moved away,etc. Week 96 VIRAMUNEImmediate-Release N=506VIRAMUNE XR N=505Virologic Success HIV RNA< 50 copies/mL 67%69%Virologic Failure 18%17%No Virologic Data at Week 96Window Reasons Discontinued trial/study drug due to adverse eventor death Discontinued trial/study drug for other reasons Missing data during window but on trial10%5% <1%8%5%1%At 96 weeks, mean change from baselinein CD4+ cell count adjusting for baselineHIV-1 viral load stratum was 222 cells/mm3 and 244 cells/mm3 for the groups receivingimmediate-release VIRAMUNE and VIRAMUNE XR, respectively.. SubjectsSwitching from Immediate-release VIRAMUNE to VIRAMUNE XR. Trial 1100.1526 (TRANxITION)is Phase trial to evaluate safety and antiviral activity of switchingfrom immediate-release VIRAMUNE to VIRAMUNE XR. In this open-labeltrial, 443 subjects already on an antiviral regimen containing immediate-releaseVIRAMUNE 200 mg twice daily with HIV-1 RNA less than 50 copies permL were randomized in 2:1 ratio to VIRAMUNE XR 400 mg once dailyor immediate-release VIRAMUNE 200 mg twice daily. Approximately halfof the subjects had tenofovir+emtricitabine as their background therapy,with the remaining subjects receiving abacavir sulfate+lamivudineor zidovudine+lamivudine. Approximately half of the subjects had atleast years of exposure to immediate-release VIRAMUNE prior to enteringthe trial.At 48 weeks afterrandomization in Trial 1100.1526, 91% of subjects receiving immediate-releaseVIRAMUNE 200 mg twice daily and 93% of subjects receiving VIRAMUNEXR 400 mg once daily continued to have HIV-1 RNA less than 50 copiesper mL.. 14.2 Pediatric Patients. Trial 1100.1518 was an open-label, multiple-dose,non-randomized, crossover trial performed in 85 HIV-1 infected pediatricsubjects to less than 18 years of age who had received at least18 weeks of immediate-release VIRAMUNE and had plasma HIV-1 RNA lessthan 50 copies per mL prior to trial enrollment. Subjects were stratifiedaccording to age (3 to less than years, to less than 12 years,and 12 to less than 18 years). Following 10-day period with immediate-releaseVIRAMUNE, subjects were treated with VIRAMUNE XR tablets once dailyin combination with other antiretrovirals for 10 days, after whichsteady-state pharmacokinetic parameters were determined. Forty ofthe 80 subjects who completed the initial part of the study were enrolledin an optional extension phase of the trial which evaluated the safetyand antiviral activity of VIRAMUNE XR through minimum of 24 weeksof treatment. Zidovudine or stavudine plus lamivudine were the mostcommonly used background therapies in subjects who entered the optionalextension phase.Baseline demographicsincluded: 55% of the subjects were female, 93% were black, 7% werewhite, and approximately 84% were from Africa. Subjects had medianbaseline CD4+ cell count of 925 cells/mm3 (range 207 to 2057 cells/mm3).Of the 40 subjects who enteredthe treatment extension phase, 39 completed at least 24 weeks of treatmentand one subject discontinued prematurely due to an adverse reaction.After 24 weeks or more of treatment with VIRAMUNE XR, all 39 subjectscontinued to have plasma HIV-1 RNA less than 50 copies per mL. MedianCD4+ cell counts for the to less than6 year, to less than 12 year, and 12 to less than 18 year age groupswere 1113 cells/mm3, 853 cells/mm3, and 682 cells/mm3, respectively.These CD4+ cell counts were similar tothose observed at baseline.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. VIRAMUNE XR is contraindicated:in patients with moderate or severe (Child-Pugh Class Bor C, respectively) hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].for use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens [see Warnings and Precautions (5.1)].. in patients with moderate or severe (Child-Pugh Class Bor C, respectively) hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].. for use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens [see Warnings and Precautions (5.1)].. Patients with moderate or severe (Child-Pugh Class orC, respectively) hepatic impairment. (4, 5.1, 8.7) Use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens, an unapproved use. (4, 5.1) Patients with moderate or severe (Child-Pugh Class orC, respectively) hepatic impairment. (4, 5.1, 8.7) Use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens, an unapproved use. (4, 5.1).

DESCRIPTION SECTION.

11 DESCRIPTION. VIRAMUNE XR is the brand name for nevirapineextended-release tablets. Nevirapine is non-nucleoside reverse transcriptaseinhibitor (NNRTI) with activity against Human Immunodeficiency VirusType (HIV-1). Nevirapine is structurally member of the dipyridodiazepinonechemical class of compounds.The chemical name of nevirapine is 11-cyclopropyl-5, 11-dihydro-4-methyl-6H-dipyrido[3,2-b:2,3-e][1,4] diazepin-6-one. Nevirapine is white to off-whitecrystalline powder with the molecular weight of 266.30 and the molecularformula C15H14N4O. Nevirapine has the following structural formula:VIRAMUNEXR Tablets are for oral administration. Each tablet contains 400 mgof nevirapine and the inactive ingredients lactose monohydrate, hypromellose,iron oxide, and magnesium stearate.. Chemical Structure Viramune.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION The 14-day lead-in period with immediate-release VIRAMUNE(200 mg once daily) must be strictly followed; it has been demonstratedto reduce the frequency of rash. (2.5, 5.2) The VIRAMUNE XR tablets must be swallowed whole and mustnot be chewed, crushed, or divided. (2.1) Adult patients must initiate therapy with one 200 mg tabletof immediate-release VIRAMUNE once daily for the first 14 days, followedby one 400 mg tablet of VIRAMUNE XR once daily. (2.2) Adult patients already on regimen of immediate-releaseVIRAMUNE twice daily can be switched to VIRAMUNE XR 400 mg once dailywithout the 14-day lead-in period of immediate-release VIRAMUNE. (2.2) Pediatric patients (ages to less than 18 years with aBSA of 1.17 m2 or greater)must initiate therapy with immediate-release VIRAMUNE (as 150 mg/m2 of VIRAMUNE Oral Suspension or as VIRAMUNE tablet)at dose not to exceed 200 mg per day administered once daily forthe first 14 days, followed by VIRAMUNE XR 400 mg once daily. (2.3) Pediatric patients with BSA of 1.17 m2 or greater already on regimen of twice-daily VIRAMUNE Oral Suspensionor immediate-release VIRAMUNE can be switched to VIRAMUNE XR 400mg once daily without the 14-day lead-in period of VIRAMUNE Oral Suspensionor immediate-release VIRAMUNE. (2.3) If any patient experiences rash during the 14-day lead-inperiod with immediate-release VIRAMUNE do not initiate VIRAMUNE XRuntil the rash has resolved. Do not continue the immediate-releaseVIRAMUNE lead-in dosing regimen beyond 28 days. (2.5) If dosing is interrupted for greater than days, restart14-day lead-in dosing. (2.5) The 14-day lead-in period with immediate-release VIRAMUNE(200 mg once daily) must be strictly followed; it has been demonstratedto reduce the frequency of rash. (2.5, 5.2) The VIRAMUNE XR tablets must be swallowed whole and mustnot be chewed, crushed, or divided. (2.1) Adult patients must initiate therapy with one 200 mg tabletof immediate-release VIRAMUNE once daily for the first 14 days, followedby one 400 mg tablet of VIRAMUNE XR once daily. (2.2) Adult patients already on regimen of immediate-releaseVIRAMUNE twice daily can be switched to VIRAMUNE XR 400 mg once dailywithout the 14-day lead-in period of immediate-release VIRAMUNE. (2.2) Pediatric patients (ages to less than 18 years with aBSA of 1.17 m2 or greater)must initiate therapy with immediate-release VIRAMUNE (as 150 mg/m2 of VIRAMUNE Oral Suspension or as VIRAMUNE tablet)at dose not to exceed 200 mg per day administered once daily forthe first 14 days, followed by VIRAMUNE XR 400 mg once daily. (2.3) Pediatric patients with BSA of 1.17 m2 or greater already on regimen of twice-daily VIRAMUNE Oral Suspensionor immediate-release VIRAMUNE can be switched to VIRAMUNE XR 400mg once daily without the 14-day lead-in period of VIRAMUNE Oral Suspensionor immediate-release VIRAMUNE. (2.3) If any patient experiences rash during the 14-day lead-inperiod with immediate-release VIRAMUNE do not initiate VIRAMUNE XRuntil the rash has resolved. Do not continue the immediate-releaseVIRAMUNE lead-in dosing regimen beyond 28 days. (2.5) If dosing is interrupted for greater than days, restart14-day lead-in dosing. (2.5) 2.1 General Dosing Considerations. VIRAMUNE XR tablets must be swallowed whole and must notbe chewed, crushed, or divided.Children should be assessed for their ability to swallowtablets before prescribing VIRAMUNE XR tablets.VIRAMUNE XR can be taken with or without food.. VIRAMUNE XR tablets must be swallowed whole and must notbe chewed, crushed, or divided.. Children should be assessed for their ability to swallowtablets before prescribing VIRAMUNE XR tablets.. VIRAMUNE XR can be taken with or without food.. 2.2 Adult Patients. Patientsnot currently taking immediate-release VIRAMUNE. Patients must initiate therapywith one 200 mg tablet of immediate-release VIRAMUNE daily for thefirst 14 days in combination with other antiretroviral agents. The14-day lead-in period with VIRAMUNE 200 mg daily dosing must be strictlyfollowed (the lead-in period has been observed to decrease the incidenceof rash), followed by one 400 mg tablet of VIRAMUNE XR once daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. If rash persists beyond the 14-day lead-in period withimmediate-release VIRAMUNE, do not begin dosing with VIRAMUNE XR. The lead-in dosing with 200 mg once daily immediate-release VIRAMUNEshould not be continued beyond 28 days, at which point an alternativeregimen should be sought.. Switchingpatients from immediate-release VIRAMUNE to VIRAMUNE XR. Patients already ona regimen of immediate-release VIRAMUNE twice daily in combinationwith other antiretroviral agents can be switched to VIRAMUNE XR 400mg once daily without the 14-day lead-in period. Patients alreadyon regimen of immediate-release VIRAMUNE twice daily who switchto VIRAMUNE XR therapy should continue with their ongoing clinicaland laboratory monitoring.. 2.3 Pediatric Patients. VIRAMUNE XR in pediatric patientsis dosed based on body surface area (BSA) calculated using the Mostellerformula. All pediatric patients must initiate therapy with immediate-releaseVIRAMUNE (as 150 mg/m2 of VIRAMUNE OralSuspension or as VIRAMUNE tablets), at dose not to exceed 200 mgper day, administered once daily for the first 14 days. This lead-inperiod should be used because it has been demonstrated to reduce thefrequency of rash. This lead-in period is not required if the patientis already on regimen of twice daily immediate-release formulationin combination with other antiretroviral agents.The recommended oral dose of VIRAMUNE XR forpediatric patients with BSA of 1.17 m2 or greater is 400 mg following the lead-in period with immediate-releaseVIRAMUNE. The total daily dose should not exceed 400 mg for any patient.. Mosteller Formula. 2.4 Monitoring of Patients Intensive clinical and laboratory monitoring,including liver enzyme tests, is essential at baseline and duringthe first 18 weeks of treatment with nevirapine. 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 prior to beginning the 14-day lead-in period with immediate-releaseVIRAMUNE, prior to initiation of VIRAMUNE XR, and at two weeks afterinitiation of VIRAMUNE XR therapy. After the initial 18-week period,frequent clinical and laboratory monitoring should continue throughoutVIRAMUNE XR treatment [see Warnings and Precautions (5)]. In some cases, hepaticinjury has progressed despite discontinuation of treatment.Patients already on regimen of immediate-releaseVIRAMUNE twice daily who switch to VIRAMUNE XR once daily should continuewith their ongoing clinical and laboratory monitoring. 2.5 Dosage Adjustment. Patients with RashDiscontinue nevirapine if apatient experiences severe rash or any rash accompanied by constitutionalfindings [see Warnings and Precautions (5.2)]. Do not initiate therapy with VIRAMUNE XRif patient experiences mild to moderate rash without constitutionalsymptoms during the 14-day lead-in period of immediate-release VIRAMUNEuntil the rash has resolved [see Warnings and Precautions (5.2)]. The total duration of theonce daily lead-in dosing period should not exceed 28 days at whichpoint an alternative regimen should be sought.. Patients with HepaticEventsIf clinical(symptomatic) hepatic event occurs, permanently discontinue nevirapine.Do not restart nevirapine after recovery [see Warnings andPrecautions (5.1)].. Patients with Dose InterruptionFor patients who interrupt VIRAMUNEXR dosing for more than days, restart the recommended lead-in dosingwith immediate-release VIRAMUNE, using one 200 mg tablet daily forthe first 14 days. Patientswith Renal ImpairmentPatients with CrCl greater than or equal to 20 mL per min and notrequiring dialysis do not require an adjustment in dosing. The pharmacokineticsof nevirapine have not been evaluated in patients with CrCl less than20 mL per min. An additional 200 mg dose of immediate-release VIRAMUNEfollowing each dialysis treatment is indicated in patients requiringdialysis. Nevirapine metabolites may accumulate in patients receivingdialysis; however, the clinical significance of this accumulationis not known [see Clinical Pharmacology (12.3)]. VIRAMUNE XRhas not been studied in patients with renal dysfunction.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. VIRAMUNE XR Tablets:400 mg,yellow, oval, biconvex extended-release tablets, debossed with V04on one side and the Boehringer Ingelheim logo on the other side.. 400 mg tablets (3) 400 mg tablets (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 results of drug interactions studies with immediate-releaseVIRAMUNE are expected to also apply to VIRAMUNE XR. The specific pharmacokineticchanges that occur with co-administration of nevirapine and otherdrugs are listed in Clinical Pharmacology, Table 4. Clinical comments about possible dosage modificationsbased on established drug interactions are listed in Table 3. Thedata in Tables and are based on the results of drug interactionstudies conducted in HIV-1 seropositive subjects unless otherwiseindicated. In addition to established drug interactions, there maybe potential pharmacokinetic interactions between nevirapine and otherdrug classes that are metabolized by the cytochrome P450 system. Thesepotential drug interactions are also listed in Table 3. Although specificdrug interaction studies in HIV-1 seropositive subjects have not beenconducted for some classes of drugs listed in Table 3, additionalclinical monitoring may be warranted when co-administering these drugs.The in vitro interaction between nevirapine and the antithrombotic agentwarfarin is complex. As result, when giving these drugs concomitantly,plasma warfarin levels may change with the potential for increasesin coagulation time. When warfarin is co-administered with nevirapine,anticoagulation levels should be 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 immediate-release VIRAMUNE and the drug was evaluated in aclinical study. The results of drug interaction studies with immediate-releaseVIRAMUNE are expected to also apply to VIRAMUNE XR.Drug NameEffect on Concentrationof Nevirapine or Concomitant DrugClinicalCommentHIV AntiviralAgents: Protease Inhibitors (PIs)Atazanavir/Ritonavir AtazanavirNevirapine Do not co-administernevirapine with atazanavir because nevirapine substantially decreasesatazanavir exposure and there is potential risk for nevirapine-associatedtoxicity due to increased nevirapine exposures. Fosamprenavir AmprenavirNevirapine 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 concentrations of telaprevirmay be decreased due to induction of CYP3A4 by nevirapine and plasmaconcentrations of nevirapine may be increased due to inhibition ofCYP3A4 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 Clarithromycin14-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 should notbe 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 EstradiolNorethindrone 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 XR, no dose adjustment of ethinyl estradiol or norethindroneis needed when used in combination for contraception. When oral contraceptives are used for hormonal regulation duringVIRAMUNE XR therapy, the therapeutic effect of the hormonal therapyshould be monitored.. Co-administration of VIRAMUNE XR 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).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of VIRAMUNE XR did not include sufficient numbersof subjects aged 65 and older to determine whether elderly subjectsrespond differently from younger subjects. In general, dose selectionfor an elderly patient should be cautious, reflecting the greaterfrequency of decreased hepatic, renal or cardiac function, and ofconcomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGEAND HANDLING. VIRAMUNEXR tablets, 400 mg, are yellow, oval, biconvex tablets, debossed withV04 on one side and the Boehringer Ingelheim logo on the other side.VIRAMUNE XR 400 mg tablets are suppliedin bottles of 30 (NDC 0597-0123-30).. StorageStore at 25C(77F); excursions permitted to 15C-30C (59F-86F) [seeUSP Controlled Room Temperature]. Store in safe place out of thereach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. VIRAMUNE XR is indicated incombination with other antiretroviral agents for the treatment ofhuman immunodeficiency virus (HIV-1) infection in adults and pediatricpatients years of age or older with body surface area (BSA) of1.17 m2 or greater [see ClinicalStudies (14.1, 14.2)].Limitations of Use:Based on seriousand life-threatening hepatotoxicity observed in controlled and uncontrolledtrials, VIRAMUNE XR is not recommended to be initiated, unless thebenefit outweighs the risk, in:adult females with CD4+ cellcounts greater than 250 cells/mm3 oradult males with CD4+ cell countsgreater than 400 cells/mm3 [seeWarnings and Precautions (5.1)]. adult females with CD4+ cellcounts greater than 250 cells/mm3 or. adult males with CD4+ cell countsgreater than 400 cells/mm3 [seeWarnings and Precautions (5.1)]. VIRAMUNE XR is an NNRTI indicated in combination with otherantiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients years ofage or older with BSA of 1.17 m2 or greater. (1) Limitations of Use:Based on serious and life-threateninghepatotoxicity observed in controlled and uncontrolled trials, VIRAMUNEXR is not recommended to be initiated, unless the benefit outweighsthe risk, in:adult females with CD4+ cellcounts greater than 250 cells/mm3 adult males with CD4+ cell countsgreater than 400 cells/mm3 (1, 5.1) VIRAMUNE XR is an NNRTI indicated in combination with otherantiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients years ofage or older with BSA of 1.17 m2 or greater. (1) adult females with CD4+ cellcounts greater than 250 cells/mm3 adult males with CD4+ cell countsgreater than 400 cells/mm3 (1, 5.1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patientlabeling (Medication Guide).Hepatotoxicity and Skin ReactionsInform patientsof the possibility of severe liver disease or skin reactions associatedwith nevirapine that may result in death. Instruct patients developingsigns or symptoms of liver disease or severe skin reactions to discontinuenevirapine 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 clinicaland laboratory monitoring, including liver enzymes, is essential duringthe first 18 weeks of therapy with nevirapine to detect potentiallylife-threatening hepatotoxicity and skin reactions. However, liverdisease can occur after this period; therefore, monitoring shouldcontinue at frequent intervals throughout nevirapine treatment. Extravigilance is warranted during the first weeks of therapy, whichis the period of greatest risk of hepatic events. Advise patientswith signs and symptoms of hepatitis to discontinue nevirapine andseek medical evaluation immediately. If nevirapine is discontinueddue to hepatotoxicity, do not restart it. Patients, particularly women,with increased CD4+ cell count at initiationof nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatichepatic events, often associated with rash. Advise patients that co-infectionwith hepatitis or and/or increased transaminases at the startof therapy with nevirapine are associated with greater risk of latersymptomatic events (6 weeks or more after starting nevirapine) andasymptomatic increases in AST or ALT [see Warningsand Precautions (5.1)].The majority of rashes associatedwith nevirapine occur within the first weeks of initiation of therapy.Instruct patients that if any rash occurs during the two-week lead-inperiod with immediate-release VIRAMUNE, do not initiate VIRAMUNE XRuntil the rash resolves. The total duration of the lead-in dosingperiod with immediate-release VIRAMUNE should not exceed 28 days,at which point an alternative regimen may need to be started. Anypatient experiencing rash should have their liver enzymes (AST,ALT) evaluated immediately. Patients with severe rash or hypersensitivityreactions should discontinue nevirapine immediately and consult aphysician. Nevirapine should not be restarted following severe skinrash or hypersensitivity reaction. Women tend to be at higher riskfor development of nevirapine-associated rash. For patients who interruptVIRAMUNE XR dosing for more than days and for whom restarting nevirapinetherapy is not contraindicated, restart the recommended lead-in dosingwith immediate-release VIRAMUNE using one 200 mg tablet daily (150mg/m2/day in pediatric patients) for thefirst 14 days [see Warnings and Precautions (5.2)] .Administration and Missed DosageInform patientsto take VIRAMUNE XR every day as prescribed. Advise patients not toalter the dose without consulting their doctor. If dose is missed,patients should take the next dose as soon as possible. However, ifa dose is skipped, the patient should not double the next dose. Inform patients that they mayoccasionally see soft remnants of VIRAMUNE XR in their stool, whichsometimes resemble intact tablets. These occurrences have not beenshown to affect drug levels or response.Instruct patients to swallow VIRAMUNE XRtablets whole. They must not be chewed, crushed, or divided.To avoid overdose, inform patientsthat they should never take immediate-release VIRAMUNE and extended-releaseVIRAMUNE XR concomitantly.Drug InteractionsVIRAMUNE XR mayinteract with some drugs; therefore, advise patients to report totheir doctor the use of any other prescription, non-prescription medicationor herbal 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 VIRAMUNEXR is 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 VIRAMUNEXR during 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 XR [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.ALL RIGHTSRESERVEDIT5243NJ022019.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Nevirapine is an antiretroviral drug [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action. Nevirapine is non-nucleoside reversetranscriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directlyto reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependentDNA polymerase activities by causing disruption of the enzymescatalytic site. The activity of nevirapine does not compete with templateor nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases(such as human DNA polymerases , or are not inhibited bynevirapine.. 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 theVIRAMUNE XR treatment group and 88% (30/34) of the subjects in theimmediate-release VIRAMUNE treatment group, respectively. The Y181Cnevirapine resistance-associated substitution was found alone or incombination with other nevirapine resistance-associated substitutions(K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H,F227L, M230L) in isolates from 14 subjects failing VIRAMUNE XR treatmentand 25 subjects failing immediate-release VIRAMUNE treatment. On-therapyisolates from subject in VIRAMUNE XR treatment group developed anovel amino acid substitution Y181I and isolates from another subjectin the immediate-release VIRAMUNE treatment group developed novelamino acid substitution Y188N. Phenotypic analysis showed that Y188Nand Y181I substitutions conferred 103- and 22-fold reductions in susceptibilityto 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies in mice and rats werecarried out with nevirapine. Mice were dosed with 0, 50, 375 or 750mg/kg/day for two years. Hepatocellular adenomas and carcinomas wereincreased at all doses in males and at the two high doses in females.In studies in which rats were administered nevirapine at doses of0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellularadenomas was seen in males at all doses and in females at the highdose. The systemic exposure (based on AUCs) at all doses in the twoanimal studies was lower than that measured in humans at the 200 mgtwice daily dose of immediate-release VIRAMUNE. The mechanism of thecarcinogenic potential is unknown.MutagenesisHowever, ingenetic toxicology assays, nevirapine showed no evidence of mutagenicor clastogenic activity in battery of in vitro and in vivo studies. These included microbial assays for genemutation (Ames: Salmonella strains and E. coli),mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assaysusing Chinese hamster ovary cell line and mouse bone marrow micronucleusassay following oral administration. Given the lack of genotoxic activityof nevirapine, the relevance to humans of hepatocellular neoplasmsin nevirapine-treated mice and rats is not known.Impairment of FertilityIn reproductive toxicology studies, evidence of impairedfertility was seen in female rats at doses providing systemic exposure,based on AUC, approximately equivalent to that provided with the recommendedclinical dose.. 13.2 Animal Toxicology and/or Pharmacology. Animal studies have shown that nevirapine is widelydistributed to nearly all tissues and readily crosses the blood-brainbarrier.

NURSING MOTHERS SECTION.

8.2 Lactation. Risk SummaryThe Centers forDisease Control and Prevention recommend that HIV-1 infected mothersin the United States not breastfeed their infants to avoid riskingpostnatal transmission of HIV-1 infection. Published data reportthat nevirapine immediate-release is present in human milk. 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 shouldnot breastfeed if they are receiving VIRAMUNE XR.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Thereis no known antidote for nevirapine overdosage. Cases of immediate-releaseVIRAMUNE overdose at doses ranging from 800 to 1800 mg per day forup to 15 days have been reported. Patients have experienced eventsincluding edema, erythema nodosum, fatigue, fever, headache, insomnia,nausea, pulmonary infiltrates, rash, vertigo, vomiting and weightdecrease. All events subsided following discontinuation of immediate-releaseVIRAMUNE.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

VIRAMUNEXR tablets, 400 mgNDC 0597-0123-30. label-012330.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. VIRAMUNE XR is indicated for use in combination with other antiretroviralagents for the treatment of HIV-1 infection in children years ofage or older with BSA of 1.17 m2 or greater [see Indications and Usage (1) andDosage and Administration (2.3)].The use of VIRAMUNE XR forthe treatment of HIV-1 infection in pediatric patients to less than18 years of age is based on pharmacokinetic, safety, and antiviralactivity data from an open-label trial with VIRAMUNE XR. The resultsof this trial were supported by previous demonstration of efficacyin adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].VIRAMUNE XR is not recommended for children less than6 years of age. Trial 1100.1518 did not provide sufficient pharmacokineticdata for children to less than years of age to support the useof VIRAMUNE XR in this age group. Furthermore, VIRAMUNE XR is notrecommended for children less than years of age because they arenot able to swallow tablets.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Adults. Absorption and BioavailabilityThe single-dose pharmacokinetics of VIRAMUNEXR was studied in 17 healthy volunteers. Nevirapine was absorbed witha median tmax of approximately 24 hrs. Themean Cmax and AUC0- of nevirapine were 2060 ng per mL and 161,000 nghr/mL, respectively.The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg ofimmediate-release VIRAMUNE, was approximately 75%.The multiple-dose pharmacokinetics of VIRAMUNE XR wasstudied in 24 HIV-1 infected subjects who switched from chronic VIRAMUNEIR to VIRAMUNE XR. The mean nevirapine AUC0-24,ss and Cmin,ss after 19 days of VIRAMUNE XRdosing under fasted conditions were 82,000 nghr/mL and 2920 ng permL, respectively. When VIRAMUNE XR was administered under fed conditions,the mean nevirapine AUC0-24,ss and Cmin,ss were 96,700 nghr/mL and 3150 ng per mL, respectively.The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg ofimmediate-release VIRAMUNE, under fasted and fed conditions, was 80%and 94%, respectively. The difference in the bioavailability of nevirapine,when VIRAMUNE XR is dosed under fasted or fed conditions, is not consideredclinically relevant. VIRAMUNE XR can be taken with or without food.. DistributionNevirapine is highly lipophilicand is essentially nonionized at physiologic pH. Following intravenousadministration to healthy adults, the apparent volume of distribution(Vdss) of nevirapine was 1.21 +- 0.09 L/kg, suggesting that nevirapineis widely distributed in humans. Nevirapine readily crosses the placentaand is also found in breast milk [see Use in SpecificPopulations (8.2)]. Nevirapine is about 60% bound to plasma proteins in the plasmaconcentration range of 1-10 mcg per mL. Nevirapine concentrationsin human cerebrospinal fluid (n=6) were 45% (+-5%) of the concentrationsin plasma; this ratio is approximately equal to the fraction not boundto plasma protein.. Metabolism/EliminationIn vivo studies in humans and 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 microsomessuggest that oxidative metabolism of nevirapine is mediated primarilyby cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families,although other isozymes may have secondary role. In mass balance/excretiontrial in eight healthy male volunteers dosed to steady state withimmediate-release VIRAMUNE 200 mg given twice daily followed by asingle 50 mg dose of 14C-nevirapine, approximately91.4 +- 10.5% of the radiolabeled dose was recovered, with urine (81.3+- 11.1%) representing the primary route of excretion compared to feces(10.1 +- 1.5%). Greater than 80% of the radioactivity in urine wasmade up of glucuronide conjugates of hydroxylated metabolites. Thuscytochrome P450 metabolism, glucuronide conjugation, and urinary excretionof glucuronidated metabolites represent the primary route of nevirapinebiotransformation and elimination in humans. Only small fraction(less than 5%) of the radioactivity in urine (representing less than3% of the total dose) was made up of parent compound; therefore, renalexcretion plays minor role in elimination of the parent compound.Nevirapine is an inducer of hepatic cytochromeP450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3Aand CYP2B6 by approximately 20-25%, as indicated by erythromycin breathtest results and urine metabolites. Autoinduction of CYP3A and CYP2B6mediated metabolism leads to an approximately 1.5- to 2-fold increasein the apparent oral clearance of nevirapine as treatment continuesfrom single dose to two-to-four weeks of dosing with 200-400 mgper day of immediate-release VIRAMUNE. Autoinduction also resultsin corresponding decrease in the terminal phase half-life of nevirapinein plasma, from approximately 45 hours (single dose) to approximately25-30 hours following multiple dosing with 200-400 mg per day.. SpecificPopulations. Renal ImpairmentHIV-1 seronegative adults withmild (CrCl 50-79 mL per min; n=7), moderate (CrCl 30-49 mL per min;n=6), or severe (CrCl less than 30 mL per min; n=4) renal impairmentreceived single 200 mg dose of immediate-release VIRAMUNE in pharmacokinetictrial. These subjects did not require dialysis. The trial includedsix additional subjects with renal failure requiring dialysis.In subjects with renal impairment (mild,moderate or severe), 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 doseof immediate-release VIRAMUNE following each dialysis treatment isindicated [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. VIRAMUNE XRhas not been studied in patients with renal dysfunction.. Hepatic ImpairmentIn steady-state trial comparing46 subjects with mild (n=17; expansion of some portal areas; IshakScore 1-2), moderate (n=20; expansion of most portal areas with occasionalportal-to-portal and portal-to-central bridging; Ishak Score 3-4),or severe (n=9; marked bridging with occasional cirrhosis withoutdecompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosisas measure of hepatic impairment, the multiple dose pharmacokineticdisposition of nevirapine and its five oxidative metabolites werenot altered. However, approximately 15% of these subjects with hepaticfibrosis had nevirapine trough concentrations above 9,000 mcg permL (2-fold the usual mean trough). Therefore, patients with hepaticimpairment should be monitored carefully for evidence of drug-inducedtoxicity [see Warnings and Precautions (5.1)]. The subjectsstudied were receiving antiretroviral therapy containing immediate-releaseVIRAMUNE 200 mg twice daily for at least weeks prior to pharmacokineticsampling, with median duration of therapy of 3.4 years.In pharmacokinetic trial where HIV-1negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate(Child-Pugh B; n=4) hepatic impairment received single 200 mg doseof immediate-release VIRAMUNE, significant increase in the AUC ofnevirapine was observed in one subject with Child-Pugh and ascitessuggesting that patients with worsening hepatic function and ascitesmay be at risk of accumulating nevirapine in the systemic circulation.Because nevirapine induces its own metabolism with multiple dosing,this single-dose trial may not reflect the impact of hepatic impairmenton multiple-dose pharmacokinetics.Do not administer nevirapine to patients with moderate or severe(Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1),and Use in Specific Populations (8.7)]. VIRAMUNE XR has not been evaluated in patientswith hepatic impairment.. GenderIn the multinational 2NN trial of immediate-releaseVIRAMUNE, population pharmacokinetic substudy of 1077 subjects wasperformed that included 391 females. Female subjects showed 13.8%lower clearance of nevirapine than did men. Since neither body weightnor Body Mass Index (BMI) had an influence on the clearance of nevirapine,the effect of gender cannot solely be explained by body size.The effects of gender on the pharmacokineticsof VIRAMUNE XR have been investigated in Trial 1100.1486. Female subjectstend to have higher (approximately 20 30%) trough concentrationsin both VIRAMUNE XR and immediate-release VIRAMUNE treatment groups.. RaceAn evaluation of nevirapine plasma concentrations(pooled data from several clinical trials) from HIV-1-infected subjects(27 Black, 24 Hispanic, 189 Caucasian) revealed no marked differencein nevirapine steady-state trough concentrations (median Cminss 4.7 mcg per mL Black, 3.8 mcg per mL Hispanic,4.3 mcg per mL Caucasian) with long-term treatment with immediate-releaseVIRAMUNE at 400 mg per day. However, the pharmacokinetics of nevirapinehave not been evaluated specifically for the effects of ethnicity.Black subjects (n=80/group) in Trial 1100.1486showed approximately 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 PatientsNevirapine pharmacokineticsin HIV-1-infected adults do not appear to change with age (range 18-68years); however, nevirapine has not been extensively evaluated inpatients beyond the age of 65 years [see Use inSpecific Populations (8.5)].PediatricPatientsThe pharmacokineticsof VIRAMUNE XR were assessed in HIV-1 infected children to lessthan 18 years of age. Children enrolled received weight or body surfacearea dose-adjusted immediate-release VIRAMUNE in combination withother antiretrovirals for minimum of 18 weeks and then were switchedto VIRAMUNE XR tablets in combination with other antiretrovirals for10 days, after which steady-state pharmacokinetic parameters weredetermined.Overall, the meansystemic nevirapine exposures in children to less than 18 yearsof age following administration of VIRAMUNE XR and immediate-releaseVIRAMUNE were similar. Based on intensive PK data (N=17), the observedgeometric mean ratios of VIRAMUNE XR to immediate-release VIRAMUNEwere approximately 97% for Cmin,ss and 94%for AUCss with 90% confidence intervals within80% 125%; the ratio for Cmax,ss was lowerand consistent with once daily extended-release dosage form.Trial 1100.1518 did not provide sufficientpharmacokinetic data for children to less than years of age tosupport the use of VIRAMUNE XR in this age group.. Drug Interactions[see Drug Interactions (7)]Nevirapineinduces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administrationof VIRAMUNE XR and drugs primarily metabolized by CYP3A or CYP2B6may result in decreased plasma concentrations of these drugs and attenuatetheir therapeutic effects.Whileprimarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapinemay also inhibit this system. Among human hepatic cytochrome P450s,nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). Theestimated Ki for the inhibition of CYP3A was270 micromolar, concentration that is unlikely to be achieved inpatients as the therapeutic range is less than 25 micromolar. Therefore,nevirapine may have minimal inhibitory effect on other substratesof CYP3A.Nevirapine does notappear to affect the plasma concentrations of drugs that are substratesof other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or2C19.Table (see below) containsthe results of drug interaction trials performed with immediate-releaseVIRAMUNE and other drugs likely to be co-administered. The effectsof nevirapine on the AUC, Cmax, and Cmin of co-administered drugs are summarized. Resultsof drug interaction studies with immediate-release VIRAMUNE are expectedto also apply to VIRAMUNE XR.Table Drug Interactions: Changes in Pharmacokinetic Parametersfor Co-administered Drug in the Presence of Immediate-Release VIRAMUNE(All interaction studies 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)]. Pediatric subjects ranging in age from months to12 years. Parallel group design;n for VIRAMUNE+lopinavir/ritonavir, for lopinavir/ritonavir alone. Parallel group design; n=23 for atazanavir/ritonavir+ nevirapine, n=22 for atazanavir/ritonavir without nevirapine. Changesin atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. Based on between-trial comparison. Based on historical controls.Co-administeredDrugDose of Co-administeredDrugDose Regimen ofimmediate-release VIRAMUNEn% 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 entry1711(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 metabolite 62(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-clarithromycin 42(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-ProgesteroneAcetate150 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-rifabutin 24(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 Table4 on nevirapine pharmacokinetics was not significant. No significantinteraction was observed when tipranavir was co-administered withlow-dose ritonavir and nevirapine.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere isa pregnancy exposure registry that monitors pregnancy outcomes inwomen exposed to nevirapine during pregnancy. Healthcare providersare encouraged to register patients by calling the AntiretroviralPregnancy Registry (APR) at 1-800-258-4263.Risk SummaryAvailable datafor nevirapine in pregnant women is from the use of VIRAMUNE immediate-release.Available data from the APR show no difference in the risk of overallmajor birth defects for nevirapine compared with the background ratefor major birth defects of 2.7% in U.S. reference population ofthe Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The rateof miscarriage is not reported in the APR. The estimated backgroundrate of miscarriage in clinically recognized pregnancies in the U.S.general population is 15-20%. The background risk of birth defectsand miscarriage for the indicated population is unknown. Methodologicallimitations of the APR include the use of MACDP as the external comparatorgroup. The MACDP population is not disease-specific, evaluates womenand infants from limited geographic area, and does not include outcomesfor births that occurred at <20 weeks gestation.There is risk for severe hepatic eventsin pregnant women exposed to VIRAMUNE XR [see Clinical Considerations]. In animal reproduction studies, no evidence of adversedevelopmental outcomes was 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 hepatic events,including fatalities, have been reported in pregnant women receivingchronic nevirapine therapy as part of combination treatment of HIV-1infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefitoutweighs the risk. It is unclear if pregnancy augments the risk observedin non-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 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%) with second/third-trimester exposure to nevirapine-containingregimens.Animal DataNevirapine was administered orally to pregnantrats (at 0, 12.5, 25, and 50 mg/kg/day), and rabbits (at 0, 30, 100,and 300 mg/kg/day) through organogenesis (on gestation days through16 and through 18, respectively). No adverse developmental effectswere observed at doses producing systemic exposures (AUC) approximatelyequivalent to (rats) or approximately 50% higher (rabbits) than humanexposure at the recommended daily dose. In rats, decreased fetal bodyweights were observed at maternally toxic dose at an exposure approximately50% higher than the recommended daily dose.

SPL MEDGUIDE SECTION.

This MedicationGuide has been approved by the U.S. Food and Drug Administration Revised: October 2019MEDICATIONGUIDEVIRAMUNE(R) (VIH-rah-mune)(nevirapine)oral suspensionVIRAMUNE(R) (VIH-rah-mune)(nevirapine)tabletsVIRAMUNE(R) (VIH-rah-mune)(nevirapine)extended-releasetabletsWhat is the mostimportant information should know about VIRAMUNEVIRAMUNE can cause severe liver and skin problems that maylead to death. These problems can happen at any time during treatment,but your 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 eyes feverfeel unwell or like you have the flutiredness 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: blistersred or inflamed eyes, like pink eye (conjunctivitis)swelling of your facefeel unwell or like you have the flumuscle or joint achesmouth soresfevertiredness 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. 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 should takeVIRAMUNETake 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.StartingVIRAMUNE tablets: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 skinrash during 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 VIRAMUNE XR extended-release tablets when thisis the first time you are taking any 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 aboutVIRAMUNEChanges 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. These are notall the possible side effects of VIRAMUNE. For more information, askyour doctor or pharmacist. Call your doctor for medical advice aboutside effects. You may report side effects to FDA at 1-800-FDA-1088.How should storeVIRAMUNEStore VIRAMUNE at room temperature between 68F to 77F(20C to 25C).Keep VIRAMUNEand 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, sodium starch glycolate, colloidal silicon dioxide, andmagnesium stearate VIRAMUNE oral suspension: carbomer 934P, methylparaben, propylparaben, sorbitol, sucrose, polysorbate80, sodium hydroxide, and purified water VIRAMUNEXR tablets: lactose monohydrate, hypromellose, iron oxide,and magnesium stearateFor current prescribing informationfor VIRAMUNE or VIRAMUNE XR, scan the codes below or for additionalinformation you may also call Boehringer Ingelheim Pharmaceuticals,Inc., at 1-800-542-6257, (TTY) 1-800-459-9906. VIRAMUNE tablets and oral suspensionVIRAMUNE XR extended-release tablets Copyright (C) 2019 BoehringerIngelheim International GmbH.Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877,USA Productand trademark licensed from: Boehringer Ingelheim International GmbHALL RIGHTS RESERVED IT5243NJ022019 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 skinrash during 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 skinrash during 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.

SPL UNCLASSIFIED SECTION.

2.1 General Dosing Considerations. VIRAMUNE XR tablets must be swallowed whole and must notbe chewed, crushed, or divided.Children should be assessed for their ability to swallowtablets before prescribing VIRAMUNE XR tablets.VIRAMUNE XR can be taken with or without food.. VIRAMUNE XR tablets must be swallowed whole and must notbe chewed, crushed, or divided.. Children should be assessed for their ability to swallowtablets before prescribing VIRAMUNE XR tablets.. VIRAMUNE XR can be taken with or without food.

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 immediate-releaseVIRAMUNE (200 mg) following each dialysis treatment. (2.5, 8.6) Monitor patients with hepatic fibrosis or cirrhosis carefullyfor evidence of drug-induced toxicity. Do not administer VIRAMUNEXR to 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 immediate-releaseVIRAMUNE (200 mg) following each dialysis treatment. (2.5, 8.6) Monitor patients with hepatic fibrosis or cirrhosis carefullyfor evidence of drug-induced toxicity. Do not administer VIRAMUNEXR to patients with Child-Pugh or C. (5.1, 8.7) 8.1 Pregnancy. Pregnancy Exposure RegistryThere isa pregnancy exposure registry that monitors pregnancy outcomes inwomen exposed to nevirapine during pregnancy. Healthcare providersare encouraged to register patients by calling the AntiretroviralPregnancy Registry (APR) at 1-800-258-4263.Risk SummaryAvailable datafor nevirapine in pregnant women is from the use of VIRAMUNE immediate-release.Available data from the APR show no difference in the risk of overallmajor birth defects for nevirapine compared with the background ratefor major birth defects of 2.7% in U.S. reference population ofthe Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The rateof miscarriage is not reported in the APR. The estimated backgroundrate of miscarriage in clinically recognized pregnancies in the U.S.general population is 15-20%. The background risk of birth defectsand miscarriage for the indicated population is unknown. Methodologicallimitations of the APR include the use of MACDP as the external comparatorgroup. The MACDP population is not disease-specific, evaluates womenand infants from limited geographic area, and does not include outcomesfor births that occurred at <20 weeks gestation.There is risk for severe hepatic eventsin pregnant women exposed to VIRAMUNE XR [see Clinical Considerations]. In animal reproduction studies, no evidence of adversedevelopmental outcomes was 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 hepatic events,including fatalities, have been reported in pregnant women receivingchronic nevirapine therapy as part of combination treatment of HIV-1infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefitoutweighs the risk. It is unclear if pregnancy augments the risk observedin non-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 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%) with second/third-trimester exposure to nevirapine-containingregimens.Animal DataNevirapine was administered orally to pregnantrats (at 0, 12.5, 25, and 50 mg/kg/day), and rabbits (at 0, 30, 100,and 300 mg/kg/day) through organogenesis (on gestation days through16 and through 18, respectively). No adverse developmental effectswere observed at doses producing systemic exposures (AUC) approximatelyequivalent to (rats) or approximately 50% higher (rabbits) than humanexposure at the recommended daily dose. In rats, decreased fetal bodyweights were observed at maternally toxic dose at an exposure approximately50% higher than the recommended daily dose.. 8.2 Lactation. Risk SummaryThe Centers forDisease Control and Prevention recommend that HIV-1 infected mothersin the United States not breastfeed their infants to avoid riskingpostnatal transmission of HIV-1 infection. Published data reportthat nevirapine immediate-release is present in human milk. 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 shouldnot breastfeed if they are receiving VIRAMUNE XR.. 8.3 Femalesand Males of Reproductive Potential. InfertilityLimited human dataare insufficient to determine the risk of infertility in humans. Basedon results from animal fertility studies conducted in rats, VIRAMUNEXR may reduce fertility in females of reproductive potential. It isnot known if these effects on fertility are reversible [seeNonclinical Toxicology (13.1)]. 8.4 Pediatric Use. VIRAMUNE XR is indicated for use in combination with other antiretroviralagents for the treatment of HIV-1 infection in children years ofage or older with BSA of 1.17 m2 or greater [see Indications and Usage (1) andDosage and Administration (2.3)].The use of VIRAMUNE XR forthe treatment of HIV-1 infection in pediatric patients to less than18 years of age is based on pharmacokinetic, safety, and antiviralactivity data from an open-label trial with VIRAMUNE XR. The resultsof this trial were supported by previous demonstration of efficacyin adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].VIRAMUNE XR is not recommended for children less than6 years of age. Trial 1100.1518 did not provide sufficient pharmacokineticdata for children to less than years of age to support the useof VIRAMUNE XR in this age group. Furthermore, VIRAMUNE XR is notrecommended for children less than years of age because they arenot able to swallow tablets.. 8.5 Geriatric Use. Clinical studies of VIRAMUNE XR did not include sufficient numbersof subjects aged 65 and older to determine whether elderly subjectsrespond differently from younger subjects. In general, dose selectionfor an elderly patient should be cautious, reflecting the greaterfrequency of decreased hepatic, renal or cardiac function, and ofconcomitant disease or other 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 doseof immediate-release VIRAMUNE (200 mg) following each dialysis treatmentis indicated [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. VIRAMUNE XRhas not been studied in patients with renal dysfunction.. 8.7 Hepatic Impairment. Because increased nevirapine levels andnevirapine accumulation may be observed in patients with serious liverdisease, do not administer nevirapine to patients with moderate orsevere (Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1),and Clinical Pharmacology (12.3)]. VIRAMUNE XR has not been evaluated in subjects with hepaticimpairment.

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 nevirapine. The risk of symptomatic hepatic events regardlessof severity is greatest in the first weeks of therapy. The riskcontinued to be greater in the nevirapine groups in controlled clinicaltrials through 18 weeks of treatment. However, hepatic events mayoccur at any time during treatment. In some cases, patients presentedwith non-specific, prodromal signs or symptoms of fatigue, malaise,anorexia, nausea, jaundice, liver tenderness or hepatomegaly, withor without initially abnormal serum transaminase levels. Rash wasobserved in approximately half of the patients with symptomatic hepaticadverse events. Fever and flu-like symptoms accompanied some of thesehepatic events. Some events, particularly those with rash and othersymptoms, have progressed to hepatic failure with transaminase elevation,with or without hyperbilirubinemia, hepatic encephalopathy, prolongedpartial thromboplastin time, or eosinophilia. Rhabdomyolysis has beenobserved in some patients experiencing skin and/or liver reactionsassociated with nevirapine use. Hepatitis/hepatic failure may be associatedwith signs of hypersensitivity which can include severe rash or rashaccompanied by fever, general malaise, fatigue, muscle or joint aches,blisters, oral lesions, conjunctivitis, facial edema, eosinophilia,granulocytopenia, lymphadenopathy, or renal dysfunction. Patientswith signs or symptoms of hepatitis must be advised to discontinuenevirapine and immediately seek medical evaluation, which should includeliver enzyme tests.The first 18 weeks of therapy with VIRAMUNE XR are critical periodduring which intensive clinical and laboratory monitoring of patientsis required to detect potentially life-threatening hepatic events.The optimal frequency of monitoring during this period has not beenestablished. Some experts recommend clinical and laboratory monitoringmore often than once per month, and in particular, include monitoringof liver enzyme tests at baseline, prior to dose escalation and attwo weeks post-dose escalation. After the initial 18-week period,frequent clinical and laboratory monitoring should continue throughoutVIRAMUNE XR treatment.Transaminasesshould be checked immediately if patient experiences signs or symptomssuggestive of hepatitis and/or hypersensitivity reaction. Transaminasesshould also be checked immediately for all patients who develop arash in the first 18 weeks of treatment. Physicians and patients shouldbe vigilant for the appearance of signs or symptoms of hepatitis,such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria,acholic stools, liver tenderness, or hepatomegaly. The diagnosis ofhepatotoxicity should be considered in this setting, even if transaminasesare initially normal or alternative diagnoses are possible [see Dosage and Administration (2.4)].If clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur, permanently discontinue nevirapine. Do not restart nevirapineafter recovery. In some cases, hepatic injury progresses despite discontinuationof treatment.The patients atgreatest risk of hepatic events, including potentially fatal events,are women with high CD4+ cell counts. Ina retrospective analysis of pooled clinical trials with immediate-releaseVIRAMUNE, during the first weeks of treatment women had 3-foldhigher risk than men for symptomatic, often rash-associated, hepaticevents (6% versus 2%). Patients with higher CD4+ cell counts at initiation of nevirapine therapy are at higher riskfor symptomatic hepatic events. Women with CD4+ cell counts greater than 250 cells/mm3 had 12-fold higher risk of symptomatic hepatic adverse eventscompared to women with CD4+ cell countsless 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+ cellcounts 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 nevirapine are associated with greaterrisk of later symptomatic events (6 weeks or more after starting nevirapine)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 immediate-releaseVIRAMUNE in the setting of post-exposure prophylaxis (PEP), an unapproveduse. Use of VIRAMUNE XR for occupational and non-occupational PEPis contraindicated [see Contraindications (4)].Increased nevirapine trough concentrations have beenobserved in some patients with hepatic fibrosis or cirrhosis. Therefore,carefully monitor patients with either hepatic fibrosis or cirrhosisfor evidence of drug-induced toxicity. Do not administer nevirapineto patients with moderate or severe (Child-Pugh Class or C, respectively)hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. VIRAMUNE XRhas not been evaluated in subjects with hepatic impairment.. 5.2 Skin Reactions. Severe and life-threatening skin reactions,including fatal cases, have been reported in patients taking nevirapine.These have occurred most frequently during the first weeks of therapy.These have included cases of Stevens-Johnson syndrome, toxic epidermalnecrolysis, and hypersensitivity reactions characterized by rash,constitutional findings, and organ dysfunction including hepatic failure.Rhabdomyolysis has been observed in some patients experiencing skinand/or liver reactions associated with nevirapine use.Patients developing signs or symptoms ofsevere skin reactions or hypersensitivity reactions (including, butnot limited to, severe rash or rash accompanied by fever, generalmalaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and renal dysfunction) must permanently discontinue nevirapine andseek medical evaluation immediately. Do not restart nevirapine followingsevere skin rash, skin rash combined with increased transaminasesor other symptoms, or hypersensitivity reaction.The first 18 weeks of therapy with VIRAMUNEXR are 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 periodhas not been established. Some experts recommend clinical and laboratorymonitoring more often than once per month, and in particular, includemonitoring of liver enzyme tests at baseline, prior to dose escalationand at two weeks post-dose escalation. After the initial 18-week period,frequent clinical and laboratory monitoring should continue throughoutVIRAMUNE XR treatment. In addition, the 14-day lead-in period withVIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequencyof rash [see Dosage and Administration (2.2)].If patientspresent with suspected nevirapine-associated rash, measure transaminasesimmediately. Permanently discontinue nevirapine in patients with rash-associatedtransaminase elevations [see Warnings and Precautions (5.1)].Patients must initiate therapy with immediate-releaseVIRAMUNE daily for the first 14 days. This lead-in period has beenshown to reduce the frequency of rash. Discontinue nevirapine if apatient experiences severe rash or any rash accompanied by constitutionalfindings. Do not initiate VIRAMUNE XR if patient experiencing amild to moderate rash without constitutional symptoms during the 14-dayimmediate-release VIRAMUNE lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved.The total duration of the immediate-release VIRAMUNE lead-in dosingperiod must not exceed 28 days at which point an alternative regimenshould be sought [see Dosage and Administration (2.5)]. Patients mustbe monitored closely if isolated rash of any severity occurs. Delayin stopping nevirapine treatment after the onset of rash may resultin more serious reaction.Womenappear to be at higher risk than men of developing rash with nevirapine.In clinical trial of immediate-releaseVIRAMUNE, concomitant prednisone use (40 mg per day for the first14 days of nevirapine administration) was associated with an increasein incidence and severity of rash during the first weeks of nevirapinetherapy. Therefore, use of prednisone to prevent nevirapine-associatedrash is not recommended.. 5.3 Resistance. VIRAMUNE XR must not be used as singleagent to treat HIV-1 or added on as sole agent to failing regimen.Resistant virus emerges rapidly when nevirapine is administered asmonotherapy. The choice of new antiretroviral agents to be used incombination with nevirapine should take into consideration the potentialfor cross resistance. When discontinuing an antiretroviral regimencontaining VIRAMUNE XR, the long half-life of nevirapine should betaken into account; if antiretrovirals with shorter half-lives thannevirapine are stopped concurrently, low plasma concentrations ofnevirapine alone may persist for week or longer and virus resistancemay 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 (Hypericum perforatum) or St. Johns wort-containingproducts and nevirapine is not recommended. Co-administration of St.Johns wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs),including nevirapine, is expected to substantially decrease NNRTIconcentrations and may result in sub-optimal levels of nevirapineand lead to loss of virologic response and possible resistance tonevirapine or to the class of NNRTIs.Co-administration of nevirapine and efavirenz is notrecommended as this combination has been associated with an increasein adverse reactions and no improvement in efficacy.. 5.5 Immune ReconstitutionSyndrome Immune reconstitutionsyndrome has been reported in patients treated with combination antiretroviraltherapy, including nevirapine. 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, Pneumocystisjiroveci pneumonia, or tuberculosis), which maynecessitate further evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis,and Guillain-Barre syndrome) have also been reported to occur in thesetting of immune reconstitution, however, the time to onset is morevariable, and can occur many months after initiation 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Clinical Trial Experience in Adult PatientsThe most serious adverse reactions associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most frequently within the first weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. The safety database in VIRAMUNE XR clinical trials contains data from 800 subjects treated with VIRAMUNE XR and 654 subjects treated with immediate release VIRAMUNE.. Trial 1100.1486 (VERxVE)In Trial 1100.1486 (VERxVE) treatment-naive subjects received lead-in dose of immediate-release VIRAMUNE 200 mg once daily for 14 days (n=1068) and then were randomized to receive either immediate-release VIRAMUNE 200 mg twice daily (n=506) or VIRAMUNE XR 400 mg once daily (n=505). All subjects received tenofovir emtricitabine as background therapy. Subjects were enrolled with CD4+ counts less than 250 cells/mm3 for women and less than 400 cells/mm3 for men [see Indications and Usage (1)]. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subjects completion of the 96-week endpoint in the trial (mean observation period 98 weeks).After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release VIRAMUNE group and 6% in the VIRAMUNE XR group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE or ALT/AST elevation was 8% in both the immediate-release VIRAMUNE group and VIRAMUNE XR group. Overall, there was comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release VIRAMUNE, and in 1% of subjects in either treatment group during the randomization phase. In addition, six cases of Stevens-Johnson syndrome were reported in the trial; all but one occurred within the first 30 days of nevirapine treatment.No Grade or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release VIRAMUNE (200 mg once daily), except for rash which occurred in 4% of subjects.Adverse reactions of at least moderate intensity (Grades or above) 2% or more of treatment-naive subjects receiving either immediate-release VIRAMUNE or VIRAMUNE XR after randomization in Trial 1100.1486 are shown in Table 1.Table 1Selected Clinical Adverse Drug Reactions of at least Moderate Intensity (Grade or above) Occurring in 2% or more of Adult Subjects Week 96 Analysis of Trial 1100.14861 Adverse Drug ReactionVIRAMUNE Immediate-ReleaseN=506 (%)VIRAMUNE XRN=505 (%) Excludes laboratory abnormalities reported as ADRs Mean observation period 98 weeks. Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS). Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, jaundice.Rash2 45Diarrhea44Headache44Clinical Hepatitis3 42Abdominal Pain23Arthralgia22Pyrexia21Nausea21Fatigue22. Laboratory AbnormalitiesLiver enzyme test abnormalities (AST, ALT) were observed in subjects receiving VIRAMUNE XR. Asymptomatic elevations in GGT occur frequently but are not contraindication to continue therapy with nevirapine in the absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 2.Table 2Grade to Grade Laboratory Abnormalities that Represent Worsening from Baseline Observed in at least 5% of Subjects in Either Treatment Group Trial 1100.1486Laboratory Parameter (unit)LimitVIRAMUNE Immediate-Release (%)(N=506)VIRAMUNE XR (%)(N=505)ChemistrySGPT/ALT (U/L)Grade 22.6-5.0 ULN1310Grade 35.1-10.0 ULN34Grade 4>10.0 ULN42SGOT/AST (U/L)Grade 22.6-5.0 ULN97Grade 35.1-10.0 ULN23Grade 4>10.0 ULN22Amylase (U/L)Grade 21.6-2.0 ULN45Grade 32.1-5.0 ULN42Grade 4>5.0 ULN0<1Phosphate (mg/dL)Grade 22.0-2.4 ULN3833Grade 31.0-1.9 ULN67Grade 4<1.0 ULN<10HematologyNeutrophilsGrade 2750-999/mm3 74Grade 3500-749/mm3 22Grade 4<500/mm3 11LipidsLDL (mg/dL)Grade 2160-190 mg/dL1515Grade 3>190 mg/dL55Cholesterol (mg/dL)Grade 2240-300 mg/dL1819Grade 3>300 mg/dL43. Trial 1100.1526 (TRANxITION)In Trial 1100.1526 (TRANxITION) subjects on immediate-release VIRAMUNE 200 mg twice daily for at least 18 weeks were randomized to either receive VIRAMUNE XR 400 mg once daily (n=295) or remain on their immediate-release VIRAMUNE treatment (n=148). Adverse reactions observed for VIRAMUNE XR subjects (48 week analysis) were similar to those observed in trial 1100.1486, as displayed in Table 1.. Clinical Trial Experience in Pediatric PatientsAdverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, non-randomized, cross-over trial to evaluate the safety and steady-state pharmacokinetic parameters of VIRAMUNE XR tablets in HIV-1-infected pediatric subjects to less than 18 years of age. Safety was further examined in an optional extension phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were treated with VIRAMUNE XR once daily in combination with other antiretrovirals for median duration of 33 weeks. The most frequently reported adverse reactions related to VIRAMUNE XR in pediatric subjects were similar to those observed in adults. In pediatric subjects the incidence of Grade or higher drug-related rash was 1%. There were no adverse reactions of Grade or above which were considered to be related to treatment by the investigator that occurred in more than 1% of subjects [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. InfertilityLimited human data are insufficient to determine the risk of infertility in humans. Based on results from animal fertility studies conducted in rats, VIRAMUNE XR may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer nevirapine to patients with moderate or severe (Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. VIRAMUNE XR has not been evaluated in subjects with hepatic impairment.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Published data report that immediate-release nevirapine is present in human milk. There are 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-negative infants), (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 XR.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of immediate-release VIRAMUNE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Body as Whole: fever, somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)] Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities [see Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.. Body as Whole: fever, somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)] Gastrointestinal: vomiting. Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure. Hematology: anemia, eosinophilia, neutropenia. Investigations: decreased serum phosphorus. Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions. Neurologic: paraesthesia. Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities [see Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCl greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional dose of immediate-release VIRAMUNE (200 mg) following each dialysis treatment is indicated [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. VIRAMUNE XR has not been studied in patients with renal dysfunction.

STORAGE AND HANDLING SECTION.

StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store in safe place out of the reach of children.